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    Working Memory for Online Memory Binding Tasks: A Hybrid Model. (arXiv:2008.04208v1 [cs.NE])

    Working Memory is the brain module that holds and manipulates information online. In this work, we design a hybrid model in which a simple feed-forward network is coupled to a balanced random network via a read-write vector called the interface vector. First, we consider some simple memory binding tasks in which the output is set to be a copy of the given input and a selective sequence of previous inputs online. Next, we design a more complex binding task based on a cue that encodes binding relations. The important result is that our dual-component model of working memory shows good performance with learning restricted to the feed-forward component only. Here we take advantage of the random network property without learning. To our knowledge, this is the first time that random networks as a flexible memory is shown to play an important role in online binding tasks. We may interpret our results as a candidate model of working memory in which the feed-forward network learns to interact with the temporary storage random network as an attentional-controlling executive system.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Bilevel Learning Model Towards Industrial Scheduling. (arXiv:2008.04130v1 [cs.AI])

    Automatic industrial scheduling, aiming at optimizing the sequence of jobs over limited resources, is widely needed in manufacturing industries. However, existing scheduling systems heavily rely on heuristic algorithms, which either generate ineffective solutions or compute inefficiently when job scale increases. Thus, it is of great importance to develop new large-scale algorithms that are not only efficient and effective, but also capable of satisfying complex constraints in practice. In this paper, we propose a Bilevel Deep reinforcement learning Scheduler, \textit{BDS}, in which the higher level is responsible for exploring an initial global sequence, whereas the lower level is aiming at exploitation for partial sequence refinements, and the two levels are connected by a sliding-window sampling mechanism. In the implementation, a Double Deep Q Network (DDQN) is used in the upper level and Graph Pointer Network (GPN) lies within the lower level. After the theoretical guarantee for the convergence of BDS, we evaluate it in an industrial automatic warehouse scenario, with job number up to $5000$ in each production line. It is shown that our proposed BDS significantly outperforms two most used heuristics, three strong deep networks, and another bilevel baseline approach. In particular, compared with the most used greedy-based heuristic algorithm in real world which takes nearly an hour, our BDS can decrease the makespan by 27.5\%, 28.6\% and 22.1\% for 3 largest datasets respectively, with computational time less than 200 seconds.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Review of Swarm Intelligence-based Feature Selection Methods. (arXiv:2008.04103v1 [cs.LG])

    In the past decades, the rapid growth of computer and database technologies has led to the rapid growth of large-scale datasets. On the other hand, data mining applications with high dimensional datasets that require high speed and accuracy are rapidly increasing. An important issue with these applications is the curse of dimensionality, where the number of features is much higher than the number of patterns. One of the dimensionality reduction approaches is feature selection that can increase the accuracy of the data mining task and reduce its computational complexity. The feature selection method aims at selecting a subset of features with the lowest inner similarity and highest relevancy to the target class. It reduces the dimensionality of the data by eliminating irrelevant, redundant, or noisy data. In this paper, a comparative analysis of different feature selection methods is presented, and a general categorization of these methods is performed. Moreover, in this paper, state-of-the-art swarm intelligence are studied, and the recent feature selection methods based on these algorithms are reviewed. Furthermore, the strengths and weaknesses of the different studied swarm intelligence-based feature selection methods are evaluated.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Contextuality Analysis of Impossible Figures. (arXiv:2008.04053v1 [q-bio.NC])

    This paper has two purposes. One is to demonstrate contextuality analysis of systems of epistemic random variables. The other is to evaluate the performance of a new, hierarchical version of the measure of (non)contextuality introduced in earlier publications. As objects of analysis we use impossible figures of the kind created by the Penroses and Escher. We make no assumptions as to how an impossible figure is perceived, taking it instead as a fixed physical object allowing one of several deterministic descriptions. Systems of epistemic random variables are obtained by probabilistically mixing these deterministic systems. This probabilistic mixture reflects our uncertainty or lack of knowledge rather than random variability in the frequentist sense.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Using Neural Networks and Diversifying Differential Evolution for Dynamic Optimisation. (arXiv:2008.04002v1 [cs.NE])

    Dynamic optimisation occurs in a variety of real-world problems. To tackle these problems, evolutionary algorithms have been extensively used due to their effectiveness and minimum design effort. However, for dynamic problems, extra mechanisms are required on top of standard evolutionary algorithms. Among them, diversity mechanisms have proven to be competitive in handling dynamism, and recently, the use of neural networks have become popular for this purpose. Considering the complexity of using neural networks in the process compared to simple diversity mechanisms, we investigate whether they are competitive and the possibility of integrating them to improve the results. However, for a fair comparison, we need to consider the same time budget for each algorithm. Thus, instead of the usual number of fitness evaluations as the measure for the available time between changes, we use wall clock timing. The results show the significance of the improvement when integrating the neural network and diversity mechanisms depends on the type and the frequency of changes. Moreover, we observe that for differential evolution, having a proper diversity in population when using neural networks plays a key role in the neural network's ability to improve the results.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    When words collide: Bayesian meta-analyses of distractor and target properties in the picture-word interference paradigm. (arXiv:2008.03972v1 [q-bio.NC])

    In the picture-word interference paradigm, participants name pictures while ignoring a written or spoken distractor word. Naming times to the pictures are slowed down by the presence of the distractor word. Various properties of the distractor modulate this slow down, for example naming times are shorter with frequent vs. infrequent distractors. Building on this line of research, the present study investigates in more detail the impact of distractor and target word properties on picture naming times. We report the results of several Bayesian meta-analyses, based on 35 datasets. The aim of the first analysis was to obtain an estimation of the size of the distractor frequency effect, and of its precision, in typical picture-word interference experiments where this variable is not manipulated. The analysis shows that a one-unit increase in log frequency results in response times to the pictures decreasing by about 4ms (95% Credible Interval: [-6, -2]). With the second and third analyses, we show that after accounting for the effect of frequency, two variables known to influence processing times in visual word processing tasks also influence picture naming times: distractor length and orthographic neighborhood. Finally, we found that distractor word frequency and target word frequency interact; the effect of distractor frequency decreases as the frequency of the target word increases. We discuss the theoretical and methodological implications of these findings, as well as the importance of obtaining high-precision estimates of experimental effects.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Intelligent Matrix Exponentiation. (arXiv:2008.03936v1 [cs.LG])

    We present a novel machine learning architecture that uses the exponential of a single input-dependent matrix as its only nonlinearity. The mathematical simplicity of this architecture allows a detailed analysis of its behaviour, providing robustness guarantees via Lipschitz bounds. Despite its simplicity, a single matrix exponential layer already provides universal approximation properties and can learn fundamental functions of the input, such as periodic functions or multivariate polynomials. This architecture outperforms other general-purpose architectures on benchmark problems, including CIFAR-10, using substantially fewer parameters.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Brain Connectomes Come of Age. (arXiv:2008.03881v1 [q-bio.NC])

    Databases of directed- and weighted- connectivity for mouse, macaque and marmoset monkeys, have recently become available and begun to be used to build dynamical models. A hierarchical organization can be defined based on laminar patterns of cortical connections, possibly improved by thalamocortical projections. A large-scale model of the macaque cortex endowed with a laminar structure accounts for layer-dependent and frequency-modulated interplays between bottom-up and top-down processes. Signal propagation in a version of the model with spiking neurons displays a threshold of stimulus amplitude for the activity to gain access to the prefrontal cortex, reminiscent of the ignition phenomenon associated with conscious perception. These two examples illustrate how connectomics may inform theory leading to discoveries. Computational modeling raises open questions for future empirical research, in a back-and-forth collaboration of experimentalists and theorists.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Randomness Evaluation of a Genetic Algorithm for Image Encryption: A Signal Processing Approach. (arXiv:2008.03681v1 [cs.CR])

    In this paper a randomness evaluation of a block cipher for secure image communication is presented. The GFHT cipher is a genetic algorithm, that combines gene fusion (GF) and horizontal gene transfer (HGT) both inspired from antibiotic resistance in bacteria. The symmetric encryption key is generated by four pairs of chromosomes with multi-layer random sequences. The encryption starts by a GF of the principal key-agent in a single block, then HGT performs obfuscation where the genes are pixels and the chromosomes are the rows and columns. A Salt extracted from the image hash-value is used to implement one-time pad (OTP) scheme, hence a modification of one pixel generates a different encryption key without changing the main passphrase or key. Therefore, an extreme avalanche effect of 99% is achieved. Randomness evaluation based on random matrix theory, power spectral density, avalanche effect, 2D auto-correlation, pixels randomness tests and chi-square hypotheses testing show that encrypted images adopt the statistical behavior of uniform white noise; hence validating the theoretical model by experimental results. Moreover, performance comparison with chaos-genetic ciphers shows the merit of the GFHT algorithm.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    DIET-SNN: Direct Input Encoding With Leakage and Threshold Optimization in Deep Spiking Neural Networks. (arXiv:2008.03658v1 [cs.NE])

    Bio-inspired spiking neural networks (SNNs), operating with asynchronous binary signals (or spikes) distributed over time, can potentially lead to greater computational efficiency on event-driven hardware. The state-of-the-art SNNs suffer from high inference latency, resulting from inefficient input encoding, and sub-optimal settings of the neuron parameters (firing threshold, and membrane leak). We propose DIET-SNN, a low latency deep spiking network that is trained with gradient descent to optimize the membrane leak and the firing threshold along with other network parameters (weights). The membrane leak and threshold for each layer of the SNN are optimized with end-to-end backpropagation to achieve competitive accuracy at reduced latency. The analog pixel values of an image are directly applied to the input layer of DIET-SNN without the need to convert to spike-train. The information is converted into spikes in the first convolutional layer where leaky-integrate-and-fire (LIF) neurons integrate the weighted inputs and generate an output spike when the membrane potential crosses the trained firing threshold. The trained membrane leak controls the flow of input information and attenuates irrelevant inputs to increase the activation sparsity in the convolutional and linear layers of the network. The reduced latency combined with high activation sparsity provides large improvements in computational efficiency. We evaluate DIET-SNN on image classification tasks from CIFAR and ImageNet datasets on VGG and ResNet architectures. We achieve top-1 accuracy of 66.52% with 25 timesteps (inference latency) on the ImageNet dataset with 3.1X less compute energy than an equivalent standard ANN. Additionally, DIET-SNN performs 5-100X faster inference compared to other state-of-the-art SNN models.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Code Building Genetic Programming. (arXiv:2008.03649v1 [cs.PL])

    In recent years the field of genetic programming has made significant advances towards automatic programming. Research and development of contemporary program synthesis methods, such as PushGP and Grammar Guided Genetic Programming, can produce programs that solve problems typically assigned in introductory academic settings. These problems focus on a narrow, predetermined set of simple data structures, basic control flow patterns, and primitive, non-overlapping data types (without, for example, inheritance or composite types). Few, if any, genetic programming methods for program synthesis have convincingly demonstrated the capability of synthesizing programs that use arbitrary data types, data structures, and specifications that are drawn from existing codebases. In this paper, we introduce Code Building Genetic Programming (CBGP) as a framework within which this can be done, by leveraging programming language features such as reflection and first-class specifications. CBGP produces a computational graph that can be executed or translated into source code of a host language. To demonstrate the novel capabilities of CBGP, we present results on new benchmarks that use non-primitive, polymorphic data types as well as some standard program synthesis benchmarks.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Lights and Shadows in Evolutionary Deep Learning: Taxonomy, Critical Methodological Analysis, Cases of Study, Learned Lessons, Recommendations and Challenges. (arXiv:2008.03620v1 [cs.NE])

    Much has been said about the fusion of bio-inspired optimization algorithms and Deep Learning models for several purposes: from the discovery of network topologies and hyper-parametric configurations with improved performance for a given task, to the optimization of the model's parameters as a replacement for gradient-based solvers. Indeed, the literature is rich in proposals showcasing the application of assorted nature-inspired approaches for these tasks. In this work we comprehensively review and critically examine contributions made so far based on three axes, each addressing a fundamental question in this research avenue: a) optimization and taxonomy (Why?), including a historical perspective, definitions of optimization problems in Deep Learning, and a taxonomy associated with an in-depth analysis of the literature, b) critical methodological analysis (How?), which together with two case studies, allows us to address learned lessons and recommendations for good practices following the analysis of the literature, and c) challenges and new directions of research (What can be done, and what for?). In summary, three axes - optimization and taxonomy, critical analysis, and challenges - which outline a complete vision of a merger of two technologies drawing up an exciting future for this area of fusion research.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Spatial Sharing of GPU for Autotuning DNN models. (arXiv:2008.03602v1 [cs.NE])

    GPUs are used for training, inference, and tuning the machine learning models. However, Deep Neural Network (DNN) vary widely in their ability to exploit the full power of high-performance GPUs. Spatial sharing of GPU enables multiplexing several DNNs on the GPU and can improve GPU utilization, thus improving throughput and lowering latency. DNN models given just the right amount of GPU resources can still provide low inference latency, just as much as dedicating all of the GPU for their inference task. An approach to improve DNN inference is tuning of the DNN model. Autotuning frameworks find the optimal low-level implementation for a certain target device based on the trained machine learning model, thus reducing the DNN's inference latency and increasing inference throughput. We observe an interdependency between the tuned model and its inference latency. A DNN model tuned with specific GPU resources provides the best inference latency when inferred with close to the same amount of GPU resources. While a model tuned with the maximum amount of the GPU's resources has poorer inference latency once the GPU resources are limited for inference. On the other hand, a model tuned with an appropriate amount of GPU resources still achieves good inference latency across a wide range of GPU resource availability. We explore the causes that impact the tuning of a model at different amounts of GPU resources. We present many techniques to maximize resource utilization and improve tuning performance. We enable controlled spatial sharing of GPU to multiplex several tuning applications on the GPU. We scale the tuning server instances and shard the tuning model across multiple client instances for concurrent tuning of different operators of a model, achieving better GPU multiplexing. With our improvements, we decrease DNN autotuning time by up to 75 percent and increase throughput by a factor of 5.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    A Novel Community Detection Based Genetic Algorithm for Feature Selection. (arXiv:2008.03543v1 [cs.LG])

    The selection of features is an essential data preprocessing stage in data mining. The core principle of feature selection seems to be to pick a subset of possible features by excluding features with almost no predictive information as well as highly associated redundant features. In the past several years, a variety of meta-heuristic methods were introduced to eliminate redundant and irrelevant features as much as possible from high-dimensional datasets. Among the main disadvantages of present meta-heuristic based approaches is that they are often neglecting the correlation between a set of selected features. In this article, for the purpose of feature selection, the authors propose a genetic algorithm based on community detection, which functions in three steps. The feature similarities are calculated in the first step. The features are classified by community detection algorithms into clusters throughout the second step. In the third step, features are picked by a genetic algorithm with a new community-based repair operation. Nine benchmark classification problems were analyzed in terms of the performance of the presented approach. Also, the authors have compared the efficiency of the proposed approach with the findings from four available algorithms for feature selection. The findings indicate that the new approach continuously yields improved classification accuracy.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Extended Particle Swarm Optimization (EPSO) for Feature Selection of High Dimensional Biomedical Data. (arXiv:2008.03530v1 [cs.NE])

    This paper proposes a novel Extended Particle Swarm Optimization model (EPSO) that potentially enhances the search process of PSO for optimization problem. Evidently, gene expression profiles are significantly important measurement factor in molecular biology that is used in medical diagnosis of cancer types. The challenge to certain classification methodologies for gene expression profiles lies in the thousands of features recorded for each sample. A modified Wrapper feature selection model is applied with the aim of addressing the gene classification challenge by replacing its randomness approach with EPSO and PSO respectively. EPSO is initializing the random size of the population and dividing them into two groups in order to promote the exploration and reduce the probability of falling in stagnation. Experimentally, EPSO has required less processing time to select the optimal features (average of 62.14 sec) than PSO (average of 95.72 sec). Furthermore, EPSO accuracy has provided better classification results (start from 54% to 100%) than PSO (start from 52% to 96%).

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Learning abstract structure for drawing by efficient motor program induction. (arXiv:2008.03519v1 [cs.AI])

    Humans flexibly solve new problems that differ qualitatively from those they were trained on. This ability to generalize is supported by learned concepts that capture structure common across different problems. Here we develop a naturalistic drawing task to study how humans rapidly acquire structured prior knowledge. The task requires drawing visual objects that share underlying structure, based on a set of composable geometric rules. We show that people spontaneously learn abstract drawing procedures that support generalization, and propose a model of how learners can discover these reusable drawing programs. Trained in the same setting as humans, and constrained to produce efficient motor actions, this model discovers new drawing routines that transfer to test objects and resemble learned features of human sequences. These results suggest that two principles guiding motor program induction in the model - abstraction (general programs that ignore object-specific details) and compositionality (recombining previously learned programs) - are key for explaining how humans learn structured internal representations that guide flexible reasoning and learning.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Why to "grow" and "harvest" deep learning models?. (arXiv:2008.03501v1 [cs.LG])

    Current expectations from training deep learning models with gradient-based methods include: 1) transparency; 2) high convergence rates; 3) high inductive biases. While the state-of-art methods with adaptive learning rate schedules are fast, they still fail to meet the other two requirements. We suggest reconsidering neural network models in terms of single-species population dynamics where adaptation comes naturally from open-ended processes of "growth" and "harvesting". We show that the stochastic gradient descent (SGD) with two balanced pre-defined values of per capita growth and harvesting rates outperform the most common adaptive gradient methods in all of the three requirements.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Visual Pattern Recognition with on On-chip Learning: towards a Fully Neuromorphic Approach. (arXiv:2008.03470v1 [cs.NE])

    We present a spiking neural network (SNN) for visual pattern recognition with on-chip learning on neuromorphichardware. We show how this network can learn simple visual patterns composed of horizontal and vertical bars sensed by a Dynamic Vision Sensor, using a local spike-based plasticity rule. During recognition, the network classifies the pattern's identity while at the same time estimating its location and scale. We build on previous work that used learning with neuromorphic hardware in the loop and demonstrate that the proposed network can properly operate with on-chip learning, demonstrating a complete neuromorphic pattern learning and recognition setup. Our results show that the network is robust against noise on the input (no accuracy drop when adding 130% noise) and against up to 20% noise in the neuron parameters.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    2$\theta$-burster for rhythm-generating circuits. (arXiv:2008.03377v1 [q-bio.NC])

    We propose and demonstrate the use of a minimal 2$\theta$ model for endogenous bursters coupled in 3-cell neural circuits. This 2$\theta$ model offers the benefit of simplicity of designing larger neural networks along with an acute reduction on the computation cost.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Protein Structured Reservoir computing for Spike-based Pattern Recognition. (arXiv:2008.03330v1 [cs.NE])

    Nowadays we witness a miniaturisation trend in the semiconductor industry backed up by groundbreaking discoveries and designs in nanoscale characterisation and fabrication. To facilitate the trend and produce ever smaller, faster and cheaper computing devices, the size of nanoelectronic devices is now reaching the scale of atoms or molecules - a technical goal undoubtedly demanding for novel devices. Following the trend, we explore an unconventional route of implementing a reservoir computing on a single protein molecule and introduce neuromorphic connectivity with a small-world networking property. We have chosen Izhikevich spiking neurons as elementary processors, corresponding to the atoms of verotoxin protein, and its molecule as a 'hardware' architecture of the communication networks connecting the processors. We apply on a single readout layer various training methods in a supervised fashion to investigate whether the molecular structured Reservoir Computing (RC) system is capable to deal with machine learning benchmarks. We start with the Remote Supervised Method, based on Spike-Timing-Dependent-Plasticity, and carry on with linear regression and scaled conjugate gradient back-propagation training methods. The RC network is evaluated as a proof-of-concept on the handwritten digit images from the MNIST dataset and demonstrates acceptable classification accuracy in comparison with other similar approaches.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    SiamSNN: Spike-based Siamese Network for Energy-Efficient and Real-time Object Tracking. (arXiv:2003.07584v2 [cs.CV] UPDATED)

    Although deep neural networks (DNNs) have achieved fantastic success in various scenarios, it's difficult to employ DNNs on many systems with limited resources due to their high energy consumption. It's well known that spiking neural networks (SNNs) are attracting more attention due to the capability of energy-efficient computing. Recently many works focus on converting DNNs into SNNs with little accuracy degradation in image classification on MNIST, CIFAR-10/100. However, few studies on shortening latency, and spike-based modules of more challenging tasks on complex datasets. In this paper, we focus on the similarity matching method of deep spike features and present a first spike-based Siamese network for object tracking called SiamSNN. Specifically, we propose a hybrid spiking similarity matching method with membrane potential and time step to evaluate the response map between exemplar and candidate images, with the same function as correlation layer in SiamFC. Then we present a coding scheme for utilizing temporal information of spike trains, and implement it in output spiking layers to improve the performance and shorten the latency. Our experiments show that SiamSNN achieves short latency and low precision loss of the original SiamFC on the tracking datasets OTB-2013, OTB-2015 and VOT2016. Moreover, SiamSNN achieves real-time (50 FPS) and extremely low energy consumption on TrueNorth.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    A Quantized Representation of Intertemporal Choice in the Brain. (arXiv:2002.10882v2 [q-bio.NC] UPDATED)

    Value [4][5] is typically modeled using a continuous representation (i.e., a Real number). A discrete representation of value has recently been postulated [6]. A quantized representation of probability in the brain was also posited and supported by experimental data [7]. Value and probability are inter-related via Prospect Theory [4][5]. In this paper, we hypothesize that intertemporal choices may also be quantized. For example, people may treat (or discount) 16 days indifferently to 17 days. To test this, we analyzed an intertemporal task by using 2 novel models: quantized hyperbolic discounting, and quantized exponential discounting. Our work here is a re-examination of the behavioral data previously collected for an fMRI study [8]. Both quantized hyperbolic and quantized exponential models were compared using AIC and BIC tests. We found that 13/20 participants were best fit to the quantized exponential model, while the remaining 7/20 were best fit to the quantized hyperbolic model. Overall, 15/20 participants were best fit to models with a 5-bit precision (i.e., 2^5 = 32 steps). In conclusion, regardless of hyperbolic or exponential, quantized versions of these models are better fit to the experimental data than their continuous forms. We finally outline some potential applications of our findings.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 11, 2020 01:30 AM.

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    Simplifying Neural Networks using Formal Verification. (arXiv:1910.12396v2 [cs.LO] UPDATED)

    Deep neural network (DNN) verification is an emerging field, with diverse verification engines quickly becoming available. Demonstrating the effectiveness of these engines on real-world DNNs is an important step towards their wider adoption. We present a tool that can leverage existing verification engines in performing a novel application: neural network simplification, through the reduction of the size of a DNN without harming its accuracy. We report on the work-flow of the simplification process, and demonstrate its potential significance and applicability on a family of real-world DNNs for aircraft collision avoidance, whose sizes we were able to reduce by as much as 10%.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 11, 2020 01:30 AM.

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    Publisher Correction: Low replicability can support robust and efficient science

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17924-9

    Publisher Correction: Low replicability can support robust and efficient science

    in Nature Communications on August 11, 2020 12:00 AM.

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    Within-individual phenotypic plasticity in flowers fosters pollination niche shift

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17875-1

    Floral phenotypes impact interactions between plants and pollinators. Here, the authors show that Moricandia arvensis displays discrete seasonal plasticity in floral phenotype, with large, lilac flowers attracting long-tongued bees in spring and small, rounded, white flowers attracting generalist pollinators in summer.

    in Nature Communications on August 11, 2020 12:00 AM.

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    Space-charge-limited electron and hole currents in hybrid organic-inorganic perovskites

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17868-0

    Space-charge-limited currents are widely used to characterize charge transport in semiconductors. Here, the authors characterize space-charge-limited electron and hole currents in metal-halide perovskites, applicable in emerging solar cells. The currents are strongly influenced by the high permittivity and ion motion.

    in Nature Communications on August 11, 2020 12:00 AM.

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    Pupil-linked arousal signals track the temporal organization of events in memory

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17851-9

    Although everyday life unfolds continuously, we tend to remember past experiences as discrete events. Here, the authors show that dynamic, pupil-linked arousal states track the encoding of such episodes, as revealed by changes in memory for the temporal order and duration of recent event sequences.

    in Nature Communications on August 11, 2020 12:00 AM.

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    Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17847-5

    Epithelial cells that line the gut secrete complex glycoproteins that form a mucus layer to protect the gut wall from enteric pathogens. Here, the authors provide a comprehensive characterisation of endo-acting glycoside hydrolases expressed by mucin-degrading members of the microbiome that are able to cleave the O-glycan chains of a range of different animal and human mucins.

    in Nature Communications on August 11, 2020 12:00 AM.

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    TMBIM6/BI-1 contributes to cancer progression through assembly with mTORC2 and AKT activation

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17802-4

    TMBIM6, a member of the transmembrane BI-1 motif-containing family of proteins, is overexpressed in many cancer types. Here, the authors show that TMBIM6 regulates AKT activation through mTORC2 assembly and ribosome association and identify an antagonist of TMBIM6 with anti-tumor properties.

    in Nature Communications on August 11, 2020 12:00 AM.

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    In vitro Cas9-assisted editing of modular polyketide synthase genes to produce desired natural product derivatives

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17769-2

    Several different genetic strategies have been reported for the modification of polyketide synthases but the highly repetitive modular structure makes this difficult. Here the authors report on an adapted Cas9 reaction and Gibson assembly to edit a target region of the polyketide synthases gene in vitro.

    in Nature Communications on August 11, 2020 12:00 AM.

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    Endogenous activity modulates stimulus and circuit-specific neural tuning and predicts perceptual behavior

    Nature Communications, Published online: 11 August 2020; doi:10.1038/s41467-020-17729-w

    Endogenous brain states influence perception. In this manuscript the authors use human intracranial recordings to provide mechanistic insight into this process by showing that endogenous brain activity facilitates neural tuning and behavior in a stimulus and circuit specific manner.

    in Nature Communications on August 11, 2020 12:00 AM.

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    Inside the mind of an animal

    Nature, Published online: 11 August 2020; doi:10.1038/d41586-020-02337-x

    Neuroscientists are scrutinizing huge piles of data to learn how brains create emotions and other internal states such as aggression and desire.

    in Nature on August 11, 2020 12:00 AM.

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    Coronavirus: full peer review in hours

    Nature, Published online: 11 August 2020; doi:10.1038/d41586-020-02333-1

    Coronavirus: full peer review in hours

    in Nature on August 11, 2020 12:00 AM.

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    Denmark recycling plan will cut waste by two-thirds

    Nature, Published online: 11 August 2020; doi:10.1038/d41586-020-02332-2

    Denmark recycling plan will cut waste by two-thirds

    in Nature on August 11, 2020 12:00 AM.

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    Coronavirus: indexed data speed up solutions

    Nature, Published online: 11 August 2020; doi:10.1038/d41586-020-02331-3

    Coronavirus: indexed data speed up solutions

    in Nature on August 11, 2020 12:00 AM.

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    Coronavirus: time to re-imagine academic publishing

    Nature, Published online: 11 August 2020; doi:10.1038/d41586-020-02330-4

    Coronavirus: time to re-imagine academic publishing

    in Nature on August 11, 2020 12:00 AM.

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    State-Dependent and Bandwidth-Specific Effects of Ketamine and Propofol on Electroencephalographic Complexity in Rats

    There is an ongoing debate as to whether ketamine anesthesia suppresses neurophysiologic complexity at doses sufficient for surgical anesthesia, with previous human studies reporting surrogates of both suppressed and preserved levels of cortical complexity. However, these studies have not assessed cortical dynamics in higher gamma frequencies, which have previously been demonstrated to correlate with the level of consciousness during anesthesia. In this study, we used Lempel-Ziv complexity (LZc) to characterize frontal and parietal electroencephalographic complexity (0.5–175 Hz, 0.5–55 Hz, 65–175 Hz) before, during, and after ketamine or propofol anesthesia in the rat. To control for the potential influence of spectral changes in complexity estimation, LZc was normalized with phase-shuffled surrogate data. We demonstrate that ketamine and propofol anesthesia were characterized by a significant reduction in broadband (0.5–175 Hz) LZc. Further analysis showed that while the reduction of LZc during ketamine anesthesia was significant in 65–175 Hz range, during propofol anesthesia, a significant decrease was observed in 0.5–55 Hz bandwidth. LZc in broadband and 0.5–55 Hz range showed a significant increase during emergence from ketamine anesthesia. Phase-shuffled normalized LZc revealed that (1) decrease in complexity during ketamine and propofol anesthesia—not increase in complexity during emergence—were dissociable from the influence of spectral changes, and (2) reduced LZc during ketamine anesthesia was present across all three bandwidths. Ketamine anesthesia was characterized by reduced complexity in high gamma bandwidth, as reflected in both raw and phase-shuffled normalized LZc, which suggests that reduced high gamma complexity is a neurophysiological feature of ketamine anesthesia.

    in Frontiers in Systems Neuroscience on August 11, 2020 12:00 AM.

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    Neuroligins and Neurodevelopmental Disorders: X-Linked Genetics

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder that results in social-communication impairments, as well as restricted and repetitive behaviors. Moreover, ASD is more prevalent in males, with a male to female ratio of 4 to 1. Although the underlying etiology of ASD is generally unknown, recent advances in genome sequencing have facilitated the identification of a host of associated genes. Among these, synaptic proteins such as cell adhesion molecules have been strongly linked with ASD. Interestingly, many large genome sequencing studies exclude sex chromosomes, which leads to a shift in focus toward autosomal genes as targets for ASD research. However, there are many genes on the X chromosome that encode synaptic proteins, including strong candidate genes. Here, we review findings regarding two members of the neuroligin (NLGN) family of postsynaptic adhesion molecules, NLGN3 and NLGN4. Neuroligins have multiple isoforms (NLGN1-4), which are both autosomal and sex-linked. The sex-linked genes, NLGN3 and NLGN4, are both on the X chromosome and were among the first few genes to be linked with ASD and intellectual disability (ID). In addition, there is a less studied human neuroligin on the Y chromosome, NLGN4Y, which forms an X-Y pair with NLGN4X. We will discuss recent findings of these neuroligin isoforms regarding function at the synapse in both rodent models and human-derived differentiated neurons, and highlight the exciting challenges moving forward to a better understanding of ASD/ID.

    in Frontiers in Synaptic Neuroscience on August 11, 2020 12:00 AM.

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    Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants

    A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.

    in Frontiers in Molecular Neuroscience on August 11, 2020 12:00 AM.

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    Vestibular Modulation of Long-Term Potentiation and NMDA Receptor Expression in the Hippocampus

    Loss of vestibular function is known to cause spatial memory deficits and hippocampal dysfunction, in terms of impaired place cell firing and abnormal theta rhythm. Based on these results, it has been of interest to determine whether vestibular loss also affects the development and maintenance of long-term potentiation (LTP) in the hippocampus. This article summarizes and critically reviews the studies of hippocampal LTP following a vestibular loss and its relationship to NMDA receptor expression, that have been published to date. Although the available in vitro studies indicate that unilateral vestibular loss (UVL) results in reduced hippocampal field potentials in CA1 and the dentate gyrus (DG), the in vivo studies involving bilateral vestibular loss (BVL) do not. This may be due to the differences between UVL and BVL or it could be a result of in vitro/in vivo differences. One in vitro study reported a decrease in LTP in hippocampal slices following UVL; however, the two available in vivo studies have reported different results: either no effect or an increase in EPSP/Population Spike (ES) potentiation. This discrepancy may be due to the different high-frequency stimulation (HFS) paradigms used to induce LTP. The increased ES potentiation following BVL may be related to an increase in synaptic NMDA receptors, possibly increasing the flow of vestibular input coming into CA1, with a loss of selectivity. This might cause increased excitability and synaptic noise, which might lead to a degradation of spatial learning and memory.

    in Frontiers in Molecular Neuroscience on August 11, 2020 12:00 AM.

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    Type 2 Diabetes Mellitus May Exacerbate Gray Matter Atrophy in Patients With Early-Onset Mild Cognitive Impairment

    Background

    The precise physiopathological association between the courses of neurodegeneration and cognitive decline in type 2 diabetes mellitus (T2DM) remains unclear. This study sought to comprehensively investigate the distribution characteristics of gray matter atrophy in middle-aged T2DM patients with newly diagnosed mild cognitive impairment (MCI).

    Methods

    Four groups, including 28 patients with early-onset MCI, 28 patients with T2DM, 28 T2DM patients with early-onset MCI (T2DM-MCI), and 28 age-, sex-, and education-matched healthy controls underwent three-dimensional high-resolution structural magnetic resonance imaging. Cortical and subcortical gray matter volumes were calculated, and a structural covariance method was used to evaluate the morphological relationships within the default mode network (DMN).

    Results

    Overlapped and unique cortical/subcortical gray matter atrophy was found in patients with MCI, T2DM and T2DM-MCI in our study, and patients with T2DM-MCI showed lower volumes in several areas than patients with MCI or T2DM. Volume loss in subcortical areas (including the thalamus, putamen, and hippocampus), but not in cortical areas, was related to cognitive impairment in patients with MCI and T2DM-MCI. No associations between biochemical measurements and volumetric reductions were found. Furthermore, patients with MCI and those with T2DM-MCI showed disrupted structural connectivity within the DMN.

    Conclusion

    These findings provide further evidence that T2DM may exacerbate atrophy of specific gray matter regions, which may be primarily associated with MCI. Impairments in gray matter volume related to T2DM or MCI are independent of cardiovascular risk factors, and subcortical atrophy may play a more pivotal role in cognitive impairment than cortical alterations in patients with MCI and T2DM-MCI. The enhanced structural connectivity within the DMN in patients with T2DM-MCI may suggest a compensatory mechanism for the chronic neurodegeneration.

    in Frontiers in Neuroscience: Neurodegeneration on August 11, 2020 12:00 AM.

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    Fingolimod Inhibits Inflammation but Exacerbates Brain Edema in the Acute Phases of Cerebral Ischemia in Diabetic Mice

    Background and Purpose: Diabetes mellitus increases stroke incidence and mortality and hampers functional recovery after stroke. Fingolimod has been shown to improve neurofunctional recovery and reduce brain infarction after ischemic injury in mice without comorbidities. In this work, we investigated the effects of fingolimod in diabetic mice after transient middle cerebral artery occlusion (tMCAO).

    Methods: Hyperglycemia was induced by a single bolus streptozotocin injection. Adult male ICR mice (n = 86) underwent 1-h tMCAO surgery and received intraperitoneal injection of fingolimod (1 mg/kg) or vehicle immediately after reperfusion. Clark neurological score, brain infarction and edema, blood–brain barrier (BBB) integrity, apoptosis, and inflammation were evaluated at 24 h after tMCAO.

    Results: Fingolimod treatment reduced the number of infiltrated inflammatory cells and lowered the mRNA level of Tnfα. It also increased the ratio of Bcl-2/Bax. However, fingolimod significantly aggravated brain edema and reduced the expression levels of tight junction proteins ZO-1 and Occludin. The negative impacts of fingolimod on BBB integrity outweighed its beneficial effects in anti-inflammation, which resulted in the lack of improvement in endpoint outcomes at 24 h after tMCAO.

    Conclusion: Caution should be taken in considering the acute treatment using fingolimod for ischemic stroke with diabetes comorbidity.

    in Frontiers in Neuroscience: Neurodegeneration on August 11, 2020 12:00 AM.

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    Understanding the Real State of Human Adult Hippocampal Neurogenesis From Studies of Rodents and Non-human Primates

    The concept of adult hippocampal neurogenesis (AHN) has been widely accepted, and a large number of studies have been performed in rodents using modern experimental techniques, which have clarified the nature and developmental processes of adult neural stem/progenitor cells, the functions of AHN, such as memory and learning, and its association with neural diseases. However, a fundamental problem is that it remains unclear as to what extent AHN actually occurs in humans. The answer to this is indispensable when physiological and pathological functions of human AHN are deduced from studies of rodent AHN, but there are controversial data on the extent of human AHN. In this review, studies on AHN performed in rodents and humans will be briefly reviewed, followed by a discussion of the studies in non-human primates. Then, how data of rodent and non-human primate AHN should be applied for understanding human AHN will be discussed.

    in Frontiers in Neuroscience: Neurodegeneration on August 11, 2020 12:00 AM.

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    CHIME: CMOS-Hosted in vivo Microelectrodes for Massively Scalable Neuronal Recordings

    Mammalian brains consist of 10s of millions to 100s of billions of neurons operating at millisecond time scales, of which current recording techniques only capture a tiny fraction. Recording techniques capable of sampling neural activity at high spatiotemporal resolution have been difficult to scale. The most intensively studied mammalian neuronal networks, such as the neocortex, show a layered architecture, where the optimal recording technology samples densely over large areas. However, the need for application-specific designs as well as the mismatch between the three-dimensional architecture of the brain and largely two-dimensional microfabrication techniques profoundly limits both neurophysiological research and neural prosthetics. Here, we discuss a novel strategy for scalable neuronal recording by combining bundles of glass-ensheathed microwires with large-scale amplifier arrays derived from high-density CMOS in vitro MEA systems or high-speed infrared cameras. High signal-to-noise ratio (<25 μV RMS noise floor, SNR up to 25) is achieved due to the high conductivity of core metals in glass-ensheathed microwires allowing for ultrathin metal cores (down to <1 μm) and negligible stray capacitance. Multi-step electrochemical modification of the tip enables ultra-low access impedance with minimal geometric area, which is largely independent of the core diameter. We show that the microwire size can be reduced to virtually eliminate damage to the blood-brain-barrier upon insertion and we demonstrate that microwire arrays can stably record single-unit activity. Combining microwire bundles and CMOS arrays allows for a highly scalable neuronal recording approach, linking the progress in electrical neuronal recordings to the rapid progress in silicon microfabrication. The modular design of the system allows for custom arrangement of recording sites. Our approach of employing bundles of minimally invasive, highly insulated and functionalized microwires to extend a two-dimensional CMOS architecture into the 3rd dimension can be translated to other CMOS arrays, such as electrical stimulation devices.

    in Frontiers in Neuroscience: Neural Technology on August 11, 2020 12:00 AM.

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    A Panel of Synapse-Related Genes as a Biomarker for Gliomas

    Gliomas are the most common primary brain cancers. In recent years, IDH mutation and 1p/19q codeletion have been suggested as biomarkers for the diagnosis, treatment, and prognosis of gliomas. However, these biomarkers are only effective for a part of glioma patients, and thus more biomarkers are still emergently needed. Recently, an electrochemical communication between normal neurons and glioma cells by neuro-glioma synapse has been reported. Moreover, it was discovered that breast-to-brain metastasis tumor cells have pseudo synapses with neurons, and these synapses were indicated to promote tumor progression and metastasis. Based on the above observations, we first curated a panel of 17 synapse-related genes and then proposed a metric, synapse score to quantify the “stemness” for each sample of 12 glioma gene expression datasets from TCGA, CGGA, and GEO. Strikingly, synapse score showed excellent predictive ability for the prognosis, diagnosis, and grading of gliomas. Moreover, being compared with the two established biomarkers, IDH mutation and 1p/19q codeletion, synapse score demonstrated independent and better predictive performance. In conclusion, this study proposed a quantitative method, synapse score, as an efficient biomarker for monitoring gliomas.

    in Frontiers in Neuroscience: Systems Biology on August 11, 2020 12:00 AM.

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    Deciphering Brain Function by Miniaturized Fluorescence Microscopy in Freely Behaving Animals

    Animal behavior is regulated by environmental stimuli and is shaped by the activity of neural networks, underscoring the importance of assessing the morpho-functional properties of different populations of cells in freely behaving animals. In recent years, a number of optical tools have been developed to monitor and modulate neuronal and glial activity at the protein, cellular, or network level and have opened up new avenues for studying brain function in freely behaving animals. Tools such as genetically encoded sensors and actuators are now commonly used for studying brain activity and function through their expression in different neuronal ensembles. In parallel, microscopy has also made major progress over the last decades. The advent of miniature microscopes (mini-microscopes also called mini-endoscopes) has become a method of choice for studying brain activity at the cellular and network levels in different brain regions of freely behaving mice. This technique also allows for longitudinal investigations while animals carrying the microscope on their head are performing behavioral tasks. In this review, we will discuss mini-endoscopic imaging and the advantages that these devices offer to research. We will also discuss current limitations of and potential future improvements in mini-endoscopic imaging.

    in Frontiers in Neuroscience: Brain Imaging Methods on August 11, 2020 12:00 AM.

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    Tracing Pilots’ Situation Assessment by Neuroadaptive Cognitive Modeling

    This study presents the integration of a passive brain-computer interface (pBCI) and cognitive modeling as a method to trace pilots’ perception and processing of auditory alerts and messages during operations. Missing alerts on the flight deck can result in out-of-the-loop problems that can lead to accidents. By tracing pilots’ perception and responses to alerts, cognitive assistance can be provided based on individual needs to ensure they maintain adequate situation awareness. Data from 24 participating aircrew in a simulated flight study that included multiple alerts and air traffic control messages in single pilot setup are presented. A classifier was trained to identify pilots’ neurophysiological reactions to alerts and messages from participants’ electroencephalogram (EEG). A neuroadaptive ACT-R model using EEG data was compared to a conventional normative model regarding accuracy in representing individual pilots. Results show that passive BCI can distinguish between alerts that are processed by the pilot as task-relevant or irrelevant in the cockpit based on the recorded EEG. The neuroadaptive model’s integration of this data resulted in significantly higher performance of 87% overall accuracy in representing individual pilots’ responses to alerts and messages compared to 72% accuracy of a normative model that did not consider EEG data. We conclude that neuroadaptive technology allows for implicit measurement and tracing of pilots’ perception and processing of alerts on the flight deck. Careful handling of uncertainties inherent to passive BCI and cognitive modeling shows how the representation of pilot cognitive states can be improved iteratively for providing assistance.

    in Frontiers in Neuroscience: Neural Technology on August 11, 2020 12:00 AM.

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    Electroencephalographic Cross-Frequency Coupling as a Sign of Disease Progression in Patients With Mild Cognitive Impairment: A Pilot Study

    Mild cognitive impairment (MCI) refers to mild objective cognitive deficits and is associated with the later development of Alzheimer’s disease (AD). However, not all patients with MCI convert to AD. EEG spectral power has shown promise as a marker of progression, but brain oscillations in different frequencies are not isolated entities. Coupling between different frequency bands, so-called cross-frequency coupling (CFC), has been associated with memory function and may further contribute to our understanding of what characterizes patients with MCI who progress to AD. In the current study, we wanted to investigate the changes in gamma/theta CFC in patients with AD and MCI compared to HC and in patients with pMCI compared to patients with sMCI. Furthermore, we wanted to investigate the association with cognitive test scores. EEGs were included at baseline for 15 patients with AD, 25 patients with MCI, and 36 older HC, and the participants were followed for up to 3 years. To investigate CFC, we calculated the modulation index (MI), which has been shown to be less affected by noisy data compared to other techniques. We found that patients with pMCI showed a significantly lower global gamma/theta CFC compared to patients with sMCI. In addition, global gamma/theta CFC was significantly correlated with Addenbrooke’s Cognitive Examination (ACE) score (p-value = 0.030, rho = 0.527). Although not significant, patients with AD and MCI showed a lower gamma/theta CFC compared to HC. These findings suggest that gamma/theta CFC is important for proper cognitive functioning and that a decrease in gamma/theta CFC in patients with MCI may be a sign of progression. Gamma/theta CFC may therefore serve as a progression marker in MCI, but larger studies are needed to validate these findings.

    in Frontiers in Neuroscience: Neurodegeneration on August 11, 2020 12:00 AM.

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    Chromatic Pupillometry Findings in Alzheimer’s Disease

    Intrinsically photosensitive melanopsin retinal ganglion cells (mRGCs) are crucial for non-image forming functions of the eye, including the photoentrainment of circadian rhythms and the regulation of the pupillary light reflex (PLR). Chromatic pupillometry, using light stimuli at different wavelengths, makes possible the isolation of the contribution of rods, cones, and mRGCs to the PLR. In particular, post-illumination pupil response (PIPR) is the most reliable pupil metric of mRGC function. We have previously described, in post-mortem investigations of AD retinas, a loss of mRGCs, and in the remaining mRGCs, we demonstrated extensive morphological abnormalities. We noted dendrite varicosities, patchy distribution of melanopsin, and reduced dendrite arborization. In this study, we evaluated, with chromatic pupillometry, the PLR in a cohort of mild-moderate AD patients compared to controls. AD and controls also underwent an extensive ophthalmological evaluation. In our AD cohort, PIPR did not significantly differ from controls, even though we observed a higher variability in the AD group and 5/26 showed PIPR values outside the 2 SD from the control mean values. Moreover, we found a significant difference between AD and controls in terms of rod-mediated transient PLR amplitude. These results suggest that in the early stage of AD there are PLR abnormalities that may reflect a pathology affecting mRGC dendrites before involving the mRGC cell body. Further studies, including AD cases with more severe and longer disease duration, are needed to further explore this hypothesis.

    in Frontiers in Neuroscience: Neurodegeneration on August 11, 2020 12:00 AM.

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    Toward Long-Term Communication With the Brain in the Blind by Intracortical Stimulation: Challenges and Future Prospects

    The restoration of a useful visual sense in a profoundly blind person by direct electrical stimulation of the visual cortex has been a subject of study for many years. However, the field of cortically based sight restoration has made few advances in the last few decades, and many problems remain. In this context, the scientific and technological problems associated with safe and effective communication with the brain are very complex, and there are still many unresolved issues delaying its development. In this work, we review some of the biological and technical issues that still remain to be solved, including long-term biotolerability, the number of electrodes required to provide useful vision, and the delivery of information to the implants. Furthermore, we emphasize the possible role of the neuroplastic changes that follow vision loss in the success of this approach. We propose that increased collaborations among clinicians, basic researchers, and neural engineers will enhance our ability to send meaningful information to the brain and restore a limited but useful sense of vision to many blind individuals.

    in Frontiers in Neuroscience: Neural Technology on August 11, 2020 12:00 AM.

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    The Role of Gesture in Communication and Cognition: Implications for Understanding and Treating Neurogenic Communication Disorders

    When people talk, they gesture. Gesture is a fundamental component of language that contributes meaningful and unique information to a spoken message and reflects the speaker’s underlying knowledge and experiences. Theoretical perspectives of speech and gesture propose that they share a common conceptual origin and have a tightly integrated relationship, overlapping in time, meaning, and function to enrich the communicative context. We review a robust literature from the field of psychology documenting the benefits of gesture for communication for both speakers and listeners, as well as its important cognitive functions for organizing spoken language, and facilitating problem-solving, learning, and memory. Despite this evidence, gesture has been relatively understudied in populations with neurogenic communication disorders. While few studies have examined the rehabilitative potential of gesture in these populations, others have ignored gesture entirely or even discouraged its use. We review the literature characterizing gesture production and its role in intervention for people with aphasia, as well as describe the much sparser literature on gesture in cognitive communication disorders including right hemisphere damage, traumatic brain injury, and Alzheimer’s disease. The neuroanatomical and behavioral profiles of these patient populations provide a unique opportunity to test theories of the relationship of speech and gesture and advance our understanding of their neural correlates. This review highlights several gaps in the field of communication disorders which may serve as a bridge for applying the psychological literature of gesture to the study of language disorders. Such future work would benefit from considering theoretical perspectives of gesture and using more rigorous and quantitative empirical methods in its approaches. We discuss implications for leveraging gesture to explore its untapped potential in understanding and rehabilitating neurogenic communication disorders.

    in Frontiers in Human Neuroscience on August 11, 2020 12:00 AM.

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    Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

    Neurodegenerative disorders such as Parkinson’s (PD) and Huntington’s disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.

    in Frontiers in Cellular Neuroscience on August 11, 2020 12:00 AM.

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    Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels

    Dominant, missense mutations in the widely and constitutively expressed GARS1 gene cause peripheral neuropathy that usually begins in adolescence and principally impacts the upper limbs. Caused by a toxic gain-of-function in the encoded glycyl-tRNA synthetase (GlyRS) enzyme, the neuropathology appears to be independent of the canonical role of GlyRS in aminoacylation. Patients display progressive, life-long weakness and wasting of muscles in hands followed by feet, with frequently associated deficits in sensation. When dysfunction is observed in motor and sensory nerves, there is a diagnosis of Charcot-Marie-Tooth disease type 2D (CMT2D), or distal hereditary motor neuropathy type V if the symptoms are purely motor. The cause of this varied sensory involvement remains unresolved, as are the pathomechanisms underlying the selective neurodegeneration characteristic of the disease. We have previously identified in CMT2D mice that neuropathy-causing Gars mutations perturb sensory neuron fate and permit mutant GlyRS to aberrantly interact with neurotrophin receptors (Trks). Here, we extend this work by interrogating further the anatomy and function of the CMT2D sensory nervous system in mutant Gars mice, obtaining several key results: (1) sensory pathology is restricted to neurons innervating the hindlimbs; (2) perturbation of sensory development is not common to all mouse models of neuromuscular disease; (3) in vitro axonal transport of signaling endosomes is not impaired in afferent neurons of all CMT2D mouse models; and (4) Gars expression is selectively elevated in a subset of sensory neurons and linked to sensory developmental defects. These findings highlight the importance of comparative neurological assessment in mouse models of disease and shed light on key proposed neuropathogenic mechanisms in GARS1-linked neuropathy.

    in Frontiers in Cellular Neuroscience on August 11, 2020 12:00 AM.

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    Rapamycin, by Inhibiting mTORC1 Signaling, Prevents the Loss of Striatal Bidirectional Synaptic Plasticity in a Rat Model of L-DOPA-Induced Dyskinesia

    Levodopa (L-DOPA) treatment is the main gold-standard therapy for Parkinson disease (PD). Besides good antiparkinsonian effects, prolonged use of this drug is associated to the development of involuntary movements known as L-DOPA-induced dyskinesia (LID). L-DOPA-induced dyskinesia is linked to a sensitization of dopamine (DA) D1 receptors located on spiny projection neurons (SPNs) of the dorsal striatum. Several evidences have shown that the emergence of LID can be related to striatal D1/cAMP/PKA/DARPP-32 and extracellular signal-regulated kinases (ERK1/2) pathway overactivation associated to aberrant N-methyl-d-aspartate (NMDA) receptor function. In addition, within striatum, ERK1/2 is also able to modulate in a D1 receptor-dependent manner the activity of the mammalian target of rapamycin complex 1 (mTORC1) pathway under DA depletion and L-DOPA therapy. Consistently, increased mTORC1 signaling appears during chronic administration of L-DOPA and shows a high correlation with the severity of dyskinesia. Furthermore, the abnormal activation of the D1/PKA/DARPP-32 cascade is paralleled by increased phosphorylation of the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor at the PKA Ser845 site. The GluA1 promotes excitatory AMPA receptor-mediated transmission and may be implicated in the alterations found at the corticostriatal synapses of dyskinetic animals. In our study, we investigated the role of mTORC1 pathway activation in modulating bidirectional striatal synaptic plasticity in L-DOPA-treated parkinsonian rats. Inhibition of mTORC1 by coadministration of rapamycin to L-DOPA was able to limit the magnitude of LID expression, accounting for a therapeutic effect of this drug. In particular, behavioral data showed that, in L-DOPA-treated rats, rapamycin administration induced a selective decrease of distinct components of abnormal involuntary movements (i.e., axial and orolingual dyskinesia). Furthermore, ex vivo patch clamp and intracellular recordings of SPNs revealed that pharmacological inhibition of mTORC1 also resulted associated with a physiological bidirectional plasticity, when compared to dyskinetic rats treated with L-DOPA alone. This study uncovers the important role of mTORC1 inhibition to prevent the loss of striatal bidirectional plasticity under chronic L-DOPA treatment in rodent models of PD.

    in Frontiers in Ageing Neuroscience on August 11, 2020 12:00 AM.

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    Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory

    Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

    in eLife on August 11, 2020 12:00 AM.

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    Irisin directly stimulates osteoclastogenesis and bone resorption in vitro and in vivo

    The myokine irisin facilitates muscle-bone crosstalk and skeletal remodeling in part by its action on osteoblasts and osteocytes. In the current study we investigated whether irisin also directly regulates osteoclasts. In vitro, irisin (2-10 ng/mL) increased osteoclast differentiation in C57BL/6J mouse bone marrow progenitors; this increase was blocked by a neutralizing antibody to integrin αVβ5. Irisin also increased bone resorption on several substrates in situ. RNAseq revealed differential gene expression induced by irisin including upregulation of markers for osteoclast differentiation and resorption, as well as osteoblast-stimulating 'clastokines'. Forced expression of the irisin precursor Fndc5 in transgenic C57BL/6J mice resulted in low bone mass at three ages, and greater in vitro osteoclastogenesis from Fndc5-transgenic bone marrow progenitors. This work demonstrates that irisin acts directly on osteoclast progenitors to increase differentiation and promote bone resorption, supporting the tenet that irisin not only stimulates bone remodeling but may also be an important counter-regulatory hormone.

    in eLife on August 11, 2020 12:00 AM.

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    MARCH8 inhibits viral infection by two different mechanisms

    Membrane-associated RING-CH 8 (MARCH8) inhibits infection with both HIV-1 and vesicular stomatitis virus G-glycoprotein (VSV-G)-pseudotyped viruses by reducing virion incorporation of envelope glycoproteins. The molecular mechanisms by which MARCH8 targets envelope glycoproteins remain unknown. Here, we show two different mechanisms by which MARCH8 inhibits viral infection. Viruses pseudotyped with the VSV-G mutant, in which cytoplasmic lysine residues were mutated, were insensitive to the inhibitory effect of MARCH8, whereas those with a similar lysine mutant of HIV-1 Env remained sensitive to it. Indeed, the wild-type VSV-G, but not its lysine mutant, was ubiquitinated by MARCH8. Furthermore, the MARCH8 mutant, which had a disrupted cytoplasmic tyrosine motif that is critical for intracellular protein sorting, did not inhibit HIV-1 Env-mediated infection, while it still impaired infection by VSV-G-pseudotyped viruses. Overall, we conclude that MARCH8 reduces viral infectivity by downregulating envelope glycoproteins through two different mechanisms mediated by a ubiquitination-dependent or tyrosine motif-dependent pathway.

    in eLife on August 11, 2020 12:00 AM.

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    A Sec14-like phosphatidylinositol transfer protein paralog defines a novel class of heme-binding proteins

    Yeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to transfer phosphatidylinositol between membranes in vitro, and to stimulate phosphoinositide signaling in vivo, Sfh5 does not exhibit these activities. Rather, Sfh5 is a redox-active penta-coordinate high spin FeIII hemoprotein with an unusual heme-binding arrangement that involves a co-axial tyrosine/histidine coordination strategy and a complex electronic structure connecting the open shell iron d-orbitals with three aromatic ring systems. That Sfh5 is not a PITP is supported by demonstrations that heme is not a readily exchangeable ligand, and that phosphatidylinositol-exchange activity is resuscitated in heme binding-deficient Sfh5 mutants. The collective data identify Sfh5 as the prototype of a new class of fungal hemoproteins, and emphasize the versatility of the Sec14-fold as scaffold for translating the binding of chemically distinct ligands to the control of diverse sets of cellular activities.

    in eLife on August 11, 2020 12:00 AM.

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    A theory of joint attractor dynamics in the hippocampus and the entorhinal cortex accounts for artificial remapping and grid cell field-to-field variability

    The representation of position in the mammalian brain is distributed across multiple neural populations. Grid cell modules in the medial entorhinal cortex (MEC) express activity patterns that span a low-dimensional manifold which remains stable across different environments. In contrast, the activity patterns of hippocampal place cells span distinct low-dimensional manifolds in different environments. It is unknown how these multiple representations of position are coordinated. Here we develop a theory of joint attractor dynamics in the hippocampus and the MEC. We show that the system exhibits a coordinated, joint representation of position across multiple environments, consistent with global remapping in place cells and grid cells. In addition, our model accounts for recent experimental observations that lack a mechanistic explanation: variability in the firing rate of single grid cells across firing fields, and artificial remapping of place cells under depolarization, but not under hyperpolarization, of layer II stellate cells of the MEC.

    in eLife on August 11, 2020 12:00 AM.

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    Caterpillar-induced rice volatiles provide enemy-free space for the offspring of the brown planthopper

    Plants typically release large quantities of volatiles in response to herbivory by insects. This benefits the plants by, for instance, attracting the natural enemies of the herbivores. We show that the brown planthopper (BPH) has cleverly turned this around by exploiting herbivore-induced plant volatiles (HIPVs) that provide safe havens for its offspring. BPH females preferentially oviposit on rice plants already infested by the rice striped stem borer (SSB), which are avoided by the egg parasitoid Anagrus nilaparvatae, the most important natural enemy of BPH. Using synthetic versions of volatiles identified from plants infested by BPH and/or SSB, we demonstrate the role of HIPVs in these interactions. Moreover, greenhouse and field cage experiments confirm the adaptiveness of the BPH oviposition strategy, resulting in 80% lower parasitism rates of its eggs. Besides revealing a novel exploitation of HIPVs, these findings may lead to novel control strategies against an exceedingly important rice pest.

    in eLife on August 11, 2020 12:00 AM.

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    Science Forum: Imaging methods are vastly underreported in biomedical research

    A variety of microscopy techniques are used by researchers in the life and biomedical sciences. As these techniques become more powerful and more complex, it is vital that scientific articles containing images obtained with advanced microscopes include full details about how each image was obtained. To explore the reporting of such details we examined 240 original research articles published in eight journals. We found that the quality of reporting was poor, with some articles containing no information about how images were obtained, and many articles lacking important basic details. Efforts by researchers, funding agencies, journals, equipment manufacturers and staff at shared imaging facilities are required to improve the reporting of experiments that rely on microscopy techniques.

    in eLife on August 11, 2020 12:00 AM.

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    Building the vertebrate codex using the gene breaking protein trap library

    One key bottleneck in understanding the human genome is the relative under-characterization of 90% of protein coding regions. We report a collection of 1,200 transgenic zebrafish strains made with the gene-break transposon (GBT) protein trap to simultaneously report and reversibly knockdown the tagged genes. Protein trap-associated mRFP expression shows previously undocumented expression of 35% and 90% of cloned genes at 2 and 4 days post-fertilization, respectively. Further, investigated alleles regularly show 99% gene-specific mRNA knockdown. Homozygous GBT animals in ryr1b, fras1, tnnt2a, edar and hmcn1 phenocopied established mutants. 204 cloned lines trapped diverse proteins, including 64 orthologs of human disease-associated genes with 40 as potential new disease models. Severely reduced skeletal muscle Ca2+ transients in GBT ryr1b homozygous animals validated the ability to explore molecular mechanisms of genetic diseases. This GBT system facilitates novel functional genome annotation towards understanding cellular and molecular underpinnings of vertebrate biology and human disease.

    in eLife on August 11, 2020 12:00 AM.

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    Neural arbitration between social and individual learning systems

    Decision making requires integrating self-gathered information with advice from others. However, the arbitration process by which one source of information is selected over the other has not been fully elucidated. In this study, we formalised arbitration as the relative precision of predictions, afforded by each learning system, using hierarchical Bayesian modelling. In a probabilistic learning task, participants predicted the outcome of a lottery using recommendations from a more informed advisor and/or self-sampled outcomes. Decision confidence, as measured by the number of points participants wagered on their predictions, varied with our relative precision definition of arbitration. Functional neuroimaging demonstrated arbitration signals that were independent of decision confidence and involved modality-specific brain regions. Arbitrating in favour of self-gathered information activated the dorsolateral prefrontal cortex and the midbrain, whereas arbitrating in favour of social information engaged the ventromedial prefrontal cortex and the amygdala. These findings indicate that relative precision captures arbitration between social and individual learning systems at both behavioural and neural levels.

    in eLife on August 11, 2020 12:00 AM.

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    Modeling the metabolic interplay between a parasitic worm and its bacterial endosymbiont allows the identification of novel drug targets

    The filarial nematode Brugia malayi represents a leading cause of disability in the developing world, causing lymphatic filariasis in nearly 40 million people. Currently available drugs are not well-suited to mass drug administration efforts, so new treatments are urgently required. One potential vulnerability is the endosymbiotic bacteria Wolbachia—present in many filariae—which is vital to the worm. Genome scale metabolic networks have been used to study prokaryotes and protists and have proven valuable in identifying therapeutic targets, but have only been applied to multicellular eukaryotic organisms more recently. Here, we present iDC625, the first compartmentalized metabolic model of a parasitic worm. We used this model to show how metabolic pathway usage allows the worm to adapt to different environments, and predict a set of 102 reactions essential to the survival of B. malayi. We validated three of those reactions with drug tests and demonstrated novel antifilarial properties for all three compounds.

    in eLife on August 11, 2020 12:00 AM.

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    <i>In silico</i> co-factor balance estimation using constraint-based modelling informs metabolic engineering in <i>Escherichia coli</i>

    by Laura de Arroyo Garcia, Patrik R. Jones

    In the growing field of metabolic engineering, where cells are treated as “factories” that synthesize industrial compounds, it is essential to consider the ability of the cells’ native metabolism to accommodate the demands of synthetic pathways, as these pathways will alter the homeostasis of cellular energy and electron metabolism. From the breakdown of substrate, microorganisms activate and reduce key co-factors such as ATP and NAD(P)H, which subsequently need to be hydrolysed and oxidized, respectively, in order to restore cellular balance. A balanced supply and consumption of such co-factors, here termed co-factor balance, will influence biotechnological performance. To aid the strain selection and design process, we used stoichiometric modelling (FBA, pFBA, FVA and MOMA) and the Escherichia coli (E.coli) core stoichiometric model to investigate the network-wide effect of butanol and butanol precursor production pathways differing in energy and electron demand on the final product yield. An FBA-based co-factor balance assessment (CBA) algorithm was developed to track and categorise how ATP and NAD(P)H pools are affected in the presence of a new pathway. CBA was compared to the balance calculations proposed by Dugar et al. (Nature Biotechnol. 29 (12), 1074–1078). Predicted solutions were compromised by excessively underdetermined systems, displaying greater flexibility in the range of reaction fluxes than experimentally measured by 13C-metabolic flux analysis (MFA) and the appearance of unrealistic futile co-factor cycles. With the assumption that futile cycles are tightly regulated in reality, the FBA models were manually constrained in a step-wise manner. Solutions with minimal futile cycling diverted surplus energy and electrons towards biomass formation. As an alternative, the use of loopless FBA or constraining the models with measured flux ranges were tried but did not prevent futile co-factor cycles. The results highlight the need to account for co-factor imbalance and confirm that better-balanced pathways with minimal diversion of surplus towards biomass formation present the highest theoretical yield. The analysis also suggests that ATP and NAD(P)H balancing cannot be assessed in isolation from each other, or even from the balance of additional co-factors such as AMP and ADP. We conclude that, through revealing the source of co-factor imbalance CBA can facilitate pathway and host selection when designing new biocatalysts for implementation by metabolic engineering.

    in PLoS Computational Biology on August 10, 2020 09:00 PM.

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    Facilitating the propagation of spiking activity in feedforward networks by including feedback

    by Hedyeh Rezaei, Ad Aertsen, Arvind Kumar, Alireza Valizadeh

    Transient oscillations in network activity upon sensory stimulation have been reported in different sensory areas of the brain. These evoked oscillations are the generic response of networks of excitatory and inhibitory neurons (EI-networks) to a transient external input. Recently, it has been shown that this resonance property of EI-networks can be exploited for communication in modular neuronal networks by enabling the transmission of sequences of synchronous spike volleys (’pulse packets’), despite the sparse and weak connectivity between the modules. The condition for successful transmission is that the pulse packet (PP) intervals match the period of the modules’ resonance frequency. Hence, the mechanism was termed communication through resonance (CTR). This mechanism has three severe constraints, though. First, it needs periodic trains of PPs, whereas single PPs fail to propagate. Second, the inter-PP interval needs to match the network resonance. Third, transmission is very slow, because in each module, the network resonance needs to build up over multiple oscillation cycles. Here, we show that, by adding appropriate feedback connections to the network, the CTR mechanism can be improved and the aforementioned constraints relaxed. Specifically, we show that adding feedback connections between two upstream modules, called the resonance pair, in an otherwise feedforward modular network can support successful propagation of a single PP throughout the entire network. The key condition for successful transmission is that the sum of the forward and backward delays in the resonance pair matches the resonance frequency of the network modules. The transmission is much faster, by more than a factor of two, than in the original CTR mechanism. Moreover, it distinctly lowers the threshold for successful communication by synchronous spiking in modular networks of weakly coupled networks. Thus, our results suggest a new functional role of bidirectional connectivity for the communication in cortical area networks.

    in PLoS Computational Biology on August 10, 2020 09:00 PM.

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    Reliable estimation of membrane curvature for cryo-electron tomography

    by Maria Salfer, Javier F. Collado, Wolfgang Baumeister, Rubén Fernández-Busnadiego, Antonio Martínez-Sánchez

    Curvature is a fundamental morphological descriptor of cellular membranes. Cryo-electron tomography (cryo-ET) is particularly well-suited to visualize and analyze membrane morphology in a close-to-native state and molecular resolution. However, current curvature estimation methods cannot be applied directly to membrane segmentations in cryo-ET, as these methods cannot cope with some of the artifacts introduced during image acquisition and membrane segmentation, such as quantization noise and open borders. Here, we developed and implemented a Python package for membrane curvature estimation from tomogram segmentations, which we named PyCurv. From a membrane segmentation, a signed surface (triangle mesh) is first extracted. The triangle mesh is then represented by a graph, which facilitates finding neighboring triangles and the calculation of geodesic distances necessary for local curvature estimation. PyCurv estimates curvature based on tensor voting. Beside curvatures, this algorithm also provides robust estimations of surface normals and principal directions. We tested PyCurv and three well-established methods on benchmark surfaces and biological data. This revealed the superior performance of PyCurv not only for cryo-ET, but also for data generated by other techniques such as light microscopy and magnetic resonance imaging. Altogether, PyCurv is a versatile open-source software to reliably estimate curvature of membranes and other surfaces in a wide variety of applications.

    in PLoS Computational Biology on August 10, 2020 09:00 PM.

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    CaMKII controls neuromodulation via neuropeptide gene expression and axonal targeting of neuropeptide vesicles

    by Alessandro Moro, Geeske M. van Woerden, Ruud F. Toonen, Matthijs Verhage

    Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and βCaMKII-deficient (αβCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αβCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αβCaMKII DKO neurons was restored by active βCaMKII but not inactive βCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to βCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.

    in PLoS Biology on August 10, 2020 09:00 PM.

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    The right temporoparietal junction enables delay of gratification by allowing decision makers to focus on future events

    by Alexander Soutschek, Marius Moisa, Christian C. Ruff, Philippe N. Tobler

    Studies of neural processes underlying delay of gratification usually focus on prefrontal networks related to curbing affective impulses. Here, we provide evidence for an alternative mechanism that facilitates delaying gratification by mental orientation towards the future. Combining continuous theta-burst stimulation (cTBS) with functional neuroimaging, we tested how the right temporoparietal junction (rTPJ) facilitates processing of future events and thereby promotes delay of gratification. Participants performed an intertemporal decision task and a mental time-travel task in the MRI scanner before and after receiving cTBS over the rTPJ or the vertex (control site). rTPJ cTBS led to both stronger temporal discounting for longer delays and reduced processing of future relative to past events in the mental time-travel task. This finding suggests that the rTPJ contributes to the ability to delay gratification by facilitating mental representation of outcomes in the future. On the neural level, rTPJ cTBS led to a reduction in the extent to which connectivity of rTPJ with striatum reflected the value of delayed rewards, indicating a role of rTPJ–striatum connectivity in constructing neural representations of future rewards. Together, our findings provide evidence that the rTPJ is an integral part of a brain network that promotes delay of gratification by facilitating mental orientation to future rewards.

    in PLoS Biology on August 10, 2020 09:00 PM.

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    Cryo-EM structure of the human concentrative nucleoside transporter CNT3

    by Yanxia Zhou, Lianghuan Liao, Chen Wang, Jialu Li, Pengliang Chi, Qingjie Xiao, Qingting Liu, Li Guo, Linfeng Sun, Dong Deng

    Concentrative nucleoside transporters (CNTs), members of the solute carrier (SLC) 28 transporter family, facilitate the salvage of nucleosides and therapeutic nucleoside derivatives across the plasma membrane. Despite decades of investigation, the structures of human CNTs remain unknown. We determined the cryogenic electron microscopy (cryo-EM) structure of human CNT (hCNT) 3 at an overall resolution of 3.6 Å. As with its bacterial homologs, hCNT3 presents a trimeric architecture with additional N-terminal transmembrane helices to stabilize the conserved central domains. The conserved binding sites for the substrate and sodium ions unravel the selective nucleoside transport and distinct coupling mechanism. Structural comparison of hCNT3 with bacterial homologs indicates that hCNT3 is stabilized in an inward-facing conformation. This study provides the molecular determinants for the transport mechanism of hCNTs and potentially facilitates the design of nucleoside drugs.

    in PLoS Biology on August 10, 2020 09:00 PM.

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    Neuroanatomy of transgender persons in a Non‐Western population and improving reliability in clinical neuroimaging

    Neuroanatomy of transgender persons in a Non‐Western population and improving reliability in clinical neuroimaging

    This study assesses the reproducibility of previous neuroanatomical findings in Western transgender persons in a Non‐Western population. It then shows that repeating an anatomical MRI sequence can increase data reliability especially in brain regions that have previously been implicated to differ between transgender and cisgender persons. This scan–rescan method might enhance the power of studies with small samples due to low prevalence of target population.


    Abstract

    Although the neuroanatomy of transgender persons is slowly being charted, findings are presently discrepant. Moreover, the major body of work has focused on Western populations. One important factor is the issue of power and low signal‐to‐noise (SNR) ratio in neuroimaging studies of rare study populations including endocrine or neurological patient groups. The present study focused on the structural neuroanatomy of a Non‐Western (Iranian) sample of 40 transgender men (TM), 40 transgender women (TW), 30 cisgender men (CM), and 30 cisgender women (CW), while assessing whether the reliability of findings across structural anatomical measures including gray matter volume (GMV), cortical surface area (CSA), and cortical thickness (CTh) could be increased by using two back‐to‐back within‐session structural MRI scans. Overall, findings in transgender persons were more consistent with sex assigned at birth in GMV and CSA, while no group differences emerged for CTh. Repeated measures analysis also indicated that having a second scan increased SNR in all regions of interest, most notably bilateral frontal poles, pre‐ and postcentral gyri and putamina. The results suggest that a simple time and cost‐effective measure to improve SNR in rare clinical populations with low prevalence rates is a second anatomical scan when structural MRI is of interest.

    in Journal of Neuroscience Research on August 10, 2020 07:44 PM.

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    Distribution of Acetylcholinesterase in the Hippocampal Formation of the Atlantic White‐sided Dolphin (Lagenorhynchus acutus)

    Distribution of Acetylcholinesterase in the Hippocampal Formation of the Atlantic White‐sided Dolphin (Lagenorhynchus acutus)

    Acetylcholinesterase and Nissl‐staining in the Atlantic white‐sided dolphin Hippocampal Formation.


    Abstract

    The cetacean hippocampal formation has been noted to be one of the smallest relative to brain size of all mammals studied. This region, comprised of the dentate gyrus, hippocampus proper, subiculum, presubiculum, parasubiculum and the entorhinal cortex, is important in learning, memory and navigation. There have been a number of studies detailing the distribution of acetylcholinesterase in the hippocampal formation of terrestrial mammals with the goal of gaining a greater understanding of some aspects of the cholinergic innervation to this region as well as its parcellation. The present study was undertaken to describe the organization, cytoarchitecture and distribution of acetylcholinesterase in the hippocampal formation of the Atlantic white‐sided dolphin (AWSD) with the view to understand similarities and differences between this aquatic mammal and terrestrial mammals. Nissl‐staining demonstrated cytoarchitecture of the hippocampal formation in the AWSD comparable to that reported in other cetaceans. In addition, the AWSD had a rich pattern of AChE staining that distinctly varied between regions and laminae. A number of differences in the distribution of AChE staining in areas comparable to those of terrestrial species reported suggested possible alterations in connectivity of this region. Overall, however, AChE‐staining suggested that cholinergic innervation, neural pathways and function of the hippocampal formation of the AWSD is conserved, similar to other mammals.

    in Journal of Comparative Neurology on August 10, 2020 05:39 PM.

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    Mapping of the excitatory, inhibitory, and modulatory afferent projections to the anatomically defined active expiratory oscillator in adult male rats

    Mapping of the excitatory, inhibitory, and modulatory afferent projections to the anatomically defined active expiratory oscillator in adult male rats

    We identified the afferent projections to the brainstem expiratory oscillator located in the lateral parafacial region (pFL). We combined retrograde viruses with RNAScope and immunofluorescence to identify the neurochemical phenotype of neurons. pFL neurons receive extensive excitatory and inhibitory inputs that contribute to the modulation of the conditional pFL oscillator.


    Abstract

    The lateral parafacial region (pFL; which encompasses the parafacial respiratory group, pFRG) is a conditional oscillator that drives active expiration during periods of high respiratory demand, and increases ventilation through the recruitment of expiratory muscles. The pFL activity is highly modulated, and systematic analysis of its afferent projections is required to understand its connectivity and modulatory control. We combined a viral retrograde tracing approach to map direct brainstem projections to the putative location of pFL, with RNAScope and immunofluorescence to identify the neurochemical phenotype of the projecting neurons. Within the medulla, retrogradely‐labeled, glutamatergic, glycinergic and GABAergic neurons were found in the ventral respiratory column (Bötzinger and preBötzinger Complex [preBötC], ventral respiratory group, ventral parafacial region [pFV] and pFL), nucleus of the solitary tract (NTS), reticular formation (RF), pontine and midbrain vestibular nuclei, and medullary raphe. In the pons and midbrain, retrogradely‐labeled neurons of the same phenotypes were found in the Kölliker‐Fuse and parabrachial nuclei, periaqueductal gray, pedunculopontine nucleus (PPT) and laterodorsal tegmentum (LDT). We also identified somatostatin‐expressing neurons in the preBötC and PHOX2B immunopositive cells in the pFV, NTS, and part of the RF. Surprisingly, we found no catecholaminergic neurons in the NTS, A5 or Locus Coeruleus , no serotoninergic raphe neurons nor any cholinergic neurons in the PPT and LDT that projected to the pFL. Our results indicate that pFL neurons receive extensive excitatory and inhibitory inputs from several respiratory and nonrespiratory related brainstem regions that could contribute to the complex modulation of the conditional pFL oscillator for active expiration.

    in Journal of Comparative Neurology on August 10, 2020 05:02 PM.

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    Random-walk model of cotransport

    Author(s): Yan B. Barreto, Béla Suki, and Adriano M. Alencar

    We present a statistical mechanical model to describe the dynamics of an arbitrary cotransport system. Our starting point was the alternating access mechanism, which suggests the existence of six states for the cotransport cycle. Then we determined the 14 transition probabilities between these state...


    [Phys. Rev. E 102, 022403] Published Mon Aug 10, 2020

    in Physical Review E: Biological physics on August 10, 2020 10:00 AM.

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    Neural and phenotypic representation under the free-energy principle. (arXiv:2008.03238v1 [q-bio.NC])

    The aim of this paper is to leverage the free-energy principle and its corollary process theory, active inference, to develop a generic, generalizable model of the representational capacities of living creatures; that is, a theory of phenotypic representation. Given their ubiquity, we are concerned with distributed forms of representation (e.g., population codes), whereby patterns of ensemble activity in living tissue come to represent the causes of sensory input or data. The active inference framework rests on the Markov blanket formalism, which allows us to partition systems of interest, such as biological systems, into internal states, external states, and the blanket (active and sensory) states that render internal and external states conditionally independent of each other. In this framework, the representational capacity of living creatures emerges as a consequence of their Markovian structure and nonequilibrium dynamics, which together entail a dual-aspect information geometry. This entails a modest representational capacity: internal states have an intrinsic information geometry that describes their trajectory over time in state space, as well as an extrinsic information geometry that allows internal states to encode (the parameters of) probabilistic beliefs about (fictive) external states. Building on this, we describe here how, in an automatic and emergent manner, information about stimuli can come to be encoded by groups of neurons bound by a Markov blanket; what is known as the neuronal packet hypothesis. As a concrete demonstration of this type of emergent representation, we present numerical simulations showing that self-organizing ensembles of active inference agents sharing the right kind of probabilistic generative model are able to encode recoverable information about a stimulus array.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 10, 2020 01:30 AM.

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    Learning as filtering: implications for spike-based plasticity. (arXiv:2008.03198v1 [q-bio.NC])

    Most normative models in computational neuroscience describe the task of learning as the optimisation of a cost function with respect to a set of parameters. However, learning as optimisation fails to account for a time varying environment during the learning process; and the resulting point estimate in parameter space does not account for uncertainty. Here, we frame learning as filtering, i.e., a principled method for including time and parameter uncertainty. We derive the filtering-based learning rule for a spiking neuronal network - the Synaptic Filter - and show its computational and biological relevance. For the computational relevance, we show that filtering in combination with Bayesian regression improves performance compared to a gradient learning rule with optimal learning rate in terms of weight estimation. Furthermore, the filtering-based rule outperforms gradient-based rules in the presence of model mismatch, indicating a better generalisation performance. The dynamics of the mean of the Synaptic Filter is consistent with the spike-timing dependent plasticity (STDP) while the dynamics of the variance makes novel predictions regarding spike-timing dependent changes of EPSP variability. Moreover, the Synaptic Filter explains experimentally observed negative correlations between homo- and heterosynaptic plasticity.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 10, 2020 01:30 AM.

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    From Connectomic to Task-evoked Fingerprints: Individualized Prediction of Task Contrasts from Resting-state Functional Connectivity. (arXiv:2008.02961v1 [cs.LG])

    Resting-state functional MRI (rsfMRI) yields functional connectomes that can serve as cognitive fingerprints of individuals. Connectomic fingerprints have proven useful in many machine learning tasks, such as predicting subject-specific behavioral traits or task-evoked activity. In this work, we propose a surface-based convolutional neural network (BrainSurfCNN) model to predict individual task contrasts from their resting-state fingerprints. We introduce a reconstructive-contrastive loss that enforces subject-specificity of model outputs while minimizing predictive error. The proposed approach significantly improves the accuracy of predicted contrasts over a well-established baseline. Furthermore, BrainSurfCNN's prediction also surpasses test-retest benchmark in a subject identification task.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 10, 2020 01:30 AM.

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    aschern at SemEval-2020 Task 11: It Takes Three to Tango: RoBERTa, CRF, and Transfer Learning. (arXiv:2008.02837v1 [cs.CL])

    We describe our system for SemEval-2020 Task 11 on Detection of Propaganda Techniques in News Articles. We developed ensemble models using RoBERTa-based neural architectures, additional CRF layers, transfer learning between the two subtasks, and advanced post-processing to handle the multi-label nature of the task, the consistency between nested spans, repetitions, and labels from similar spans in training. We achieved sizable improvements over baseline fine-tuned RoBERTa models, and the official evaluation ranked our system 3rd (almost tied with the 2nd) out of 36 teams on the span identification subtask with an F1 score of 0.491, and 2nd (almost tied with the 1st) out of 31 teams on the technique classification subtask with an F1 score of 0.62.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 10, 2020 01:30 AM.

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    Going in circles is the way forward: the role of recurrence in visual inference. (arXiv:2003.12128v2 [q-bio.NC] UPDATED)

    Biological visual systems exhibit abundant recurrent connectivity. State-of-the-art neural network models for visual recognition, by contrast, rely heavily or exclusively on feedforward computation. Any finite-time recurrent neural network (RNN) can be unrolled along time to yield an equivalent feedforward neural network (FNN). This important insight suggests that computational neuroscientists may not need to engage recurrent computation, and that computer-vision engineers may be limiting themselves to a special case of FNN if they build recurrent models. Here we argue, to the contrary, that FNNs are a special case of RNNs and that computational neuroscientists and engineers should engage recurrence to understand how brains and machines can (1) achieve greater and more flexible computational depth, (2) compress complex computations into limited hardware, (3) integrate priors and priorities into visual inference through expectation and attention, (4) exploit sequential dependencies in their data for better inference and prediction, and (5) leverage the power of iterative computation.

    in arXiv: Quantitative Biology: Neurons and Cognition on August 10, 2020 01:30 AM.

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    On Warm-Starting Neural Network Training. (arXiv:1910.08475v2 [cs.LG] UPDATED)

    In many real-world deployments of machine learning systems, data arrive piecemeal. These learning scenarios may be passive, where data arrive incrementally due to structural properties of the problem (e.g., daily financial data) or active, where samples are selected according to a measure of their quality (e.g., experimental design). In both of these cases, we are building a sequence of models that incorporate an increasing amount of data. We would like each of these models in the sequence to be performant and take advantage of all the data that are available to that point. Conventional intuition suggests that when solving a sequence of related optimization problems of this form, it should be possible to initialize using the solution of the previous iterate---to "warm start" the optimization rather than initialize from scratch---and see reductions in wall-clock time. However, in practice this warm-starting seems to yield poorer generalization performance than models that have fresh random initializations, even though the final training losses are similar. While it appears that some hyperparameter settings allow a practitioner to close this generalization gap, they seem to only do so in regimes that damage the wall-clock gains of the warm start. Nevertheless, it is highly desirable to be able to warm-start neural network training, as it would dramatically reduce the resource usage associated with the construction of performant deep learning systems. In this work, we take a closer look at this empirical phenomenon and try to understand when and how it occurs. We also provide a surprisingly simple trick that overcomes this pathology in several important situations, and present experiments that elucidate some of its properties.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 10, 2020 01:30 AM.

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    Application and Computation of Probabilistic Neural Plasticity. (arXiv:1907.00689v2 [q-bio.NC] UPDATED)

    The discovery of neural plasticity has proved that throughout the life of a human being, the brain reorganizes itself through forming new neural connections. The formation of new neural connections are achieved through the brain's effort to adapt to new environments or to changes in the existing environment. Despite the realization of neural plasticity, there is a lack of understanding the probability of neural plasticity occurring given some event. Using ordinary differential equations, neural firing equations and spike-train statistics, we show how an additive short-term memory (STM) equation can be formulated to approach the computation of neural plasticity. We then show how the additive STM equation can be used for probabilistic inference in computable neural plasticity, and the computation of probabilistic neural plasticity. We will also provide a brief introduction to the theory of probabilistic neural plasticity and conclude with showing how it can be applied to multiple disciplines such as behavioural science, machine learning, artificial intelligence and psychiatry.

    in arXiv: Computer Science: Neural and Evolutionary Computing on August 10, 2020 01:30 AM.

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    Author Correction: AHR is a Zika virus host factor and a candidate target for antiviral therapy

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0700-0

    Author Correction: AHR is a Zika virus host factor and a candidate target for antiviral therapy

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    Goal-directed actions transiently depend on dorsal hippocampus

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0693-8

    This study shows that the dorsal hippocampus is necessary for goal-directed action, but only transiently, during initial learning. Convergently, goal-directed actions also depend transiently on the physical context.

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    First, tau causes NO problem

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0691-x

    Pathological tau disrupts the association between nitric oxide (NO) synthase and PSD95, impairing NO signaling and neurovascular coupling before causing neurodegeneration. Stopping production of pathological tau rescues NO signaling, neurovascular coupling and neuronal function, but doesn’t remove tangles, suggesting that (like amyloid-β) soluble tau is an important driver of early neurovascular dysfunction and subsequent neuronal damage.

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    A quantitative reward prediction error signal in the ventral pallidum

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0688-5

    The nervous system is hypothesized to calculate reward prediction errors to estimate reward availability in the environment. The authors quantify a robust prediction error signal in the ventral pallidum derived from recently received rewarding outcomes.

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    Synergy between amyloid-β and tau in Alzheimer’s disease

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0687-6

    Busche and Hyman review emerging evidence for an interaction between Aβ and tau during Alzheimer’s disease (AD) progression that challenges the classical linear trajectory model and offers a new perspective on AD pathophysiology and therapy.

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    Tau induces PSD95–neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0686-7

    Park et al. demonstrate in tauopathy models that tau disrupts the interaction between neuronal nitric oxide synthase and PSD95, uncoupling glutamatergic synaptic activity from nitric oxide production and dampening the hemodynamic response to activation.

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    Cortical-like dynamics in recurrent circuits optimized for sampling-based probabilistic inference

    Nature Neuroscience, Published online: 10 August 2020; doi:10.1038/s41593-020-0671-1

    Neural oscillations, transients and variability are widely observed in sensory cortices. All these features emerge in neural networks optimized for the singular task of representing perceptual uncertainty in the variability of neural responses.

    in Nature Neuroscience on August 10, 2020 12:00 AM.

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    Actin chromobody imaging reveals sub-organellar actin dynamics

    Nature Methods, Published online: 10 August 2020; doi:10.1038/s41592-020-0926-5

    Genetically encoded fluorescent-protein-tagged actin nanobodies fused to organelle membrane-targeting sequences enables high-resolution imaging of transient organelle–actin contact sites in live cells.

    in Nature Methods on August 10, 2020 12:00 AM.

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    Time-resolved cryo-EM using Spotiton

    Nature Methods, Published online: 10 August 2020; doi:10.1038/s41592-020-0925-6

    A spraying-mixing approach for preparing cryo-EM grids using the Spotiton robot allows time-resolved observations of short-lived biomolecular states.

    in Nature Methods on August 10, 2020 12:00 AM.

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    Genetically encoded tags for direct synthesis of EM-visible gold nanoparticles in cells

    Nature Methods, Published online: 10 August 2020; doi:10.1038/s41592-020-0911-z

    Genetically encoded cysteine-rich tags enable formation of gold nanoparticles in situ for single-molecule imaging of individual proteins in the context of cellular ultrastructure in bacterial, yeast and mammalian cells.

    in Nature Methods on August 10, 2020 12:00 AM.

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    Direct observation of two-dimensional magnons in atomically thin CrI3

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0999-1

    Magnons are collective excitations that dictate many of a magnet’s low-temperature properties. By means of Raman scattering, the magnon spectra of CrI3 are measured in the monolayer limit.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Efficient learning of quantum noise

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0992-8

    A protocol for the reliable, efficient and precise characterization of quantum noise is reported and implemented in an architecture consisting of 14 superconducting qubits. Correlated noise within arbitrary sets of qubits can be easily detected.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Photon-pressure strong coupling between two superconducting circuits

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0987-5

    Analogous to the radiation-pressure coupling known in optomechanics, photon-pressure interaction between superconducting circuits can reach the strong coupling regime, which allows flexible control of the electromagnetic resonator’s quantum state.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Suppression of superconductivity by anisotropic strain near a nematic quantum critical point

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0983-9

    Using doped BaFe2As2, the authors test whether nematicity is linked to superconductivity in the iron pnictides by applying the conjugate field to nematicity—a specific form of strain—and observe that the critical temperature decreases.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Superconductivity and quantum criticality linked by the Hall effect in a strange metal

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0982-x

    The strange metal phase in unconventional superconductors is probed by Hall measurements. This reveals that quantum criticality drives the Hall effect, which also correlates with the superconductivity. This indicates that all three may be linked.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Active mucus–cilia hydrodynamic coupling drives self-organization of human bronchial epithelium

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0980-z

    The flow of fluid, such as mucus in the human respiratory tract, can affect biological function. Here the authors show that the hydrodynamic interactions mediated by mucus are essential for the directional coordination of ciliary beating in the lungs.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Universal scaling laws rule explosive growth in human cancers

    Nature Physics, Published online: 10 August 2020; doi:10.1038/s41567-020-0978-6

    The authors investigate the relationship between the volume of malignant tumours and their metabolic processes using a large dataset of patients with cancer. They find that cancers follow a superlinear metabolic scaling law, which implies that the proliferation of cancer cells accelerates with increasing volume.

    in Nature Physics on August 10, 2020 12:00 AM.

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    Sub-nanometre resolution in single-molecule photoluminescence imaging

    Nature Photonics, Published online: 10 August 2020; doi:10.1038/s41566-020-0677-y

    Through the use of a plasmon-active atomically sharp tip and an ultrathin insulating film, and precise junction control in a highly confined nanocavity plasmon field at the scanning tunnelling microscope junction, sub-nanometre-resolved single-molecule near-field photoluminescence imaging with a spatial resolution down to ∼8 Å is achieved.

    in Nature Photomics on August 10, 2020 12:00 AM.

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    Intense Brillouin amplification in gas using hollow-core waveguides

    Nature Photonics, Published online: 10 August 2020; doi:10.1038/s41566-020-0676-z

    A strong Brillouin amplification per unit length, observed in a gas-filled hollow-core fibre, is used to realize a low-threshold continuous-wave single-frequency laser that can in principle operate at any wavelength and to demonstrate distributed temperature sensing with no strain cross-sensitivity.

    in Nature Photomics on August 10, 2020 12:00 AM.

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    Acceleration of relativistic beams using laser-generated terahertz pulses

    Nature Photonics, Published online: 10 August 2020; doi:10.1038/s41566-020-0674-1

    Relativistic 35 MeV electron bunches with charges of 60 pC are accelerated in a terahertz-wave-driven dielectric waveguide. When the terahertz pulse energy is 0.8 μJ, an accelerating gradient of 2 MeV m−1 and energy gain of 10 keV are achieved.

    in Nature Photomics on August 10, 2020 12:00 AM.

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    Non-adiabatic stripping of a cavity field from electrons in the deep-strong coupling regime

    Nature Photonics, Published online: 10 August 2020; doi:10.1038/s41566-020-0673-2

    Deactivation of deep-strong light–matter coupling is achieved by femtosecond switching of terahertz cavities. This disruption leads to pronounced high-frequency polarization oscillations evolving much faster than the oscillation cycle of light.

    in Nature Photomics on August 10, 2020 12:00 AM.

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    Photoelectric effect with a twist

    Nature Photonics, Published online: 10 August 2020; doi:10.1038/s41566-020-0669-y

    The findings that the spatial distribution of an optical field with vortex phase profile can be imprinted coherently onto a propagating electron wave reveal new aspects of light–matter interactions and will help develop future single-photon electron spectroscopy.

    in Nature Photomics on August 10, 2020 12:00 AM.

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    3D printable tough silicone double networks

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17816-y

    Additive manufacturing processing requirements pose restrictions on materials and joining chemically dissimilar components. Here the authors use silicone double networks that participate in orthogonal crosslinking mechanisms for independent control of the shape forming process and final mechanical properties.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Reconfigurable structured light generation in a multicore fibre amplifier

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17809-x

    Structured light is a valuable addition to many optical applications. Here, the authors introduce a method for producing tailorable structured light beams at the output of a multicore fiber amplifier by controlling the input to each fiber core.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Nanoscale mechanism of UO2 formation through uranium reduction by magnetite

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17795-0

    In anoxic environments, soluble hexavalent uranium is reduced and immobilized, however, the underlying molecular-scale reduction mechanism remains unknown. Here, the authors find that U reduction can occur on the surface of magnetite via transient U nanowire structures which collapse into ordered UO2 nanoclusters, which may have implications for understanding nuclear waste evolution and remediation of uranium contamination.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Developmental potential of aneuploid human embryos cultured beyond implantation

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17764-7

    Aneuploidy, abnormal chromosome number, is a major cause of early pregnancy loss. Here the authors determine the extent of post-implantation development of human embryos with common aneuploidies in culture, finding developmental arrest of monosomy 21 embryos, and trophoblast hypo-proliferation in trisomy 16 embryos.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Turbulent hydrodynamics in strongly correlated Kagome metals

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17663-x

    Viscous electron fluids are predicted in strongly correlated systems but remain challenging to realize. Here, the authors predict enhanced effective Coulomb interaction and reduced ratio of the shear viscosity over entropy density in a Kagome metal, inferring turbulent flow of viscous electron fluids.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Topological flat bands in frustrated kagome lattice CoSn

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17465-1

    The experimental realization of lattice-born flat bands with nontrivial topology has been elusive. Here, the authors observe topological flat bands near the Fermi level in a kagome metal CoSn, with flat bands as well as Dirac bands originating from 3d orbitals in a frustrated kagome geometry.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Orbital-selective Dirac fermions and extremely flat bands in frustrated kagome-lattice metal CoSn

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17462-4

    The understanding of kagome bands, which are characterized by Dirac-like bands capped by a flat band, remains largely elusive. Here, Liu et al. report the observation of a flat band and Dirac bands as ideal features of kagome bands in CoSn, revealing orbital-selective character.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Electronic correlations and flattened band in magnetic Weyl semimetal candidate Co3Sn2S2

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17234-0

    How electron correlation interplays with topological states remains rarely explored. Here, the authors report flat band arising due to electron correlations in magnetic Weyl semimetal Co3Sn2S2 from a combined optical-spectroscopy and simulation study.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Impact heat driven volatile redistribution at Occator crater on Ceres as a comparative planetary process

    Nature Communications, Published online: 10 August 2020; doi:10.1038/s41467-020-17184-7

    Dawn mission’s second extended phase provided high resolution observations of Occator crater of the dwarf planet Ceres. Here, the authors show stereo imaging and topographic maps of this crater revealing the influence of crustal composition on impact related melt and hydrothermal processes, and compare features to those on Mars, Earth and the Moon.

    in Nature Communications on August 10, 2020 12:00 AM.

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    Daily briefing: The physics of the tragic explosion in Beirut

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02368-4

    A blast-injury specialist explores the tragic chemistry and physics of the Beirut explosion. Plus, front-line physicians tussle over unproven coronavirus treatments and a question of bias in pulse oximeters.

    in Nature on August 10, 2020 12:00 AM.

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    Why Beirut’s ammonium nitrate blast was so devastating

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02361-x

    The tragedy is one of the largest industrial accidents involving the explosive chemical, and it hit Lebanon amid the coronavirus pandemic and an economic crisis.

    in Nature on August 10, 2020 12:00 AM.

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    Mesmerized by maritime marvels

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02340-2

    Marine biologist Greg Rouse is elated to have been on a research cruise that discovered the world’s longest creature.

    in Nature on August 10, 2020 12:00 AM.

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    Crunch, rip, freeze or decay — how will the Universe end?

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02338-w

    Astrophysicist Katie Mack’s book explores all the ways the cosmos could destroy itself.

    in Nature on August 10, 2020 12:00 AM.

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    Conferences failing to protect LGBT+ researchers

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02325-1

    Promoting equity, diversity and inclusion at meetings requires more than a code of conduct, analysis finds.

    in Nature on August 10, 2020 12:00 AM.

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    ‘We’re in one of the cataclysmic times of change’: first female NSF director on discrimination and COVID-19

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02314-4

    One-time head of the US National Science Foundation Rita Colwell speaks out on sexism — and how her experiences as a leader in science can inform pandemic response.

    in Nature on August 10, 2020 12:00 AM.

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    Australia is cracking down on foreign interference in research. Is the system working?

    Nature, Published online: 10 August 2020; doi:10.1038/d41586-020-02188-6

    Pioneering guidelines aren’t enough to prevent overseas militaries such as China’s from co-opting the country’s science, say some experts.

    in Nature on August 10, 2020 12:00 AM.

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    Antero-Posterior vs. Lateral Vestibular Input Processing in Human Visual Cortex

    Visuo-vestibular integration is crucial for locomotion, yet the cortical mechanisms involved remain poorly understood. We combined binaural monopolar galvanic vestibular stimulation (GVS) and functional magnetic resonance imaging (fMRI) to characterize the cortical networks activated during antero-posterior and lateral stimulations in humans. We focused on functional areas that selectively respond to egomotion-consistent optic flow patterns: the human middle temporal complex (hMT+), V6, the ventral intraparietal (VIP) area, the cingulate sulcus visual (CSv) area and the posterior insular cortex (PIC). Areas hMT+, CSv, and PIC were equivalently responsive during lateral and antero-posterior GVS while areas VIP and V6 were highly activated during antero-posterior GVS, but remained silent during lateral GVS. Using psychophysiological interaction (PPI) analyses, we confirmed that a cortical network including areas V6 and VIP is engaged during antero-posterior GVS. Our results suggest that V6 and VIP play a specific role in processing multisensory signals specific to locomotion during navigation.

    in Frontiers in Integrative Neuroscience on August 10, 2020 12:00 AM.

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    Endoplasmic Reticulum Lumenal Indicators in Drosophila Reveal Effects of HSP-Related Mutations on Endoplasmic Reticulum Calcium Dynamics

    Genes for endoplasmic reticulum (ER)-shaping proteins are among the most commonly mutated in hereditary spastic paraplegia (HSP). Mutation of these genes in model organisms can lead to disruption of the ER network. To investigate how the physiological roles of the ER might be affected by such disruption, we developed tools to interrogate its Ca2+ signaling function. We generated GAL4-driven Ca2+ sensors targeted to the ER lumen, to record ER Ca2+ fluxes in identified Drosophila neurons. Using GAL4 lines specific for Type Ib or Type Is larval motor neurons, we compared the responses of different lumenal indicators to electrical stimulation, in axons and presynaptic terminals. The most effective sensor, ER-GCaMP6-210, had a Ca2+ affinity close to the expected ER lumenal concentration. Repetitive nerve stimulation generally showed a transient increase of lumenal Ca2+ in both the axon and presynaptic terminals. Mutants lacking neuronal reticulon and REEP proteins, homologs of human HSP proteins, showed a larger ER lumenal evoked response compared to wild type; we propose mechanisms by which this phenotype could lead to neuronal dysfunction or degeneration. Our lines are useful additions to a Drosophila Ca2+ imaging toolkit, to explore the physiological roles of ER, and its pathophysiological roles in HSP and in axon degeneration more broadly.

    in Frontiers in Neuroscience: Neurodegeneration on August 10, 2020 12:00 AM.

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    Distinct Residential and Infiltrated Macrophage Populations and Their Phagocytic Function in Mild and Severe Neonatal Hypoxic-Ischemic Brain Damage

    Neonatal brain injury, especially severe injury induced by hypoxia-ischemia (HI), causes mortality and long-term neurological impairments. Our previous study demonstrated activation of CD11b+ myeloid cells, including residential microglial cells (MGs) and infiltrating monocyte-derived macrophages (MDMs) in a murine model of hypoxic-ischemic brain damage (HIBD), with unknown functions. Here, we study the differences in the phagocytic function of MGs and MDMs to clarify their potential roles after HIBD. HI was induced in 9–10-day postnatal mice. On days 1 and 3 after injury, pathological and neurobehavioral tests were performed to categorize the brain damage as mild or severe. Flow cytometry was applied to quantify the dynamic change in the numbers of MGs and MDMs according to the relative expression level of CD45 in CD11b+ cells. CX3CR1GFPCCR2RFP double-transformed mice were used to identify MGs and MDMs in the brain parenchyma after HIBD. Lysosome-associated membrane protein 1 (LAMP1), toll-like receptor 2 (TLR2), CD36, and transforming growth factor (TGF-β) expression levels were measured to assess the underlying function of phagocytes and neuroprotective factors in these cells. The FITC-dextran 40 phagocytosis assay was applied to examine the change in phagocytic function under oxygen-glucose deprivation (OGD) in vitro. We found that neonatal HI induced a different degree of brain damage: mild or severe injury. Compared with mildly injured animals, mice with severe injury had lower weight, worse neurobehavioral scores, and abnormal brain morphology. In a severely injured brain, CD11b+ cells remarkably increased, including an increase in the MDM population and a decrease in the MG population. Furthermore, MDM infiltration into the brain parenchyma was evident in CX3CR1GFPCCR2RFP double-transformed mice. Mild and severe brain injury caused different phagocytosis-related responses and neuroprotective functions of MDMs and MGs at 1 and 3 days following HI. The phagocytic function was activated in BV2 cells but downregulated in Raw264.7 cells under OGD in vitro. These observations indicate that neonatal HI induced different degrees of brain injury. The proportion of infiltrated macrophage MDMs was increased and they were recruited into the injured brain parenchyma in severe brain injury. The resident macrophage MGs proportion decreased and maintained activated phagocytic function in both mild and severe brain injury, and restored neuroprotective function in severe brain injury.

    in Frontiers in Cellular Neuroscience on August 10, 2020 12:00 AM.

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    The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment

    The selective autophagy pathways of xenophagy and mitophagy are initiated when the adaptor NDP52 recruits the ULK1 complex to autophagic cargo. Hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS) was used to map the membrane and NDP52 binding sites of the ULK1 complex to unique regions of the coiled coil of the FIP200 subunit. Electron microscopy of the full-length ULK1 complex shows that the FIP200 coiled coil projects away from the crescent-shaped FIP200 N-terminal domain dimer. NDP52 allosterically stimulates membrane-binding by FIP200 and the ULK1 complex by promoting a more dynamic conformation of the membrane-binding portion of the FIP200 coiled coil. Giant unilamellar vesicle (GUV) reconstitution confirmed that membrane recruitment by the ULK1 complex is triggered by NDP52 engagement. These data reveal how the allosteric linkage between NDP52 and the ULK1 complex could drive the first membrane recruitment event of phagophore biogenesis in xenophagy and mitophagy.

    in eLife on August 10, 2020 12:00 AM.

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    Discovery of surrogate agonists for visceral fat Treg cells that modulate metabolic indices in vivo

    T regulatory (Treg) cells play vital roles in modulating immunity and tissue homeostasis. Their actions depend on TCR recognition of peptide-MHC molecules; yet the degree of peptide specificity of Treg-cell function, and whether Treg ligands can be used to manipulate Treg cell biology are unknown. Here, we developed an Ab-peptide library that enabled unbiased screening of peptides recognized by a bona fide murine Treg cell clone isolated from the visceral adipose tissue (VAT), and identified surrogate agonist peptides, with differing affinities and signaling potencies. The VAT-Treg cells expanded in vivo by one of the surrogate agonists preserved the typical VAT-Treg transcriptional programs. Immunization with this surrogate, especially when coupled with blockade of TNFa signaling, expanded VAT-Treg cells, resulting in protection from inflammation and improved metabolic indices, including promotion of insulin sensitivity. These studies suggest that antigen-specific targeting of VAT-localized Treg cells could eventually be a strategy for improving metabolic disease.

    in eLife on August 10, 2020 12:00 AM.

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    Cryo-EM structure of VASH1-SVBP bound to microtubules

    The dynamic tyrosination-detyrosination cycle of α-tubulin regulates microtubule functions. Perturbation of this cycle impairs mitosis, neural physiology, and cardiomyocyte contraction. The carboxypeptidases vasohibins 1 and 2 (VASH1 and VASH2), in complex with the small vasohibin-binding protein (SVBP), mediate α-tubulin detyrosination. These enzymes detyrosinate microtubules more efficiently than soluble αβ-tubulin heterodimers. The structural basis for this substrate preference is not understood. Using cryo-electron microscopy (cryo-EM), we have determined the structure of human VASH1-SVBP bound to microtubules. The acidic C-terminal tail of α-tubulin binds to a positively charged groove near the active site of VASH1. VASH1 forms multiple additional contacts with the globular domain of α-tubulin, including contacts with a second α-tubulin in an adjacent protofilament. Simultaneous engagement of two protofilaments by VASH1 can only occur within the microtubule lattice, but not with free αβ heterodimers. These lattice-specific interactions enable preferential detyrosination of microtubules by VASH1.

    in eLife on August 10, 2020 12:00 AM.

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    The role of the NMD factor UPF3B in olfactory sensory neurons

    The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of anti-microbial genes in OSNs, and promotes the selection of specific olfactory receptor (Olfr) genes for expression in mature OSNs (mOSNs). RNA-seq and Ribotag analyses identified classes of mRNAs expressed and translated at different levels in WT and Upf3b-null mOSNs. Integrating multiple computational approaches, UPF3B-dependent NMD target transcripts that are candidates to mediate the functions of NMD in mOSNs were identified in vivo. Together, our data provides a valuable resource for the olfactory field and insights into the roles of NMD in vivo.

    in eLife on August 10, 2020 12:00 AM.

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    Population-scale proteome variation in human induced pluripotent stem cells

    Human disease phenotypes are ultimately driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein coding sequences and variants with trans regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution.

    in eLife on August 10, 2020 12:00 AM.

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    Differentiating Drosophila female germ cells initiate Polycomb silencing by regulating PRC2-interacting proteins

    Polycomb silencing represses gene expression and provides a molecular memory of chromatin state that is essential for animal development. We show that Drosophila female germline stem cells (GSCs) provide a powerful system for studying Polycomb silencing. GSCs have a non-canonical distribution of PRC2 activity and lack silenced chromatin, like embryonic progenitors. As GSC daughters differentiate into nurse cells and oocytes, nurse cells silence genes in traditional Polycomb domains and in generally inactive chromatin like embryonic somatic cells. Developmentally controlled expression of two Polycomb repressive complex 2 (PRC2)-interacting proteins, Pcl and Scm, initiate silencing during differentiation. In GSCs, abundant Pcl inhibits PRC2-dependent silencing globally, while in nurse cells Pcl declines and newly-induced Scm concentrates PRC2 activity on traditional Polycomb domains. Our results suggest that PRC2-dependent silencing is developmentally regulated by accessory proteins that either increase the concentration of PRC2 at target sites or inhibit the rate that PRC2 samples chromatin.

    in eLife on August 10, 2020 12:00 AM.

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    A large effective population size for established within-host influenza virus infection

    Strains of the influenza virus form coherent global populations, yet exist at the level of single infections in individual hosts. The relationship between these scales is a critical topic for understanding viral evolution. Here we investigate the within-host relationship between selection and the stochastic effects of genetic drift, estimating an effective population size of infection Ne for influenza infection. Examining whole-genome sequence data describing a chronic case of influenza B in a severely immunocompromised child we infer an Ne of 2.5 x 107 (95% confidence range 1.0 x 107 to 9.0 x 107) suggesting that genetic drift is of minimal importance during an established influenza infection. Our result, supported by data from influenza A infection, suggests that positive selection during within-host infection is primarily limited by the typically short period of infection. Atypically long infections may have a disproportionate influence upon global patterns of viral evolution.

    in eLife on August 10, 2020 12:00 AM.

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    Inhibition of striatonigral autophagy as a link between cannabinoid intoxication and impairment of motor coordination

    The use of cannabis is rapidly expanding worldwide. Thus, innovative studies aimed to identify, understand and potentially reduce cannabis-evoked harms are warranted. Here, we found that Δ9-tetrahydrocannabinol, the psychoactive ingredient of cannabis, disrupts autophagy selectively in the striatum, a brain area that controls motor behavior, both in vitro and in vivo. Boosting autophagy, either pharmacologically (with temsirolimus) or by dietary intervention (with trehalose), rescued the Δ9-tetrahydrocannabinol-induced impairment of motor coordination in mice. The combination of conditional knockout mouse models and viral vector-mediated autophagy-modulating strategies in vivo showed that cannabinoid CB1 receptors located on neurons belonging to the direct (striatonigral) pathway are required for the motor-impairing activity of Δ9-tetrahydrocannabinol by inhibiting local autophagy. Taken together, these findings identify inhibition of autophagy as an unprecedented mechanistic link between cannabinoids and motor performance, and suggest that activators of autophagy might be considered as potential therapeutic tools to treat specific cannabinoid-evoked behavioral alterations.

    in eLife on August 10, 2020 12:00 AM.

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    Genomic architecture and evolutionary antagonism drive allelic expression bias in the social supergene of red fire ants

    Supergene regions maintain alleles of multiple genes in tight linkage through suppressed recombination. Despite their importance in determining complex phenotypes, our empirical understanding of early supergene evolution is limited. Here we focus on the young "social" supergene of fire ants, a powerful system for disentangling the effects of evolutionary antagonism and suppressed recombination. We hypothesize that gene degeneration and social antagonism shaped the evolution of the fire ant supergene, resulting in distinct patterns of gene expression. We test these ideas by identifying allelic differences between supergene variants, characterizing allelic expression across populations, castes and body parts, and contrasting allelic expression biases with differences in expression between social forms. We find strong signatures of gene degeneration and gene-specific dosage compensation. On this background, a small portion of the genes has the signature of adaptive responses to evolutionary antagonism between social forms.

    in eLife on August 10, 2020 12:00 AM.

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    Ecdysone steroid hormone remote controls intestinal stem cell fate decisions via the PPARγ-homolog Eip75B in Drosophila

    Developmental studies revealed fundamental principles on how organ size and function is achieved, but less is known about organ adaptation to new physiological demands. In fruit flies, juvenile hormone (JH) induces intestinal stem cell (ISC) driven absorptive epithelial expansion balancing energy uptake with increased energy demands of pregnancy. Here, we show 20-Hydroxy-Ecdysone (20HE)-signaling controlling organ homeostasis with physiological and pathological implications. Upon mating, 20HE titer in ovaries and hemolymph are increased and act on nearby midgut progenitors inducing Ecdysone-induced-protein-75B (Eip75B). Strikingly, the PPARγ-homologue Eip75B drives ISC daughter cells towards absorptive enterocyte lineage ensuring epithelial growth. To our knowledge, this is the first time a systemic hormone is shown to direct local stem cell fate decisions. Given the protective, but mechanistically unclear role of steroid hormones in female colorectal cancer patients, our findings suggest a tumor-suppressive role for steroidal signaling by promoting postmitotic fate when local signaling is deteriorated.

    in eLife on August 10, 2020 12:00 AM.

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    Geometric models for robust encoding of dynamical information into embryonic patterns

    During development, cells gradually assume specialized fates via changes of transcriptional dynamics, sometimes even within the same developmental stage. For anterior-posterior (AP) patterning in metazoans, it has been suggested that the gradual transition from a dynamic genetic regime to a static one is encoded by different transcriptional modules. In that case, the static regime has an essential role in pattern formation in addition to its maintenance function. In this work, we introduce a geometric approach to study such transition. We exhibit two types of genetic regime transitions, respectively arising through local or global bifurcations. We find that the global bifurcation type is more generic, more robust, and better preserves dynamical information. This could parsimoniously explain common features of metazoan segmentation, such as changes of periods leading to waves of gene expressions, 'speed/frequency-gradient' dynamics, and changes of wave patterns. Geometric approaches appear as possible alternatives to gene regulatory networks to understand development.

    in eLife on August 10, 2020 12:00 AM.

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    Learning steers the ontogeny of an efficient hunting sequence in zebrafish larvae

    Goal-directed behaviours may be poorly coordinated in young animals but, with age and experience, behaviour progressively adapts to efficiently exploit the animal's ecological niche. How experience impinges on the developing neural circuits of behaviour is an open question. We have conducted a detailed study of the effects of experience on the ontogeny of hunting behaviour in larval zebrafish. We report that larvae with prior experience of live prey consume considerably more prey than naive larvae. This is mainly due to increased capture success and a modest increase in hunt rate. We demonstrate that the initial turn to prey and the final capture manoeuvre of the hunting sequence were jointly modified by experience and that modification of these components predicted capture success. Our findings establish an ethologically relevant paradigm in zebrafish for studying how the brain is shaped by experience to drive the ontogeny of efficient behaviour.

    in eLife on August 10, 2020 12:00 AM.

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    Atomic Structures of Amyloid-β Oligomers Illuminate a Neurotoxic Mechanism

    Amyloid-β (Aβ) accumulation in the brain is a cardinal event in Alzheimer’s disease (AD), but the structural basis of Aβ-elicited neurotoxicity is unknown. In a recent paper, Ciudad et al. elucidate the first atomic structures of Aβ oligomers, which reveal how they form lipid-stabilized pores that might disrupt neuronal membranes and ion homeostasis.

    in Trends in Neurosciences: In press on August 10, 2020 12:00 AM.

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    A Neural Habituation Account of the Negative Compatibility Effect

    The Negative Compatibility Effect (NCE) is slower reaction times (RTs) to report the direction of a target arrow that follows a matching prime arrow. The cause has been debated, with some studies indicating perception, while others indicate a response effect. We applied the neural habituation model of Huber and O'Reilly (2003) to the NCE, explaining the varied results as reflecting changes in the timing of events. We developed a novel variant of the NCE task, specifying the perceptual dynamics of orientation priming as measured with threshold accuracy. This revealed a transition from positive to negative priming as a function of prime duration, and a second experiment ruled out response priming. The perceptual dynamics of the neural habituation model were fit to these results and the parameter values were fixed in applying the model to the NCE literature. Application of the model to RTs necessitated a response representation that accumulates response information during the trial. Our results indicate that the NCE reflects rapid perceptual priming and slower response priming. Because the accumulation of response information is slow and does not suffer from habituation, the response factor of the prime is a positive effect (lingering response information). In contrast, because perceptual activation is fast and habituates, the perceptual factor can be positive or negative priming depending on the timing of the display sequence. These factors interact with the post-prime mask, which can prime the alternative direction when the mask is a related mask created by combining arrows pointing in both directions.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Oculomotor Target Selection is Cortically Mediated by Complex Objects

    Successful oculomotor target selection often requires discriminating visual features but it remains contentious whether oculomotor substrates encoding saccade vectors functionally contribute to this process. One possibility is that visual features are discriminated cortically and oculomotor modules select the object with the highest activation in the set of all preprocessed cortical object representations, while an alternative possibility is that oculomotor modules actively discriminate potential targets based on visual features. If the latter view is correct, these modules should not require input from specialized visual cortices encoding the task relevant features. We therefore examined whether the latency of visual onset responses elicited by abrupt distractor onsets is consistent with input from specialized visual cortices by non-invasively measuring human saccade metrics (saccade curvature, endpoint deviations, saccade frequency, error proportion) as a function of distractor processing time for novel, visually complex distractors that had to be discriminated from a target to guide saccades. Visual onset response latencies were ~110 ms, consistent with projections from anterior cortical sites specialized for object processing. Surprisingly, oculomotor visual onset responses encoded features, as we manipulated the visual similarity between targets and distractors and observed an increased visual onset response magnitude and duration when the distractor was highly similar to the target, which was not attributable to an inhibitory processing delay. Visual onset responses were dynamically modulated by executive function, as these responses were anticipatorily extinguished over the time course of the experiment. As expected, the latency of distractor-related inhibition was modulated by the behavioral relevance of the distractor.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Scanned optogenetic control of mammalian somatosensory input to map input-specific behavioral outputs

    Somatosensory stimuli guide and shape behavior, from immediate protective reflexes to longer-term learning and high-order processes related to pain and touch. However, somatosensory inputs are challenging to control in awake mammals due to the diversity and nature of contact stimuli. Application of cutaneous stimuli is currently limited to relatively imprecise methods as well as subjective behavioral measures. The strategy we present here overcomes these difficulties by achieving spatiotemporally precise, remote and dynamic optogenetic stimulation of skin by projecting light to a small defined area in freely-behaving mice. We mapped behavioral responses to specific nociceptive inputs and revealed a sparse code for stimulus intensity: using the first action potential, the number of activated nociceptors governs the timing and magnitude of rapid protective pain-related behavior. The strategy can be used to define specific behavioral repertoires, examine the timing and nature of reflexes, and dissect sensory, motor, cognitive and motivational processes guiding behavior.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    A spiking neural program for sensory-motor control during foraging in flying insects.

    Foraging is a vital behavioral task for living organisms. Behavioral strategies and abstract mathematical models thereof have been described in detail for various species. To explore the link between underlying neural circuits and computational principles we present how a biologically detailed neural circuit model of the insect mushroom body implements sensory processing, learning and motor control. We focus on cast & surge strategies employed by flying insects when foraging within turbulent odor plumes. Using a spike-based plasticity rule the model rapidly learns to associate individual olfactory sensory cues paired with food in a classical conditioning paradigm. We show that, without retraining, the system dynamically recalls memories to detect relevant cues in complex sensory scenes. Accumulation of this sensory evidence on short time scales generates cast & surge motor commands. Our generic systems approach predicts that population sparseness facilitates learning, while temporal sparseness is required for dynamic memory recall and precise behavioral control. Our work successfully combines biological computational principles with spike-based machine learning. It shows how knowledge transfer from static to arbitrary complex dynamic conditions can be achieved by foraging insects and may serve as inspiration for agent-based machine learning.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Unification of Sparse Bayesian Learning Algorithms for Electromagnetic Brain Imaging with the Majorization Minimization Framework

    Methods for electro- or magnetoencephalography (EEG/MEG) based brain source imaging (BSI) using sparse Bayesian learning (SBL) have been demonstrated to achieve excellent performance in situations with low numbers of distinct active sources, such as event-related designs. This paper extends the theory and practice of SBL in three important ways. First, we reformulate three existing SBL algorithms under the majorization-minimization (MM) framework. This unification perspective not only provides a useful theoretical framework for comparing different algorithms in terms of their convergence behavior, but also provides a principled recipe for constructing novel algorithms with specific properties by designing appropriate bounds of the Bayesian marginal likelihood function. Second, building on the MM principle, we propose a novel method called LowSNR-BSI that achieves favorable source reconstruction performance in low signal-to-noise-ratio settings. Third, precise knowledge of the noise level is a crucial requirement for accurate source reconstruction. Here we present a novel principled technique to accurately learn the noise variance from the data either jointly within the source reconstruction procedure or using one of two proposed cross-validation strategies. Empirically, we could show that the monotonous convergence behavior predicted from MM theory is confirmed in numerical experiments. Using simulations, we further demonstrate the advantage of LowSNR-BSI over conventional SBL in low-SNR regimes, and the advantage of learned noise levels over estimates derived from baseline data. To demonstrate the usefulness of our novel approach we show neurophysiologically plausible source reconstructions on averaged auditory evoked potential data.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Dysregulation of the secretory pathway connects Alzheimer's disease genetics to aggregate formation

    A hallmark of amyloid disorders, such as Alzheimer's disease, is aggregation of secreted proteins. However it is largely unclear how the hundreds of secretory pathway proteins contribute to amyloid formation. We developed a systems biology framework that integrates expression data with protein-protein interaction networks to successfully estimate a tissue's fitness for producing specific secreted proteins. Using this framework, we analyzed the fitness of the secretory pathway of various brain regions and cell types for synthesizing the Alzheimer's disease-associated amyloid-precursor protein (APP). While none of the key amyloidogenic pathway components were differentially expressed in AD brain, we found the deposition of A{beta} is associated with repressed expression of the secretory pathway components proximal to APP. Concurrently, we detected systemic up-regulation of the secretory pathway components proximal to {beta}- and {gamma}-secretases in AD brains. Our analyses suggest that perturbations from 3 high confidence AD risk genes cascade through the secretory machinery support network for APP and into the endocytosis pathway. Thus, we present a model where amyloidogenesis is associated with dysregulation of dozens of secretory pathway components supporting APP, which could yield novel therapeutic targets for the treatment of AD.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Adult-born neurons promote cognitive flexibility by improving memory precision and indexing

    The dentate gyrus (DG) of the hippocampus is fundamental for cognitive flexibility and has the extraordinary ability to generate new neurons throughout life. Recent evidence suggested that adult-born neurons differentially modulate input to the DG during the processing of spatial information and novelty. However, how this differential regulation by neurogenesis is translated into different aspects contributing cognitive flexibility is unclear. Here, we increased adult-born neurons by a genetic expansion of neural stem cells and studied their influence during navigational learning. We found that increased neurogenesis improved memory precision, indexing and retention and that each of these gains was associated with a differential activation of specific DG compartments and better separation of memory representations in the DG-CA3 network. Our results highlight the role of adult-born neurons in promoting memory precision in the infrapyramidal and indexing in the suprapyramidal blade of the DG and together contributing to cognitive flexibility.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Predictability in natural images determines V1 firing rates and synchronization: A deep neural network approach

    Feedforward deep neural networks for object recognition are a promising model of visual processing and can accurately predict firing-rate responses along the ventral stream. Yet, these networks have limitations as models of various aspects of cortical processing related to recurrent connectivity, including neuronal synchronization and the integration of sensory inputs with spatio-temporal context. We trained self-supervised, generative neural networks to predict small regions of natural images based on the spatial context (i.e. inpainting). Using these network predictions, we determined the spatial predictability of visual inputs into (macaque) V1 receptive fields (RFs), and distinguished low- from high-level predictability. Spatial predictability strongly modulated V1 activity, with distinct effects on firing rates and synchronization in gamma- (30-80Hz) and beta-bands (18-30Hz). Furthermore, firing rates, but not synchronization, were accurately predicted by a deep neural network for object recognition. Neural networks trained to specifically predict V1 gamma-band synchronization developed large, grating-like RFs in the deepest layer. These findings suggest complementary roles for firing rates and synchronization in self-supervised learning of natural-image statistics.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    A simple Ca2+-imaging approach to neural network analysis in cultured neurons

    Ca2+-imaging is a powerful tool to measure neuronal dynamics and network activity. To monitor network-level changes in cultured neurons, neuronal activity is often evoked by electrical or optogenetic stimulation and assessed using multi-electrode arrays or sophisticated imaging. Although such approaches allow detailed network analyses, multi-electrode arrays lack single-cell precision, whereas optical physiology requires advanced instrumentation. Here we developed a simple, stimulation-free protocol with associated Matlab algorithms that enables scalable analyses of spontaneous network activity in cultured human and mouse neurons. The approach allows analysis of overall networks and single-neuron dynamics, and is amenable to scale-up for screening purposes. We validated the new method by assessing human neurons with a heterozygous conditional deletion of Munc18-1, and mouse neurons with homozygous conditional deletions of neurexins. The approach described here enabled identification of differential changes in the amplitudes and synchronicity of neuronal spikes during network activity in these mutant neurons, demonstrating the utility of the approach. Compared with current imaging platforms, our method is simple, scalable, accessible, and easy to implement. It enables quantification of more detailed parameters than multi-electrode arrays, but does not have the resolution and depth of more sophisticated yet labour-intensive analysis methods, such as patch-clamp electrophysiology. The method reported here is scalable for a rapid direct assessment of neuronal function in culture, and can be applied to both human and mouse neurons. Thus, the method can serve as a basis for phenotypical analysis of mutations and for drug discovery efforts.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Neonatal LPS exposure results in ATP8A2 down-regulation in the prefrontal cortex and depressive-like behaviors in mice through increasing IFN-γ level

    Neonatal lipopolysaccharide (LPS) exposure can lead to depressive-like behaviors in mice through inducing pro-inflammatory cytokines including interferon(IFN)-{gamma}. ATP8A2 is a phospholipid transporter located on the cell membrane. Studies have shown that the decrease in ATP8A2 expression in the prefrontal cortex (PFC) is associated with depressive behavior. Moreover, it has been reported that IFN-{gamma} could reduce ATP8A2 expression in non-neuronal cells. These findings prompted us to hypothesize that neonatal LPS exposure might induce ATP8A2 down-regulation in PFC in mice by increasing the IFN-{gamma} level. Mice pups consisting approximately evenly of both sexes were intraperitoneally injected with 3 doses of LPS (50 g/kg body weight for each dose) on postnatal day (PND5), PND7 and PND9. Here, we first found that PFC ATP8A2 expression decreased significantly and transiently till ten days after neonatal LPS exposure with the lowest level at two days after it. Moreover, a negative correlation of PFC ATP8A2 expression was found with the PFC level of IFN-{gamma}, rather than the other LPS-induced pro-inflammatory cytokines. Using anti-IFN-{gamma} neutralizing mAb, IFN-{gamma} was identified as the key mediator of LPS-induced ATP8A2 down-regulation in PFC in mice. Besides, neutralizing IFN-{gamma} partially but significantly rescued the depressive-like behaviors in adulthood induced by neonatal LPS exposure. In sum, the present study showed that neonatal LPS exposure induced ATP8A2 down-regulation in PFC and depressive-like behaviors in mice through increasing the IFN-{gamma} level.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Anatomical modeling of brain vasculature in two-photon microscopy by generalizable deep learning

    Segmentation of blood vessels from two-photon microscopy (2PM) angiograms of brains has important applications in hemodynamic analysis and disease diagnosis. Here we develop a generalizable deep-learning technique for accurate 2PM vascular segmentation of sizable regions in mouse brains acquired from multiple 2PM setups. In addition, the technique is computationally efficient, making it ideal for large-scale neurovascular analysis. Introduction: Vascular segmentation from 2PM angiograms is usually an important first step in hemodynamic modeling of brain vasculature. Existing state-of-the-art segmentation methods based on deep learning either lack the ability to generalize to data from various imaging systems, or are computationally infeasible for large-scale angiograms. In this work, we present a method which improves upon both these limitations by being generalizable to various imaging systems, and also being able to segment very large-scale angiograms. Methods: We employ a computationally efficient deep learning framework based on a semi-supervised learning strategy, whose effectiveness we demonstrate on experimentally acquired in-vivo angiograms from mouse brains of dimensions up to 808x808x702 micrometers. Results: After training on data from only one 2PM microscope, we perform vascular segmentation on data from another microscope without any network tuning. Our method demonstrates 10x faster computation in terms of voxels-segmented-persecond and 3x larger depth compared to the state-of-the-art. Conclusion: Our work provides a generalizable and computationally efficient anatomical modeling framework for the brain vasculature, which consists of deeplearning based vascular segmentation followed by graphing. It paves the way for future modeling and analysis of hemodynamic response at much greater scales that were inaccessible before.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Probabilistic, entropy-maximizing control of large-scale neural synchronization

    Oscillatory neural activity is dynamically controlled to coordinate perceptual, attentional and cognitive processes. On the macroscopic scale, this control is reflected in the U-shaped deviations of EEG spectral-power dynamics from stochastic dynamics, characterized by disproportionately elevated occurrences of the lowest and highest ranges of power. To understand the mechanisms that generate these low- and high-power states, we fit a simple mathematical model of synchronization of oscillatory activity to human EEG data. The results consistently indicated that the majority (~95%) of synchronization dynamics is controlled by slowly adjusting the probability of synchronization while maintaining maximum entropy within the timescale of a few seconds. This strategy appears to be universal as the results generalized across oscillation frequencies, EEG current sources, and participants (N = 52) whether they rested with their eyes closed, rested with their eyes open in a darkened room, or viewed a silent nature video. Given that precisely coordinated behavior requires tightly controlled oscillatory dynamics, the current results suggest that the large-scale spatial synchronization of oscillatory activity is controlled by the relatively slow, entropy-maximizing adjustments of synchronization probability (demonstrated here) in combination with temporally precise phase adjustments (e.g., phase resetting generated by sensorimotor interactions). Interestingly, we observed a modest but consistent spatial pattern of deviations from the maximum-entropy rule, potentially suggesting that the mid-central-posterior region serves as an "entropy dump" to facilitate the temporally precise control of spectral-power dynamics in the surrounding regions.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    "Supersessioning": A hardware/software system for electrophysiology spanning multiple sessions in marmosets

    We introduce a straightforward, robust method for recording and analyzing spiking activity over timeframes longer than a single session, with primary application to the marmoset (Callithrix jacchus). Although in theory the marmoset's smooth brain allows for broad deployment of powerful tools in primate cortex, in practice marmosets do not typically engage in long experimental sessions akin to rhesus monkeys. This potentially limits their value for detailed, quantitative neurophysiological study. Here we describe chronically-implanted arrays with a 3D arrangement of electrodes yielding stable single and multi- unit responses, and an analytic method for creating "supersessions" combining that array data across multiple experiments. We could match units across different recording sessions over several weeks, demonstrating the feasibility of pooling data over sessions. This could be a key tool for extending the viability of marmosets for dissecting neural computations in primate cortex.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Nonlinear System Identification of Neural Systems from Neurophysiological Signals

    The human nervous system is one of the most complicated systems in nature. The complex nonlinear behaviours have been shown from the single neuron level to the system level. For decades, linear connectivity analysis methods, such as correlation, coherence and Granger causality, have been extensively used to assess the neural connectivities and input-output interconnections in neural systems. Recent studies indicate that these linear methods can only capture a small amount of neural activities and functional relationships, and therefore cannot describe neural behaviours in a precise or complete way. In this review, we highlight recent advances on nonlinear system identification of neural systems, corresponding time and frequency domain analysis, and novel neural connectivity measures based on nonlinear system identification techniques. We argue that nonlinear modelling and analysis are necessary to study neuronal processing and signal transfer in neural systems quantitatively. These approaches can hopefully provide new insights to advance our understanding of neurophysiological mechanisms underlying neural functions. They also have the potential to produce sensitive biomarkers to facilitate the development of precision diagnostic tools for evaluating neurological disorders and the effects of targeted intervention.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    P2X receptors in Aplysia californica: Chemosensory systems, bio-energetic and development

    ATP and its ionotropic P2X receptors are components of one of the most ancient signaling systems. However, little is known about the distribution and function of purinergic transmission in invertebrates. Here, we cloned, expressed, and pharmacologically characterized P2X receptors in the sea slug Aplysia californica, a prominent model in cellular and system neuroscience. We showed that ATP and P2X receptors are essential signaling components within the unique bioenergetic center located in the CNS of Aplysia, also known as the cerebral F-cluster of insulin-containing neurons. Functional P2X receptors were successfully expressed in Xenopus oocytes to characterize their ATP-dependence (EC50 = 306uM), two-phased kinetics, ion selectivity (Na+-dependence), sensitivity to the ATP analog Bz-ATP (~20% compare to ATP) and antagonists (with PPADS as a more potent inhibitor compared to suramin). Next, using RNA-seq, we characterized the expression of P2X receptors across more than a dozen Aplysia peripheral tissues and developmental stages. We showed that P2X receptors are predominantly expressed in chemosensory structures and during early cleavage stages. The localization and pharmacology of P2X receptors in Aplysia highlight the evolutionary conservation of bioenergetic sensors and chemosensory purinergic transmission across animals. This study also provides a foundation to decipher homeostatic mechanisms in development and neuroendocrine systems.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Brain-wide mapping of neural activity mediating collicular-dependent behaviors

    Neuronal cell-types are arranged in brain-wide circuits to guide behavior. In mice, the superior colliculus is comprised of a set of cell-types that each innervate distinct downstream targets. Here we reveal the brain-wide networks downstream of four collicular cell-types by combining functional ultrasound imaging (fUSi) with optogenetics to monitor neural activity at a resolution of ~100 m. Each neuronal group triggered different behaviors, and activated distinct, partially overlapping sets of brain nuclei. This included regions not previously thought to mediate defensive behaviors, e.g. the posterior paralaminar nuclei of the thalamus (PPnT), that we show to play a role in suppressing habituation. Electrophysiological recordings support the fUSi findings and show that neurons in the downstream nuclei preferentially respond to innately threatening visual stimuli. This work provides insight into the functional organization of the networks governing defensive behaviors and demonstrates an experimental approach to explore the whole-brain neuronal activity downstream of targeted cell-types

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Input-output signal processing plasticity of vagal motorneurons in response to cardiac ischemic injury

    Vagal stimulation is emerging as the next frontier in bioelectronic medicine to modulate peripheral organ health and treat disease. The neuronal molecular phenotypes in the dorsal motor nucleus of the vagus (DMV) remain largely unexplored, limiting the potential for harnessing the DMV plasticity for therapeutic interventions. We developed a mesoscale single cell transcriptomics data from hundreds of DMV neurons under homeostasis and following physiological perturbations. Our results revealed that homeostatic DMV neuronal states can be organized into distinguishable input-output signal processing units. Remote ischemic preconditioning induced a distinctive shift in the neuronal states towards diminishing the role of inhibitory inputs, with concomitant changes in regulatory microRNAs miR-218a and miR-495. Chronic cardiac ischemic injury resulted in a dramatic shift in DMV neuronal states suggestive of enhanced neurosecretory function. We propose a DMV molecular network mechanism that integrates combinatorial neurotransmitter inputs from multiple brain regions and humoral signals to modulate cardiac health.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Alcohol boosts pheromone production in male flies and makes them sexier

    The attraction of Drosophila melanogaster towards byproducts of alcoholic fermentation, especially ethanol, has been extensively studied. However, the adaptive value of this behavior has not been elucidated. Previous studies have suggested anthropomorphic interpretations of D. melanogaster behavior towards alcohols. Here, we instead assert that there exists a simple yet vital biological rationale for alcohol contact and consumption by these insects. We show that exposure to alcohols, especially methanol, results in an immediate amplification of fatty acid ester pheromone levels, which in turn elevates the probability that a male will successfully compete for a female during courtship. We proceed to identify three types of olfactory sensory neurons that detect ethanol and methanol. Moreover, we trace the ensuing neural circuits and reveal their role in controlling both attraction and aversion, where valence is balanced around mating status. Based on our results, we deduce that male flies associate with sources of alcohol as a biological imperative related to reproduction, and we provide an assessment of how and why D. melanogaster is associated with alcohol using a sound ecological and natural history approach to this previously enigmatic biological phenomenon.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Independent respiratory and locomotor rhythms in running mice

    Examining whether and how the rhythms of limb and breathing movements interact is highly informative about the mechanistic origin of hyperpnoea to exercise. However, studies have failed to reveal regularities. In particular, whether breathing frequency is inherently proportional to limb velocity and/or imposed by a synchronization of breaths to strides is still unclear. Here, we examined the specifications of respiratory changes during running in mice, the premier model for investigating, in a standardized manner, complex integrative tasks including adaptive breathing. We show that respiratory rate increases during running to a fixed and stable value, irrespective of trotting velocities and of inclination. Yet, respiratory rate was further enhanced during gallop. We also demonstrate the absence of temporal coordination of breaths to strides at any speed, intensity or gait. Our work thus highlights a hardwired mechanism that sets respiratory frequency independently of limb movements but in relation with the engaged locomotor program.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Zbtb16 regulates social cognitive behaviors and neocortical development.

    Recent genetic studies have underscored the pleiotropic effects of single genes to multiple cognitive disorders. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how the function of ZBTB16 is related to ASD or SCZ remains unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of ZBTB16 in ASD and SCZ.

    in bioRxiv: Neuroscience on August 10, 2020 12:00 AM.

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    Unsupervised multi-domain multimodal image-to-image translation with explicit domain-constrained disentanglement

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Weihao Xia, Yujiu Yang, Jing-Hao Xue

    in Neural Networks on August 09, 2020 05:49 PM.

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    Exponential synchronization of stochastic delayed memristive neural networks via a novel hybrid control

    Publication date: Available online 4 August 2020

    Source: Neural Networks

    Author(s): Nijing Yang, Yongbin Yu, Shouming Zhong, Xiangxiang Wang, Kaibo Shi, Jingye Cai

    in Neural Networks on August 09, 2020 05:49 PM.

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    Memristor-based LSTM network with in situ training and its applications

    Publication date: Available online 4 August 2020

    Source: Neural Networks

    Author(s): Xiaoyang Liu, Zhigang Zeng, Donald C. Wunsch II

    in Neural Networks on August 09, 2020 05:49 PM.

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    MetalGAN: Multi-domain label-less image synthesis using cGANs and meta-learning

    Publication date: Available online 1 August 2020

    Source: Neural Networks

    Author(s): Tomaso Fontanini, Eleonora Iotti, Luca Donati, Andrea Prati

    in Neural Networks on August 09, 2020 05:49 PM.

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    Deep learning on image denoising: An overview

    Publication date: Available online 6 August 2020

    Source: Neural Networks

    Author(s): Chunwei Tian, Lunke Fei, Wenxian Zheng, Yong Xu, Wangmeng Zuo, Chia-Wen Lin

    in Neural Networks on August 09, 2020 05:49 PM.

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    Leveraging maximum entropy and correlation on latent factors for learning representations

    Publication date: Available online 5 August 2020

    Source: Neural Networks

    Author(s): Zhicheng He, Jie Liu, Kai Dang, Fuzhen Zhuang, Yalou Huang

    in Neural Networks on August 09, 2020 05:49 PM.

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    Improved object recognition using neural networks trained to mimic the brain’s statistical properties

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Callie Federer, Haoyan Xu, Alona Fyshe, Joel Zylberberg

    in Neural Networks on August 09, 2020 05:49 PM.

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    Theory of deep convolutional neural networks II: Spherical analysis

    Publication date: Available online 6 August 2020

    Source: Neural Networks

    Author(s): Zhiying Fang, Han Feng, Shuo Huang, Ding-Xuan Zhou

    in Neural Networks on August 09, 2020 05:49 PM.

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    ASSAF: Advanced and Slim StegAnalysis Detection Framework for JPEG images based on deep convolutional denoising autoencoder and Siamese networks

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Assaf Cohen, Aviad Cohen, Nir Nissim

    in Neural Networks on August 09, 2020 05:49 PM.

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    Hungarian layer: A novel interpretable neural layer for paraphrase identification

    Publication date: Available online 5 August 2020

    Source: Neural Networks

    Author(s): Han Xiao

    in Neural Networks on August 09, 2020 05:49 PM.

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    Twin minimax probability machine for pattern classification

    Publication date: Available online 1 August 2020

    Source: Neural Networks

    Author(s): Liming Yang, Yakun Wen, Min Zhang, Xue Wang

    in Neural Networks on August 09, 2020 05:49 PM.

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    Finite-time stabilization and energy consumption estimation for delayed neural networks with bounded activation function

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Chongyang Chen, Song Zhu, Min Wang, Chunyu Yang, Zhigang Zeng

    in Neural Networks on August 09, 2020 05:49 PM.

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    DANTE: Deep alternations for training neural networks

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Vaibhav B. Sinha, Sneha Kudugunta, Adepu Ravi Sankar, Surya Teja Chavali, Vineeth N. Balasubramanian

    in Neural Networks on August 09, 2020 05:49 PM.

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    Integral reinforcement learning based event-triggered control with input saturation

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Shan Xue, Biao Luo, Derong Liu

    in Neural Networks on August 09, 2020 05:49 PM.

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    Relation-Guided Representation Learning

    Publication date: November 2020

    Source: Neural Networks, Volume 131

    Author(s): Zhao Kang, Xiao Lu, Jian Liang, Kun Bai, Zenglin Xu

    in Neural Networks on August 09, 2020 05:49 PM.

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    Compressing 3DCNNs based on tensor train decomposition

    Publication date: Available online 7 August 2020

    Source: Neural Networks

    Author(s): Dingheng Wang, Guangshe Zhao, Guoqi Li, Lei Deng, Yang Wu

    in Neural Networks on August 09, 2020 05:49 PM.

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    Postnatal neuronal migration in health and disease

    Publication date: February 2021

    Source: Current Opinion in Neurobiology, Volume 66

    Author(s): Chikako Nakajima, Masato Sawada, Kazunobu Sawamoto

    in Current Opinion in Neurobiology on August 09, 2020 05:49 PM.

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    Posterior parietal cortex contributions to cross-modal brain plasticity upon sensory loss

    Publication date: April 2021

    Source: Current Opinion in Neurobiology, Volume 67

    Author(s): Sara RJ Gilissen, Lutgarde Arckens

    in Current Opinion in Neurobiology on August 09, 2020 05:49 PM.

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    Optical interrogation of multi-scale neuronal plasticity underlying behavioral learning

    Publication date: April 2021

    Source: Current Opinion in Neurobiology, Volume 67

    Author(s): Shinichiro Tsutsumi, Akiko Hayashi-Takagi

    in Current Opinion in Neurobiology on August 09, 2020 05:49 PM.

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    Symptomatic Hydrocephalus with Normal Cerebrospinal Pressure and Alzheimer’s Disease

    in Annals of Neurology on August 09, 2020 05:42 PM.

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    Intraspinal gouty tophus

    in Annals of Neurology on August 09, 2020 05:20 PM.

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    Role of peroxisome proliferator‐activated receptors in stroke prevention and therapy—The best is yet to come?

    Abstract

    Role of peroxisome proliferator‐activated receptors (PPARs) in the pathophysiology of stroke and protective effects of PPAR ligands have been widely investigated in the last 20 years. Activation of all three PPAR isoforms, but especially PPAR‐γ, was documented to limit postischemic injury in the numerous in vivo , as well as in in vitro studies. PPARs have been demonstrated to act on multiple mechanisms and were shown to activate multiple protective pathways related to inflammation, apoptosis, BBB protection, neurogenesis, and oxidative stress. The aim of this review was to summarize two decades of PPAR research in stroke with emphasis on in vivo animal studies. We focus on each PPAR receptor separately and detail their implication in stroke. This review also discusses recent clinical efforts in the field and the epidemiological data with regard to role of PPAR polymorphisms in susceptibility to stroke, and tries to draw conclusions and describe future perspectives.

    in Journal of Neuroscience Research on August 09, 2020 11:08 AM.

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    Slow‐sustained delivery of naloxone reduces typical naloxone‐induced precipitated opioid withdrawal effects in male morphine‐dependent mice

    Slow‐sustained delivery of naloxone reduces typical naloxone‐induced precipitated opioid withdrawal effects in male morphine‐dependent mice

    Morphine‐dependent mice treated with unmodified naloxone exhibit precipitated opioid withdrawal (POW) behaviors. POW behaviors observed in morphine‐dependent mice treated with covalent naloxone nanoparticles (Nal‐c NPs) are minimal to none.


    Abstract

    Thousands of individuals die each year from opioid‐related overdoses. While naloxone (Narcan®) is currently the most widely employed treatment to reverse opioid toxicity, high or repeated doses of this antidote often lead to precipitated opioid withdrawal (POW). We hypothesized that a slow linear release of naloxone from a nanoparticle would induce fewer POW symptoms compared to high‐dose free naloxone. First, we measured the acute impact of covalent naloxone nanoparticles (Nal‐c NPs) on morphine‐induced antinociception in the hotplate test. We found that Nal‐c NP treatment blocked the antinociceptive effect of morphine within 15 min of administration. Next, we tested the impact of Nal‐c NPs on POW symptoms in male morphine‐dependent mice. To induce morphine dependence, mice were treated with 5 mg/kg morphine (or saline) twice‐daily for six consecutive days. On day 7 mice received 5 mg/kg morphine (or saline) injections 2 hr prior to receiving treatment of either unmodified free naloxone, a high or low dose of Nal‐c NP, empty nanoparticle (c NP‐empty), or saline. Behavior was analyzed for 0–6 hr followed by 24 and 48 hr time points after treatment. As expected, free naloxone induced a significant increase in POW behavior in morphine‐dependent mice compared to saline‐treated mice upon free naloxone administration. In comparison, reduced POW behavior was observed with both doses of Nal‐c NP. Side effects of Nal‐c NP on locomotion and fecal boli production were measured and no significant side‐effects were observed. Overall, our data show that sustained release of naloxone from a covalent nanoparticle does not induce severe POW symptoms in morphine‐dependent mice.

    in Journal of Neuroscience Research on August 08, 2020 04:55 PM.

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    Prior Dual Antiplatelet Therapy and Thrombolysis in Acute Stroke

    in Annals of Neurology on August 08, 2020 03:34 PM.

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    Presynaptic inhibition rapidly stabilises recurrent excitation in the face of plasticity

    by Laura Bella Naumann, Henning Sprekeler

    Hebbian plasticity, a mechanism believed to be the substrate of learning and memory, detects and further enhances correlated neural activity. Because this constitutes an unstable positive feedback loop, it requires additional homeostatic control. Computational work suggests that in recurrent networks, the homeostatic mechanisms observed in experiments are too slow to compensate instabilities arising from Hebbian plasticity and need to be complemented by rapid compensatory processes. We suggest presynaptic inhibition as a candidate that rapidly provides stability by compensating recurrent excitation induced by Hebbian changes. Presynaptic inhibition is mediated by presynaptic GABA receptors that effectively and reversibly attenuate transmitter release. Activation of these receptors can be triggered by excess network activity, hence providing a stabilising negative feedback loop that weakens recurrent interactions on sub-second timescales. We study the stabilising effect of presynaptic inhibition in a recurrent networks, in which presynaptic inhibition is implemented as a multiplicative reduction of recurrent synaptic weights in response to increasing inhibitory activity. We show that networks with presynaptic inhibition display a gradual increase of firing rates with growing excitatory weights, in contrast to traditional excitatory-inhibitory networks. This alleviates the positive feedback loop between Hebbian plasticity and network activity and thereby allows homeostasis to act on timescales similar to those observed in experiments. Our results generalise to spiking networks with a biophysically more detailed implementation of the presynaptic inhibition mechanism. In conclusion, presynaptic inhibition provides a powerful compensatory mechanism that rapidly reduces effective recurrent interactions and thereby stabilises Hebbian learning.

    in PLoS Computational Biology on August 07, 2020 09:00 PM.

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    A machine learning and network framework to discover new indications for small molecules

    by Coryandar Gilvary, Jamal Elkhader, Neel Madhukar, Claire Henchcliffe, Marcus D. Goncalves, Olivier Elemento

    Drug repurposing, identifying novel indications for drugs, bypasses common drug development pitfalls to ultimately deliver therapies to patients faster. However, most repurposing discoveries have been led by anecdotal observations (e.g. Viagra) or experimental-based repurposing screens, which are costly, time-consuming, and imprecise. Recently, more systematic computational approaches have been proposed, however these rely on utilizing the information from the diseases a drug is already approved to treat. This inherently limits the algorithms, making them unusable for investigational molecules. Here, we present a computational approach to drug repurposing, CATNIP, that requires only biological and chemical information of a molecule. CATNIP is trained with 2,576 diverse small molecules and uses 16 different drug similarity features, such as structural, target, or pathway based similarity. This model obtains significant predictive power (AUC = 0.841). Using our model, we created a repurposing network to identify broad scale repurposing opportunities between drug types. By exploiting this network, we identified literature-supported repurposing candidates, such as the use of systemic hormonal preparations for the treatment of respiratory illnesses. Furthermore, we demonstrated that we can use our approach to identify novel uses for defined drug classes. We found that adrenergic uptake inhibitors, specifically amitriptyline and trimipramine, could be potential therapies for Parkinson’s disease. Additionally, using CATNIP, we predicted the kinase inhibitor, vandetanib, as a possible treatment for Type 2 Diabetes. Overall, this systematic approach to drug repurposing lays the groundwork to streamline future drug development efforts.

    in PLoS Computational Biology on August 07, 2020 09:00 PM.

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    Achieving stable dynamics in neural circuits

    by Leo Kozachkov, Mikael Lundqvist, Jean-Jacques Slotine, Earl K. Miller

    The brain consists of many interconnected networks with time-varying, partially autonomous activity. There are multiple sources of noise and variation yet activity has to eventually converge to a stable, reproducible state (or sequence of states) for its computations to make sense. We approached this problem from a control-theory perspective by applying contraction analysis to recurrent neural networks. This allowed us to find mechanisms for achieving stability in multiple connected networks with biologically realistic dynamics, including synaptic plasticity and time-varying inputs. These mechanisms included inhibitory Hebbian plasticity, excitatory anti-Hebbian plasticity, synaptic sparsity and excitatory-inhibitory balance. Our findings shed light on how stable computations might be achieved despite biological complexity. Crucially, our analysis is not limited to analyzing the stability of fixed geometric objects in state space (e.g points, lines, planes), but rather the stability of state trajectories which may be complex and time-varying.

    in PLoS Computational Biology on August 07, 2020 09:00 PM.

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    Multimodal neuroimaging in anorexia nervosa

    Abstract

    Anorexia nervosa (AN) is a severe and complex psychiatric disorder characterized by intense fear about weight gain and finalized to food‐related control behaviors. Growing interest has been demonstrated about neurobiological processes subtend to AN physiopathology. The present review aimed to collect neurostructural and neurofunctional available data from 2010 to 2019. Results have been organized according to the neuroimaging technique employed, also including a specific section on electroencephalographic results, mostly neglected in previous reviews. Diffuse cerebral vulnerability has been demonstrated and the contribution of several structures has been identified. Insula, cingulate cortex, parietal and frontal areas are primarily involved both by structural and functional perspectives. Moreover, consistent alterations in white matter integrity and brain electrical activity have been reported. Neuroimaging findings give a substantial contribution to AN pathophysiological description, also in order to understand altered but reversible processes in the passage from acute illness phase to disorder's remission, useful also for defining therapy.

    in Journal of Neuroscience Research on August 07, 2020 04:57 PM.

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    Pain‐induced alterations in the dynorphinergic system within the mesocorticolimbic pathway: Implication for alcohol addiction

    Abstract

    Latest studies have revealed that pain negatively impacts on reward processing and motivation leading to negative affective states and stress. These states not only reduce quality of life of patients by increasing the appearance of psychiatric comorbidities, but also have an important impact on vulnerability to drug abuse, including alcohol. In fact, clinical, epidemiological but also preclinical studies have revealed that the presence of pain is closely related to alcohol use disorders (AUDs). All this evidence suggests that pain is a factor that increases the risk of suffering AUD, predicting heavy drinking behavior and relapse drinking in those patients with a previous history of AUD. The negative consequences of chronic pain and its impact on stress and AUD are likely mediated by alterations in the central nervous system, especially in the stress and reward systems. Therefore, pain and stress impact on dopaminergic mesolimbic pathway can lead to an increase in drug abuse liability. In this mini review we analyze the interaction between pain, stress, and alcohol addiction, and how dynamic changes in the kappa opioid system might play a crucial role in the development of compulsive alcohol drinking in chronic pain patients.

    in Journal of Neuroscience Research on August 07, 2020 04:56 PM.

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    Pain management with opioids in adults

    Abstract

    Given the ubiquitous nature of opioids in the treatment of pain, it is an interesting paradox that this class of medications also represents one of the least understood components of clinical pain medicine. For many years, there has been intense interest in the mechanisms of opioid activity, but this has not resulted in a corresponding increase in convincing clinical data. This review focuses primarily on the evidence surrounding the long‐term use of opioids in chronic pain, but discussions of this research are often conflated with the very different data governing acute and cancer‐related pain, where evidence of efficacy is clearer. It is therefore important to clarify the evidence‐based indications for opioid therapy. There remains very little evidence that opioids improve function or quality of life beyond 3 months in people with chronic pain conditions. In all three patient populations, the development of tolerance, dependence, hyperalgesia and withdrawal are key phenomena that affect the patient experience, and in particular the decision to remain on opioids in the long term. This is a common thread that connects the opioid literature in all of these spheres, and justifies the burgeoning interest in these phenomena in the basic science literature. There is an urgent need to address these negative consequences of opioid use, in order to maximize the therapeutic benefit that opioids can offer.

    in Journal of Neuroscience Research on August 07, 2020 04:56 PM.

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    Optic Disc Classification by Deep Learning versus Expert Neuro‐Ophthalmologists

    Objective

    To compare the diagnostic performance of an artificial intelligence deep learning system with that of expert neuro‐ophthalmologists in classifying optic disc appearance.

    Methods

    The deep learning system was previously trained and validated on 14,341 ocular fundus photographs from 19 international centers. The performance of the system was evaluated on 800 new fundus photographs (400 normal optic discs, 201 papilledema [disc edema from elevated intracranial pressure], 199 other optic disc abnormalities) and compared with that of 2 expert neuro‐ophthalmologists who independently reviewed the same randomly presented images without clinical information. Area under the receiver operating characteristic curve, accuracy, sensitivity, and specificity were calculated.

    Results

    The system correctly classified 678 of 800 (84.7%) photographs, compared with 675 of 800 (84.4%) for Expert 1 and 641 of 800 (80.1%) for Expert 2. The system yielded areas under the receiver operating characteristic curve of 0.97 (95% confidence interval [CI] = 0.96–0.98), 0.96 (95% CI = 0.94–0.97), and 0.89 (95% CI = 0.87–0.92) for the detection of normal discs, papilledema, and other disc abnormalities, respectively. The accuracy, sensitivity, and specificity of the system's classification of optic discs were similar to or better than the 2 experts. Intergrader agreement at the eye level was 0.71 (95% CI = 0.67–0.76) between Expert 1 and Expert 2, 0.72 (95% CI = 0.68–0.76) between the system and Expert 1, and 0.65 (95% CI = 0.61–0.70) between the system and Expert 2.

    Interpretation

    The performance of this deep learning system at classifying optic disc abnormalities was at least as good as 2 expert neuro‐ophthalmologists. Future prospective studies are needed to validate this system as a diagnostic aid in relevant clinical settings. ANN NEUROL 2020

    in Annals of Neurology on August 07, 2020 02:19 PM.

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    Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

    Objective

    Calcitonin gene–related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP‐mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.

    Methods

    Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1–1mg/kg) or rimegepant (single doses of 10–100mg/kg) versus vehicle. We also determined their potency on CGRP‐induced relaxations in mouse and human vessels, in vitro.

    Results

    Olcegepant (1mg/kg, single dose) increased infarct risk after 12‐ to 20‐minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p  < 0.022), and doubled infarct volumes (p  < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p  = 0.008) after 60‐minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20‐minute ischemia (p  = 0.03); 100mg/kg caused 75% mortality after 60‐minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30‐minute occlusion (1.6‐fold, p  = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10‐fold more potent than rimegepant on CGRP‐induced relaxations in mouse aorta.

    Interpretation

    Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020

    in Annals of Neurology on August 07, 2020 02:15 PM.

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    CRISPR Rube Goldberg machines for visualizing cell lineage

    Nature Neuroscience, Published online: 07 August 2020; doi:10.1038/s41593-020-0694-7

    A new technique developed by Garcia-Marques and colleagues uses CRISPR–Cas9 editing to activate an ordered sequence of fluorescent markers in stem cells and their progeny. These tools represent a new way to probe the spatial and temporal patterns of cell lineage progression.

    in Nature Neuroscience on August 07, 2020 12:00 AM.

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    Genomic and enzymatic evidence of acetogenesis by anaerobic methanotrophic archaea

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17860-8

    Ocean cold seeps are poorly understood relative to related systems like hydrothermal vents. Here the authors use high pressure bioreactors and microbial communities from a cold seep mud volcano and find a previously missing step of methane conversion to acetate that likely fuels heterotrophic communities.

    in Nature Communications on August 07, 2020 12:00 AM.

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    Artificial van der Waals hybrid synapse and its application to acoustic pattern recognition

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17849-3

    Designing high-performance and energy efficient neural network hardware remains a challenge. Here, the authors develop a van der Waals hybrid synaptic device that features linear and symmetric conductance-update characteristics and demonstrate the feasibility for hardware neural network performing acoustic pattern recognition.

    in Nature Communications on August 07, 2020 12:00 AM.

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    Reply to “Acid inhibitors and allergy: comorbidity, causation and confusion”

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17830-0

    Reply to “Acid inhibitors and allergy: comorbidity, causation and confusion”

    in Nature Communications on August 07, 2020 12:00 AM.

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    Machine learning-based prediction of acute coronary syndrome using only the pre-hospital 12-lead electrocardiogram

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17804-2

    Diagnosing a heart attack requires excessive testing and prolonged observation, which frequently requires hospital admission. Here the authors report a machine learning-based system based exclusively on ECG data that can help clinicians identify 37% more heart attacks during initial screening.

    in Nature Communications on August 07, 2020 12:00 AM.

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    A nature-inspired hydrogen-bonded supramolecular complex for selective copper ion removal from water

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17757-6

    Heavy metals and metalloids pose major threats to health and environmental ecosystems, thus systems for low-cost remediation are needed. Here the authors report the scalable design of a hydrogen-bonded organic–inorganic framework for selective removal of trace heavy metal ions from water.

    in Nature Communications on August 07, 2020 12:00 AM.

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    Revealing the role of crystal orientation of protective layers for stable zinc anode

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17752-x

    Zinc affinity plays a key role in the zinc plating and stripping processes but its internal mechanism is still unclear. Here, the authors report a protective layer with controllable zinc affinity by adjusting the crystal orientation to suppress the dendrite growth on the zinc anode interface.

    in Nature Communications on August 07, 2020 12:00 AM.

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    Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17740-1

    To define and distinguish fibroblasts from vascular mural cells have remained challenging. Here, using single-cell RNA sequencing and tissue imaging, the authors provide a molecular basis for cell type classification and reveal inter- and intra-organ diversity of these cell types.

    in Nature Communications on August 07, 2020 12:00 AM.

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    Universal growth of ultra-thin III–V semiconductor single crystals

    Nature Communications, Published online: 07 August 2020; doi:10.1038/s41467-020-17693-5

    Here, the authors synthesize a variety of ultra-thin III–V single crystals, ranging from ultra-narrow to wide bandgap semiconductors, through enhancing the interfacial interaction between the III–V crystals and the growth substrates.

    in Nature Communications on August 07, 2020 12:00 AM.

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    Daily briefing: The wildly complicated immune response to COVID-19

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-02356-8

    SARS-CoV-2 seems to interact with the immune system in some unusual ways. Plus: the first cancer tumour seen in a dinosaur and the study that has tracked the survivors of the Hiroshima and Nagasaki atomic bombs for decades.

    in Nature on August 07, 2020 12:00 AM.

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    How researchers overturned US sanctions on a virtual summer school

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-02347-9

    US rules forced an online neuroscience course to block people in Iran from signing up, but the organizers won a last-minute reprieve.

    in Nature on August 07, 2020 12:00 AM.

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    Satellites find penguins by following the poo

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-02346-w

    Images from space bolster the population count, but the birds remain vulnerable to climate change.

    in Nature on August 07, 2020 12:00 AM.

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    Why deforestation and extinctions make pandemics more likely

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-02341-1

    Researchers are redoubling efforts to understand links between biodiversity and emerging diseases — and use that information to predict and stop future outbreaks.

    in Nature on August 07, 2020 12:00 AM.

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    Audio long-read: Pluto’s dark side is overflowing with secrets

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-02327-z

    Images sent back by the New Horizons spacecraft reveal much about this mysterious dwarf planet’s far side and hint at the existence of a subterranean ocean.

    in Nature on August 07, 2020 12:00 AM.

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    Parents’ desire for one boy and one girl pushed trend in family patterns

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-02313-5

    A change in the sex ratio of offspring in the United Kingdom might reflect shifting attitudes about gender.

    in Nature on August 07, 2020 12:00 AM.

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    Coronavirus research updates: For fast and low-cost COVID-19 testing, just spit

    Nature, Published online: 07 August 2020; doi:10.1038/d41586-020-00502-w

    Nature wades through the literature on the new coronavirus — and summarizes key papers as they appear.

    in Nature on August 07, 2020 12:00 AM.

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    Cortical Inactivation Does Not Block Response Enhancement in the Superior Colliculus

    Repetitive visual stimulation is successfully used in a study on the visual evoked potential (VEP) plasticity in the visual system in mammals. Practicing visual tasks or repeated exposure to sensory stimuli can induce neuronal network changes in the cortical circuits and improve the perception of these stimuli. However, little is known about the effect of visual training at the subcortical level. In the present study, we extend the knowledge showing positive results of this training in the rat’s Superior colliculus (SC). In electrophysiological experiments, we showed that a single training session lasting several hours induces a response enhancement both in the primary visual cortex (V1) and in the SC. Further, we tested if collicular responses will be enhanced without V1 input. For this reason, we inactivated the V1 by applying xylocaine solution onto the cortical surface during visual training. Our results revealed that SC’s response enhancement was present even without V1 inputs and showed no difference in amplitude comparing to VEPs enhancement while the V1 was active. These data suggest that the visual system plasticity and facilitation can develop independently but simultaneously in different parts of the visual system.

    in Frontiers in Systems Neuroscience on August 07, 2020 12:00 AM.

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    A Critical Analysis on Characterizing the Meditation Experience Through the Electroencephalogram

    Meditation practices, originated from ancient traditions, have increasingly received attention due to their potential benefits to mental and physical health. The scientific community invests efforts into scrutinizing and quantifying the effects of these practices, especially on the brain. There are methodological challenges in describing the neural correlates of the subjective experience of meditation. We noticed, however, that technical considerations on signal processing also don't follow standardized approaches, which may hinder generalizations. Therefore, in this article, we discuss the usage of the electroencephalogram (EEG) as a tool to study meditation experiences in healthy individuals. We describe the main EEG signal processing techniques and how they have been translated to the meditation field until April 2020. Moreover, we examine in detail the limitations/assumptions of these techniques and highlight some good practices, further discussing how technical specifications may impact the interpretation of the outcomes. By shedding light on technical features, this article contributes to more rigorous approaches to evaluate the construct of meditation.

    in Frontiers in Systems Neuroscience on August 07, 2020 12:00 AM.

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    Accounting for Changing Structure in Functional Network Analysis of TBI Patients

    Over the last 15 years, network analysis approaches based on MR data have allowed a renewed understanding of the relationship between brain function architecture and consciousness. Application of this approach to Disorders of Consciousness (DOC) highlights the relationship between specific aspects of network topology and levels of consciousness. Nonetheless, such applications do not acknowledge that DOC patients present with a dramatic level of heterogeneity in structural connectivity (SC) across groups (e.g., etiology, diagnostic categories) and within individual patients (e.g., over time), which possibly affects the level and quality of functional connectivity (FC) patterns that can be expressed. In addition, it is rarely acknowledged that the most frequently employed outcome metrics in the study of brain connectivity (e.g., degree distribution, inter- or intra-resting state network connectivity, and clustering coefficient) are interrelated and cannot be assumed to be independent of each other. We present empirical data showing that, when the two points above are not taken into consideration with an appropriate analytic model, it can lead to a misinterpretation of the role of each outcome metric in the graph's structure and thus misinterpretation of FC results. We show that failing to account for either SC or the inter-relation between outcome measures can lead to inflated false positives (FP) and/or false negatives (FN) in inter- or intra-resting state network connectivity results (defined, respectively, as a positive or negative result in network connectivity that is present when not accounting for SC and/or outcome measure inter-relation, but becomes not significant when accounting for all variables). Overall, we find that unconscious patients have lower rates of FP and FN for within cortical connectivity, lower rates of FN for cortico-subcortical connectivity, and lower rates of FP for within subcortical connectivity. These lower rates in unconscious patients may reflect differences in their triadic closure and SC metrics, which bias the interpretations of the inter- or intra-resting state network connectivity if the SC metrics and triadic closure are not modeled. We suggest that future studies of functional connectivity in DOC patients (i) incorporate where possible SC metrics and (ii) properly account for the intercorrelated nature of outcome variables.

    in Frontiers in Systems Neuroscience on August 07, 2020 12:00 AM.

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    SNARE-Mediated Exocytosis in Neuronal Development

    The formation of the nervous system involves establishing complex networks of synaptic connections between proper partners. This developmental undertaking requires the rapid expansion of the plasma membrane surface area as neurons grow and polarize, extending axons through the extracellular environment. Critical to the expansion of the plasma membrane and addition of plasma membrane material is exocytic vesicle fusion, a regulated mechanism driven by soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNAREs). Since their discovery, SNAREs have been implicated in several critical neuronal functions involving exocytic fusion in addition to synaptic transmission, including neurite initiation and outgrowth, axon specification, axon extension, and synaptogenesis. Decades of research have uncovered a rich variety of SNARE expression and function. The basis of SNARE-mediated fusion, the opening of a fusion pore, remains an enigmatic event, despite an incredible amount of research, as fusion is not only heterogeneous but also spatially small and temporally fast. Multiple modes of exocytosis have been proposed, with full-vesicle fusion (FFV) and kiss-and-run (KNR) being the best described. Whereas most in vitro work has reconstituted fusion using VAMP-2, SNAP-25, and syntaxin-1; there is much to learn regarding the behaviors of distinct SNARE complexes. In the past few years, robust heterogeneity in the kinetics and fate of the fusion pore that varies by cell type have been uncovered, suggesting a paradigm shift in how the modes of exocytosis are viewed is warranted. Here, we explore both classic and recent work uncovering the variety of SNAREs and their importance in the development of neurons, as well as historical and newly proposed modes of exocytosis, their regulation, and proteins involved in the regulation of fusion kinetics.

    in Frontiers in Molecular Neuroscience on August 07, 2020 12:00 AM.

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    ATP Signaling Controlling Dyskinesia Through P2X7 Receptors

    Dopamine replacement therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) is the only temporary therapy for Parkinson’s disease (PD), but it triggers dyskinesia over time. Since dyskinesia is associated with increased neuronal firing that bolsters purinergic signaling, we now tested whether the selective and blood-brain barrier-permeable P2X7 receptor antagonist Brilliant Blue-G (BBG, 22.5–45 mg/kg ip) attenuated behavioral, neurochemical and biochemical alterations in rats turned hemiparkinsonian upon unilateral striatal injection of 6-hydroxydopamine (6-OHDA) and treated daily with L-DOPA (30 mg/kg by gavage) for 22 days. The blockade of P2X7 receptors decreased L-DOPA-induced dyskinesia and motor incoordination in hemiparkinsonian rats. In parallel, BBG treatment rebalanced the altered dopamine D1 and D2 receptor density and signaling as well as some neuroinflammation-associated parameters in the striatum and substantia nigra. These findings herald a hitherto unrecognized role for purinergic signaling in the etiopathology of dyskinesia and prompt P2X7 receptor antagonists as novel candidate anti-dyskinesia drugs.

    in Frontiers in Molecular Neuroscience on August 07, 2020 12:00 AM.

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    Editorial: Music Training, Neural Plasticity, and Executive Function

    in Frontiers in Integrative Neuroscience on August 07, 2020 12:00 AM.

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    Impact of Brain Surface Boundary Conditions on Electrophysiology and Implications for Electrocorticography

    Volume conduction of electrical potentials in the brain is highly influenced by the material properties and geometry of the tissue and recording devices implanted into the tissue. These effects are very large in EEG due to the volume conduction through the skull and scalp but are often neglected in intracranial electrophysiology. When considering penetrating electrodes deep in the brain, the assumption of an infinite and homogenous medium can be used when the sources are far enough from the brain surface and the electrodes to minimize the boundary effect. When the electrodes are recording from the brain's surface the effect of the boundary cannot be neglected, and the large surface area and commonly used insulating materials in surface electrode arrays may further increase the effect by altering the nature of the boundary in the immediate vicinity of the electrodes. This gives the experimenter some control over the spatial profiles of the potentials by appropriate design of the electrode arrays. We construct a simple three-layer model to describe the effect of material properties and geometry above the brain surface on the electric potentials and conduct empirical experiments to validate this model. A laminar electrode array is used to measure the effect of insulating and relatively conducting layers above the cortical surface by recording evoked potentials alternating between a dried surface and saline covering layer, respectively. Empirically, we find that an insulating boundary amplifies the potentials relative to conductive saline by about a factor of 4, and that the effect is not constrained to potentials that originate near the surface. The model is applied to predict the influence of array design and implantation procedure on the recording amplitude and spatial selectivity of the surface electrode arrays.

    in Frontiers in Neuroscience: Neural Technology on August 07, 2020 12:00 AM.

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    The Importance of Anti-correlations in Graph Theory Based Classification of Autism Spectrum Disorder

    With the release of the multi-site Autism Brain Imaging Data Exchange, many researchers have applied machine learning methods to distinguish between healthy subjects and autistic individuals by using features extracted from resting state functional MRI data. An important part of applying machine learning to this problem is extracting these features. Specifically, whether to include negative correlations between brain region activities as relevant features and how best to define these features. For the second question, the graph theoretical properties of the brain network may provide a reasonable answer. In this study, we investigated the first issue by comparing three different approaches. These included using the positive correlation matrix (comprising only the positive values of the original correlation matrix), the absolute value of the correlation matrix, or the anticorrelation matrix (comprising only the negative correlation values) as the starting point for extracting relevant features using graph theory. We then trained a multi-layer perceptron in a leave-one-site out manner in which the data from a single site was left out as testing data and the model was trained on the data from the other sites. Our results show that on average, using graph features extracted from the anti-correlation matrix led to the highest accuracy and AUC scores. This suggests that anti-correlations should not simply be discarded as they may include useful information that would aid the classification task. We also show that adding the PCA transformation of the original correlation matrix to the feature space leads to an increase in accuracy.

    in Frontiers in Neuroscience: Brain Imaging Methods on August 07, 2020 12:00 AM.

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    Advances in Astrocyte Computational Models: From Metabolic Reconstructions to Multi-omic Approaches

    The growing importance of astrocytes in the field of neuroscience has led to a greater number of computational models devoted to the study of astrocytic functions and their metabolic interactions with neurons. The modeling of these interactions demands a combined understanding of brain physiology and the development of computational frameworks based on genomic-scale reconstructions, system biology, and dynamic models. These computational approaches have helped to highlight the neuroprotective mechanisms triggered by astrocytes and other glial cells, both under normal conditions and during neurodegenerative processes. In the present review, we evaluate some of the most relevant models of astrocyte metabolism, including genome-scale reconstructions and astrocyte-neuron interactions developed in the last few years. Additionally, we discuss novel strategies from the multi-omics perspective and computational models of other glial cell types that will increase our knowledge in brain metabolism and its association with neurodegenerative diseases.

    in Frontiers in Neuroinformatics on August 07, 2020 12:00 AM.

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    A Quantitative EEG Toolbox for the MNI Neuroinformatics Ecosystem: Normative SPM of EEG Source Spectra

    The Tomographic Quantitative Electroencephalography (qEEGt) toolbox is integrated with the Montreal Neurological Institute (MNI) Neuroinformatics Ecosystem as a docker into the Canadian Brain Imaging Research Platform (CBRAIN). qEEGt produces age-corrected normative Statistical Parametric Maps of EEG log source spectra testing compliance to a normative database. This toolbox was developed at the Cuban Neuroscience Center as part of the first wave of the Cuban Human Brain Mapping Project (CHBMP) and has been validated and used in different health systems for several decades. Incorporation into the MNI ecosystem now provides CBRAIN registered users access to its full functionality and is accompanied by a public release of the source code on GitHub and Zenodo repositories. Among other features are the calculation of EEG scalp spectra, and the estimation of their source spectra using the Variable Resolution Electrical Tomography (VARETA) source imaging. Crucially, this is completed by the evaluation of z spectra by means of the built-in age regression equations obtained from the CHBMP database (ages 5–87) to provide normative Statistical Parametric Mapping of EEG log source spectra. Different scalp and source visualization tools are also provided for evaluation of individual subjects prior to further post-processing. Openly releasing this software in the CBRAIN platform will facilitate the use of standardized qEEGt methods in different research and clinical settings. An updated precis of the methods is provided in Appendix I as a reference for the toolbox. qEEGt/CBRAIN is the first installment of instruments developed by the neuroinformatic platform of the Cuba-Canada-China (CCC) project.

    in Frontiers in Neuroinformatics on August 07, 2020 12:00 AM.

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    Sparse Logistic Regression With L1/2 Penalty for Emotion Recognition in Electroencephalography Classification

    Emotion recognition based on electroencephalography (EEG) signals is a current focus in brain-computer interface research. However, the classification of EEG is difficult owing to large amounts of data and high levels of noise. Therefore, it is important to determine how to effectively extract features that include important information. Regularization, one of the effective methods for EEG signal processing, can effectively extract important features from the signal and has potential applications in EEG emotion recognition. Currently, the most popular regularization technique is Lasso (L1) and Ridge Regression (L2). In recent years, researchers have proposed many other regularization terms. In theory, Lq-type regularization has a lower q value, which means that it can be used to find solutions with better sparsity. L1/2 regularization is of Lq type (0 < q < 1) and has been shown to have many attractive properties. In this work, we studied the L1/2 penalty in sparse logistic regression for three-classification EEG emotion recognition, and used a coordinate descent algorithm and a univariate semi-threshold operator to implement L1/2 penalty logistic regression. The experimental results on simulation and real data demonstrate that our proposed method is better than other existing regularization methods. Sparse logistic regression with L1/2 penalty achieves higher classification accuracy than the conventional L1, Ridge Regression, and Elastic Net regularization methods, using fewer but more informative EEG signals. This is very important for high-dimensional small-sample EEG data and can help researchers to reduce computational complexity and improve computational accuracy. Therefore, we propose that sparse logistic regression with the L1/2 penalty is an effective technique for emotion recognition in practical classification problems.

    in Frontiers in Neuroinformatics on August 07, 2020 12:00 AM.

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    What Direct Electrostimulation of the Brain Taught Us About the Human Connectome: A Three-Level Model of Neural Disruption

    For a long time, the relevance of the information provided by direct electrostimulation (DES) for mapping brain functions was debated. Recently, major advances in intraoperative DES for guiding resection of cerebral tumors in awake patients enabled the validation of this method and its increased utilization in basic neurosciences. Indeed, in addition to the cortical stimulation used for many decades in epilepsy surgery, axonal mapping was developed thanks to DES of the white matter tracts, giving original insights into the neural connectivity. Moreover, functional results collected during intrasurgical mapping have been correlated with neuropsychological performances before and after DES-guided resection, and with perioperative neuroimaging data. Thus, it was evidenced that DES offers the unique opportunity to identify both cortical and subcortical structures critical for cerebral functions. Here, the first aim is to propose a three-level model of DES-generated functional disruption, able to explain the behavioral consequences elicited during awake surgery, i.e., (i) DES of an input/output unimodal (e.g., somatosensory or motor) network inducing “positive” responses (as involuntary movement); (ii) DES of a distributed specialized network inducing a within-system disruption leading to specific “negative” disorders (e.g., exclusive language deficit with no other disorders); (iii) DES generating an inter-system disruption leading to more complex behavioral disturbances (e.g., the inability to perform dual-task while each function can be performed separately). Second, in light of this model, original findings gained from DES concerning the human connectome, complementary to those provided by functional neuroimaging (FNI), are reviewed. Further longitudinal multimodal investigations are needed to explore neuroplasticity mechanisms.

    in Frontiers in Human Neuroscience on August 07, 2020 12:00 AM.

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    Neural Field Theory of Evoked Response Potentials With Attentional Gain Dynamics

    A generalized neural field model of large-scale activity in the corticothalamic system is used to predict standard evoked potentials. This model embodies local feedbacks that modulate the gains of neural activity as part of the response to incoming stimuli and thus enables both activity changes and effective connectivity changes to be calculated as parts of a generalized evoked response, and their relative contributions to be determined. The results show that incorporation of gain modulations enables a compact and physically justifiable description of the differences in gain between background-EEG and standard-ERP conditions, with the latter able to be initiated from the background state, rather than requiring distinct parameters as in earlier work. In particular, top-down gains are found to be reduced during an ERP, consistent with recent theoretical suggestions that the role of internal models is diminished in favor of external inputs when the latter change suddenly. The static-gain and modulated-gain system transfer functions are analyzed via control theory in terms of system resonances that were recently shown to implement data filtering whose gain adjustments can be interpreted as attention. These filters are shown to govern early and late features in standard evoked responses and their gain parameters are shown to be dynamically adjusted in a way that implements a form of attention. The results show that dynamically modulated resonant filters responsible for the low-frequency oscillations in an evoked potential response have different parameters than those responsible for low-frequency resting EEG responses, while both responses share similar mid- and high-frequency resonant filters. These results provide a biophysical mechanism by which oscillatory activity in the theta, alpha, and beta frequency ranges of an evoked response are modulated as reflections of attention; notably theta is enhanced and alpha suppressed during the latter parts of the ERP. Furthermore, the model enables the part of the ERP response induced by gain modulations to be estimated and interpreted in terms of attention.

    in Frontiers in Human Neuroscience on August 07, 2020 12:00 AM.

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    Optimal Self-Induced Stochastic Resonance in Multiplex Neural Networks: Electrical vs. Chemical Synapses

    Electrical and chemical synapses shape the dynamics of neural networks, and their functional roles in information processing have been a longstanding question in neurobiology. In this paper, we investigate the role of synapses on the optimization of the phenomenon of self-induced stochastic resonance in a delayed multiplex neural network by using analytical and numerical methods. We consider a two-layer multiplex network in which, at the intra-layer level, neurons are coupled either by electrical synapses or by inhibitory chemical synapses. For each isolated layer, computations indicate that weaker electrical and chemical synaptic couplings are better optimizers of self-induced stochastic resonance. In addition, regardless of the synaptic strengths, shorter electrical synaptic delays are found to be better optimizers of the phenomenon than shorter chemical synaptic delays, while longer chemical synaptic delays are better optimizers than longer electrical synaptic delays; in both cases, the poorer optimizers are, in fact, worst. It is found that electrical, inhibitory, or excitatory chemical multiplexing of the two layers having only electrical synapses at the intra-layer levels can each optimize the phenomenon. Additionally, only excitatory chemical multiplexing of the two layers having only inhibitory chemical synapses at the intra-layer levels can optimize the phenomenon. These results may guide experiments aimed at establishing or confirming to the mechanism of self-induced stochastic resonance in networks of artificial neural circuits as well as in real biological neural networks.

    in Frontiers in Computational Neuroscience on August 07, 2020 12:00 AM.

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    Type 2 Innate Lymphoid Cells Accumulate in the Brain After Hypoxia-Ischemia but Do Not Contribute to the Development of Preterm Brain Injury

    Background

    The immune system of human and mouse neonates is relatively immature. However, innate lymphoid cells (ILCs), commonly divided into the subsets ILC1, ILC2, and ILC3, are already present in the placenta and other fetal compartments and exhibit higher activity than what is seen in adulthood. Recent reports have suggested the potential role of ILCs, especially ILC2s, in spontaneous preterm labor, which is associated with brain damage and subsequent long-term neurodevelopmental deficits. Therefore, we hypothesized that ILCs, and especially ILC2s, play a role in preterm brain injury.

    Methods

    C57Bl/6J mice at postnatal day 6 were subjected to hypoxia-ischemia (HI) insult induced by left carotid artery ligation and subsequent exposure to 10% oxygen in nitrogen. The presence of ILCs and ILC2s in the brain was examined at different time points after HI. The contribution of ILC2s to HI-induced preterm brain damage was explored using a conditionally targeted ILC2-deficient mouse strain (Rorαfl/flIL7rCre), and gray and white-matter injury were evaluated at 7 days post-HI. The inflammatory response in the injured brain was assessed using immunoassays and immunochemistry staining.

    Results

    Significant increases in ILCs and ILC2s were observed at 24 h, 3 days, and 7 days post-HI in the injured brain hemisphere compared with the uninjured hemisphere in wild-type mice. ILC2s in the brain were predominantly located in the meninges of the injured ipsilateral hemispheres after HI but not in the brain parenchyma. Overall, we did not observe changes in cytokine/chemokine levels in the brains of Rorαfl/flIL7rCre mice compared with wild type animals apart from IL-13. Gray and white-matter tissue loss in the brain was not affected after HI in Rorαfl/flIL7rCre mice. Correspondingly, we did not find any differences in reactive microglia and astrocyte numbers in the brain in Rorαfl/flIL7rCre mice compared with wild-type mice following HI insult.

    Conclusion

    After HI, ILCs and ILC2s accumulate in the injured brain hemisphere. However, ILC2s do not contribute to the development of brain damage in this mouse model of preterm brain injury.

    in Frontiers in Cellular Neuroscience on August 07, 2020 12:00 AM.

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    The Molecular Determinants of Mitochondrial Membrane Contact With ER, Lysosomes and Peroxisomes in Neuronal Physiology and Pathology

    Membrane tethering is an important communication method for membrane-packaged organelles. Mitochondria are organelles with a bilayer membrane, and the membrane contact between mitochondria and other organelles is indispensable for maintaining cellular homeostasis. Increased levels of molecular determinants that mediate the membrane contact between mitochondria and other organelles, and their functions, have been revealed in recent years. In this review article, we aim to summarize the findings on the tethering between mitochondria and other organelles in physiological or pathological conditions, and discuss their roles in cellular homeostasis, neural activity, and neurodegenerative diseases.

    in Frontiers in Cellular Neuroscience on August 07, 2020 12:00 AM.

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    Cerebral Arterial Pulsatility and Global White Matter Microstructure Impact Spatial Working Memory in Older Adults With and Without Cardiovascular Risk Factors

    Aging is associated with an increased prevalence of vascular health conditions that are linked to a disruption in the cerebral vasculature and white matter microstructural organization. In people with cardiovascular risk factors, increased cerebral arterial pulsatility is associated with poorer white matter microstructural organization and cognitive functioning. This study examines the relationship among arterial pulsatility, white matter microstructural organization, and cognitive ability in a healthy adult lifespan sample. One hundred and eighty-nine adults were divided into a younger adult (<50 years, n = 97) and older adult (>50 years, n = 92). The latter were further subdivided into two subgroups with (CV+, n = 25) and without (CV−, n = 67) cardiovascular risk factors. Arterial pulsatility was measured using cardiac-gated phase-contrast flow quantification sequence and three indexes of whole-brain white matter microstructural organization [i.e., fractional anisotropy (FA), radial diffusivity (RaD), mean diffusivity (MD)] were derived from diffusion-weighted imaging (DWI). Cognitive ability was assessed using global cognitive functioning (MoCA) and a measure of working memory [sensitivity (d′) from a 2-back task]. Neither the whole group analysis nor the younger adult group showed an association between measures of arterial pulsatility, global white matter microstructural organization, and cognition. In older adults, higher MD and RaD were associated with increased arterial pulsatility and poorer working memory performance. The indirect pathway from arterial pulsatility to working memory performance via both MD and RaD measures was significant in this group. Interestingly, a comparison of CV+ and CV− subgroups showed that this mediating relationship was only evident in older adults with at least one CV risk factor. These findings are consistent with cardiovascular risk factors as underlying arterial, white matter, and cognitive decline in cognitively normal older adults.

    in Frontiers in Ageing Neuroscience on August 07, 2020 12:00 AM.

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    Transmembrane Protein 230 Mediates a Poly(ADP-ribose) Polymerase-1-Linked Apoptosis

    Mutations in transmembrane protein 230 (TMEM230) gene are suggested to be associated with the autosomal dominant Parkinson’s disease (PD) with typical movement disorders and Lewy body pathology. However, the normal functions and the pathological roles of TMEM230 are not clear. In this study, we used TMEM230 isoform II constructs including wild-type (WT) and four reported PD-linked mutation constructs (Y92C, R141L, 184Wext*5, and 184PGext*5). Ectopic expression of WT and PD-linked mutant TMEM230 variants in cultured cells dramatically induced apoptotic cell death compared with that of vector control cells. Mutant TMEM230 caused cell toxicity at an increased severity than WT TMEM230. Moreover, expression of TMEM230 increased mitochondrial reactive oxygen species (ROS) levels, decreased cellular ATP, activated caspase 3/7, and increased poly(ADP-ribose) polymerase-1 (PARP1) cleavage. Treatment with N-acetylcysteine (NAC; an ROS scavenger) or Z-VAD-FMK (a caspase inhibitor) significantly attenuated TMEM230-induced apoptosis in both cultured cells and primary neurons. Our results indicated that TMEM230 mediated a PARP1-linked apoptotic cell death pathway. These findings not only provide the novel insight into the biological roles of TMEM230 in the PARP1-linked pathway but also provide a TMEM230-induced cell death mechanism underlying PD pathogenesis.

    in Frontiers in Ageing Neuroscience on August 07, 2020 12:00 AM.

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    The Two-Step Strategy Could Be Inadequate and Counteracting to Diagnose Prodromal Dementia or Mild Cognitive Impairment

    in Frontiers in Ageing Neuroscience on August 07, 2020 12:00 AM.

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    Structural insights into the Ca2+-dependent gating of the human mitochondrial calcium uniporter

    Mitochondrial Ca2+ uptake is mediated by an inner mitochondrial membrane protein called the mitochondrial calcium uniporter. In humans, the uniporter functions as a holocomplex consisting of MCU, EMRE, MICU1 and MICU2, among which MCU and EMRE form a subcomplex and function as the conductive channel while MICU1 and MICU2 are EF-hand proteins that regulate the channel activity in a Ca2+ dependent manner. Here we present the EM structures of the human mitochondrial calcium uniporter holocomplex (uniplex) in the presence and absence of Ca2+, revealing distinct Ca2+ dependent assembly of the uniplex. Our structural observations suggest that Ca2+ changes the dimerization interaction between MICU1 and MICU2, which in turn determines how the MICU1-MICU2 subcomplex interacts with the MCU-EMRE channel and, consequently, changes the distribution of the uniplex assemblies between the blocked and unblocked states.

    in eLife on August 07, 2020 12:00 AM.

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    Actionable recommendations from trainees to improve science training

    Over the past 20 years, a series of reports written by groups of senior researchers and administrators have recommended changes to improve the training environments for graduate students and postdoctoral researchers in the United States. However, academic institutions and departments have largely failed to implement these recommendations, which has exacerbated the problems faced by these trainees. Here, based on input from trainees at different career stages, we outline seven practical changes that academic institutions and departments can make to improve their training environments.

    in eLife on August 07, 2020 12:00 AM.

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    HetL, HetR and PatS form a reaction-diffusion system to control pattern formation in the cyanobacterium Nostoc PCC 7120

    Local activation and long-range inhibition are mechanisms conserved in self-organizing systems leading to biological patterns. A number of them involve the production by the developing cell of an inhibitory morphogen, but how this cell becomes immune to self-inhibition is rather unknown. Under combined nitrogen starvation, the multicellular cyanobacterium Nostoc PCC 7120 develops nitrogen-fixing heterocysts with a pattern of one heterocyst every 10-12 vegetative cells. Cell differentiation is regulated by HetR which activates the synthesis of its own inhibitory morphogens, diffusion of which establishes the differentiation pattern. Here we show that HetR interacts with HetL at the same interface as PatS, and that this interaction is necessary to suppress inhibition and to differentiate heterocysts. hetL expression is induced under nitrogen-starvation and is activated by HetR, suggesting that HetL provides immunity to the heterocyst. This protective mechanism might be conserved in other differentiating cyanobacteria as HetL homologues are spread across the phylum.

    in eLife on August 07, 2020 12:00 AM.

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    Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling

    Frizzleds (Fzd) are the primary receptors for Wnt morphogens, which are essential regulators of stem cell biology, yet the structural basis of Wnt signaling through Fzd remains poorly understood. Here we report the structure of an unliganded human Fzd5 determined by single-particle cryo-EM at 3.7 Å resolution, with the aid of an antibody chaperone acting as a fiducial marker. We also analyzed the topology of low-resolution XWnt8/Fzd5 complex particles, which revealed extreme flexibility between the Wnt/Fzd-CRD and the Fzd-TM regions. Analysis of Wnt/β-catenin signaling in response to Wnt3a versus a 'surrogate agonist' that cross-links Fzd to LRP6, revealed identical structure-activity relationships. Thus, canonical Wnt/β-catenin signaling appears to be principally reliant on ligand-induced Fzd/LRP6 heterodimerization, versus the allosteric mechanisms seen in structurally analogous class A G protein-coupled receptors, and Smoothened. These findings deepen our mechanistic understanding of Wnt signal transduction, and have implications for harnessing Wnt agonism in regenerative medicine.

    in eLife on August 07, 2020 12:00 AM.

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    Mechanisms underlying genome instability mediated by formation of foldback inversions in Saccharomyces cerevisiae

    Foldback inversions, also called inverted duplications, have been observed in human genetic diseases and cancers. Here we used a Saccharomyces cerevisiae genetic system that generates gross chromosomal rearrangements (GCRs) mediated by foldback inversions combined with whole-genome sequencing to study their formation. Foldback inversions were mediated by formation of single-stranded DNA hairpins. Two types of hairpins were identified: small-loop hairpins that were suppressed by MRE11, SAE2, SLX1, and YKU80 and large-loop hairpins that were suppressed by YEN1, TEL1, SWR1, and MRC1. Analysis of CRISPR/Cas9-induced double strand breaks (DSBs) revealed that long-stem hairpin-forming sequences could form foldback inversions when proximal or distal to the DSB, whereas short-stem hairpin-forming sequences formed foldback inversions when proximal to the DSB. Finally, we found that foldback inversion GCRs were stabilized by secondary rearrangements, mostly mediated by different homologous recombination mechanisms including single-strand annealing; however, POL32-dependent break-induced replication did not appear to be involved forming secondary rearrangements.

    in eLife on August 07, 2020 12:00 AM.

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    Stem cell regionalization during olfactory bulb neurogenesis depends on regulatory interactions between Vax1 and Pax6

    Different subtypes of interneurons, destined for the olfactory bulb, are continuously generated by neural stem cells located in the ventricular and subventricular zones along the lateral forebrain ventricles of mice. Neuronal identity in the olfactory bulb depends on the existence of defined microdomains of pre-determined neural stem cells along the ventricle walls. The molecular mechanisms underlying positional identity of these neural stem cells are poorly understood. Here we show that the transcription factor Vax1 controls the production of two specific neuronal sub-types. First, it is directly necessary to generate Calbindin expressing interneurons from ventro-lateral progenitors. Second, it represses the generation of dopaminergic neurons by dorsolateral progenitors through inhibition of Pax6 expression. We present data indicating that this repression occurs, at least in part, via activation of microRNA miR-7.

    in eLife on August 07, 2020 12:00 AM.

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    Mitochondrial volume fraction and translation duration impact mitochondrial mRNA localization and protein synthesis

    Mitochondria are dynamic organelles that must precisely control their protein composition according to cellular energy demand. Although nuclear-encoded mRNAs can be localized to the mitochondrial surface, the importance of this localization is unclear. As yeast switch to respiratory metabolism, there is an increase in the fraction of the cytoplasm that is mitochondrial. Our data point to this change in mitochondrial volume fraction increasing the localization of certain nuclear-encoded mRNAs to the surface of the mitochondria. We show that mitochondrial mRNA localization is necessary and sufficient to increase protein production to levels required during respiratory growth. Furthermore, we find that ribosome stalling impacts mRNA sensitivity to mitochondrial volume fraction and counterintuitively leads to enhanced protein synthesis by increasing mRNA localization to mitochondria. This points to a mechanism by which cells are able to use translation elongation and the geometric constraints of the cell to fine-tune organelle-specific gene expression through mRNA localization.

    in eLife on August 07, 2020 12:00 AM.

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    Positively selected modifications in the pore of TbAQP2 allow pentamidine to enter Trypanosoma brucei

    Mutations in the Trypanosoma brucei aquaporin AQP2 are associated with resistance to pentamidine and melarsoprol. We show that TbAQP2 but not TbAQP3 was positively selected for increased pore size from a common ancestor aquaporin. We demonstrate that TbAQP2's unique architecture permits pentamidine permeation through its central pore and show how specific mutations in highly conserved motifs affect drug permeation. Introduction of key TbAQP2 amino acids into TbAQP3 renders the latter permeable to pentamidine. Molecular dynamics demonstrates that permeation by dicationic pentamidine is energetically favourable in TbAQP2, driven by the membrane potential, although aquaporins are normally strictly impermeable for ionic species. We also identify the structural determinants that make pentamidine a permeant although most other diamidine drugs are excluded. Our results have wide-ranging implications for optimising antitrypanosomal drugs and averting cross-resistance. Moreover, these new insights in aquaporin permeation may allow the pharmacological exploitation of other members of this ubiquitous gene family.

    in eLife on August 07, 2020 12:00 AM.

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    Dual-Color Single-Cell Imaging of the Suprachiasmatic Nucleus Reveals a Circadian Role in Network Synchrony

    Shan et al. generate a Cre-inducible mouse reporter with green and red luciferases fused to PER2, enabling cell-specific circadian measurements with a dual-color imaging device. Using genetically directed bioluminescence from AVP or VIP neurons in the SCN circadian pacemaker, they unravel distinct functions of the circadian clock in these neuronal subtypes.

    in Neuron: In press on August 07, 2020 12:00 AM.

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    Sex and estrogen receptor β have modest effects on gene expression in the mouse brain posterior cortex

    Introduction: Sex differences in brain cortical function affect cognition, behavior, and susceptibility to neural diseases, but the molecular basis of sexual dimorphism in cortical function is still largely unknown. Estrogen and estrogen receptors (ERs), specifically ER{beta}, the most abundant ER in the cortex, may play a role in determining sex differences in gene expression, which could underlie functional sex differences. However, further investigation is needed to address brain region specificity of the effects of sex and ER{beta} on gene expression. The goal of this study was to investigate sex differences in gene expression in the mouse posterior cortex, where sex differences in transcription have never been examined, and to determine how genetic ablation of ER{beta} affects transcription. Methods: In this study, we performed unbiased transcriptomics on RNA from the posterior cortex of adult wild-type and ER{beta} knockout mice (n=4/sex/genotype). We used unbiased clustering to analyze whole-transcriptome changes between the groups. We also performed differential expression analysis on the data using DESeq2 to identify specific changes in gene expression. Results: We found only 27 significantly differentially expressed genes (DEGs) in wild-type (WT) males vs females, of which 17 were autosomal genes. Interestingly, in ER{beta}KO males vs females all the autosomal DEGs were lost. Gene Ontology analysis of the subset of DEGs with sex differences only in the WT cortex revealed a significant enrichment of genes annotated with the function cation channel activity. Moreover, within each sex we found only a few DEGs in ER{beta}KO vs WT mice (8 and 5 in males and females, respectively). Conclusions: Overall, our results suggest that in the adult mouse posterior cortex there are surprisingly few sex differences in gene expression, and those that exist are mainly related to cation channel activity. Additionally, they indicate that brain region-specific functional effects of ER{beta} may be largely post-transcriptional.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Neural circuit mechanisms of sexual receptivity in Drosophila females

    Choosing a mate is one of the most consequential decisions a female will make during her lifetime. This is particularly true for species in which females either mate repeatedly with the same partner or mate infrequently but use the sperm from a single copulation to fertilize eggs over an extended period of time. Drosophila melanogaster uses the latter strategy. Here, we characterize the neural circuitry that implements mating decisions in the female brain. A female fly signals her mating choice by opening her vaginal plates to allow a courting male to copulate. Vaginal plate opening (VPO) occurs in response to the male courtship song and is dependent upon the female's mating status. We sought to understand how these exteroceptive (song) and interoceptive (mating status) inputs are integrated to control VPO. We show that VPO is triggered by a pair of female-specific descending neurons, the vpoDNs. The vpoDNs receive excitatory input from vpoEN auditory neurons, which are tuned to specific features of the melanogaster song. The song responses of vpoDNs, but not vpoENs, are attenuated upon mating, accounting for the reduced receptivity of mated females. This modulation is mediated by pC1 neurons, which encode the female's mating status and also provide excitatory input to vpoDNs. The vpoDNs thus directly integrate the external and internal signals to control the mating decisions of Drosophila females.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Body mass variations relate to fractionated functional brain hierarchies

    Variations in body mass index (BMI) have been suggested to relate to atypical brain organization, yet connectome-level substrates of BMI and their neurobiological underpinnings remain unclear. Studying 325 healthy young adults, we examined association between functional connectome organization and BMI variations. We capitalized on connectome manifold learning techniques, which represent macroscale functional connectivity patterns along continuous hierarchical axes that dissociate low level and higher order brain systems. We observed an increased differentiation between unimodal and heteromodal association networks in individuals with higher BMI, indicative of an increasingly segregated modular architecture and a disruption in the hierarchical integration of different brain system. Transcriptomic decoding and subsequent gene enrichment analyses identified genes previously implicated in genome-wide associations to BMI and specific cortical, striatal, and cerebellar cell types. These findings provide novel insights for functional connectome substrates of BMI variations in healthy young adults and point to potential molecular associations.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Trace Imbalance in Reinforcement and Punishment Systems Can Mis-reinforce Implicit Choices Leading to Anxiety

    Nobody wants to experience anxiety. However, anxiety may be induced by our own implicit choices that are mis-reinforced by some imbalance in reinforcement learning. Here we focused on obsessive-compulsive disorder (OCD) as a candidate for implicitly learned anxiety. Simulations in the reinforcement learning framework showed that agents implicitly learn to become anxious when the memory trace signal for past actions decays differently for positive and negative prediction errors. In empirical data, we confirmed that OCD patients showed extremely imbalanced traces, which were normalized by serotonin enhancers. We also used fMRI to identify the neural signature of OCD and healthy participants with imbalanced traces. Beyond the spectrum of clinical phenotypes, these behavioral and neural characteristics can be generalized to variations in the healthy population.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Hidden population modes in social brain morphology: Its parts are more than its sum

    The complexity of social interactions is a defining property of the human species. Many social neuroscience experiments have sought to map "perspective taking", "empathy", and other canonical psychological constructs to distinguishable brain circuits. This predominant research paradigm was seldom complemented by bottom-up studies of the unknown sources of variation that add up to measures of social brain structure; perhaps due to a lack of large population datasets. We aimed at a systematic de-construction of social brain morphology into its elementary building blocks in the UK Biobank cohort (n=~10,000). Coherent patterns of structural co-variation were explored within a recent atlas of social brain locations, enabled through translating autoencoder algorithms from deep learning. The artificial neural networks learned rich subnetwork representations that became apparent from social brain variation at population scale. The learned subnetworks carried essential information about the co-dependence configurations between social brain regions, with the nucleus accumbens, medial prefrontal cortex, and temporoparietal junction embedded at the core. Some of the uncovered subnetworks contributed to predicting examined social traits in general, while other subnetworks helped predict specific facets of social functioning, such as feelings of loneliness. Our population-level evidence indicates that hidden subsystems of the social brain underpin interindividual variation in dissociable aspects of social lifestyle.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Acat1 gene KO restores TGN cholesterol deficiency in mutant NPC1 cells and expands mutant Npc1 mouse lifespan

    Niemann-Pick type C (NPC) is a neurological disorder with no cure. NPC proteins deliver cholesterol from endosomes to other compartments including trans-Golgi network (TGN) and endoplasmic reticulum (ER). Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is a resident ER enzyme that converts cholesterol to cholesteryl esters for storage. Here, we report the surprising finding that in a mutant Npc1 mice, Acat1-deficiency delayed the onset of weight loss and declining motor skill, prolonged lifespan, delayed Purkinje neuron death, and improved hepatosplenic pathology. Furthermore, syntaxin 6, a cholesterol-binding t-SNARE normally localized to TGN, is mislocalized in mutant NPC cells. However, upon ACAT1 inhibition this mislocalization is corrected, and increase the level of a few proteins further downstream. Our results imply that ACAT1 inhibition diverts a cholesterol storage pool in a way that replenished the low cholesterol level in NPC-deficient TGN. Taking together, we identify ACAT1 inhibition as a potential therapeutic target for NPC treatment.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Specification of oxytocinergic and vasopressinergic circuits in the developing mouse brain

    Oxytocin (OXT) and arginine vasopressin (AVP) support sex-specific and context-appropriate social behaviors. Although alterations of these systems underlie the appearance of neuropsychiatric disorders, their formation and developmental dynamics remain largely unknown. Using novel brain clearing techniques and 3D imaging, we have reconstructed the specification of oxytocinergic and vasopressinergic circuits in the developing mouse brain with unprecedented cellular resolution. A systematic quantification indicates that OXT and AVP neurons in the hypothalamus display distinctive dynamics, but also share common features as a high cellular plasticity from embryonic to early postnatal stages. Our findings reveal new insights into the appearance and consolidation of neuropeptidergic systems in the developing CNS which is a critical step to unveil brain formation and function.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Suppress me if you can: neurofeedback of the readiness potential

    Voluntary movements are usually preceded by a slow, negative-going brain signal over motor areas, the so-called readiness potential (RP). To date, the exact nature and causal role of the RP in movement preparation have remained heavily debated. One important open question is whether people can exert conscious control over their RP, for example by learning to suppress it. If people were able to initiate spontaneous movements without eliciting an RP, this would challenge the idea that the RP is a necessary stage of the causal chain leading up to a voluntary movement. We tested the ability of participants to control the magnitude of their RP in a neurofeedback experiment. Participants performed self-initiated movements and after every movement they were provided with immediate feedback about the magnitude of their RP. They were asked to find a mental strategy to perform voluntary movements such that the RPs were as small as possible. We found no evidence that participants were able to to willfully modulate or suppress their RPs while still eliciting voluntary movements. This suggests that the RP might be an involuntary component of voluntary action over which people cannot exert conscious control.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy

    Autophagy is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodelling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified superoxide dismutase 1, an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased mTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point towards an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and mTOR-dependent autophagy.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Light stimuli and circadian clock affect neural development in Drosophila melanogaster

    Endogenous clocks enable organisms to adapt their physiology and behavior to daily variation in environmental conditions. Metabolic processes in cyanobacteria to humans are effected by the circadian clock, and its dysregulation causes metabolic disorders. In mouse and Drosophila were shown that the circadian clock directs translation of factors involved in ribosome biogenesis and synchronizes protein synthesis. However, the role of clocks in Drosophila neurogenesis and the potential impact of clock impairment on neural circuit formation and function is less understood. Here we demonstrate that light stimuli or circadian clock causes a defect in neural stem cell growth and proliferation accompanied by reduced nucleolar size. Further, we define that light and clock independently affect the InR/TOR growth regulatory pathway due to the effect on regulators of protein biosynthesis. Altogether, these data suggest that alterations in growth regulatory pathways induced by light and clock are associated with impaired neural development.

    in bioRxiv: Neuroscience on August 07, 2020 12:00 AM.

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    Effect of magnitude and variability of energy of activation in multisite ultrasensitive biochemical processes

    by Leonila Lagunes, Lee Bardwell, German A. Enciso

    Protein activity is often regulated by ligand binding or by post-translational modifications such as phosphorylation. Moreover, proteins that are regulated in this way often contain multiple ligand binding sites or modification sites, which can operate to create an ultrasensitive dose response. Here, we consider the contribution of the individual modification/binding sites to the activation process, and how their individual values affect the ultrasensitive behavior of the overall system. We use a generalized Monod-Wyman-Changeux (MWC) model that allows for variable conformational free energy contributions from distinct sites, and associate a so-called activation parameter to each site. Our analysis shows that the ultrasensitivity generally increases as the conformational free energy contribution from one or more sites is strengthen. Furthermore, ultrasensitivity depends on the mean of the activation parameters and not on their variability. In some cases, we find that the best way to maximize ultrasensitivity is to make the contribution from all sites as strong as possible. These results provide insights into the performance objectives of multiple modification/binding sites and thus help gain a greater understanding of signaling and its role in diseases.

    in PLoS Computational Biology on August 06, 2020 09:00 PM.

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    Integrative illustration for coronavirus outreach

    by David S. Goodsell, Maria Voigt, Christine Zardecki, Stephen K. Burley

    Two illustrations integrate current knowledge about severe acute respiratory syndrome (SARS) coronaviruses and their life cycle. They have been widely used in education and outreach through free distribution as part of a coronavirus-related resource at Protein Data Bank (PDB)-101, the education portal of the RCSB PDB. Scientific sources for creation of the illustrations and examples of dissemination and response are presented.

    in PLoS Biology on August 06, 2020 09:00 PM.

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    Radiation causes tissue damage by dysregulating inflammasome–gasdermin D signaling in both host and transplanted cells

    by Jianqiu Xiao, Chun Wang, Juo-Chin Yao, Yael Alippe, Tong Yang, Dustin Kress, Kai Sun, Kourtney L. Kostecki, Joseph B. Monahan, Deborah J. Veis, Yousef Abu-Amer, Daniel C. Link, Gabriel Mbalaviele

    Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens.

    in PLoS Biology on August 06, 2020 09:00 PM.

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    Dynamic centriolar localization of Polo and Centrobin in early mitosis primes centrosome asymmetry

    by Emmanuel Gallaud, Anjana Ramdas Nair, Nicole Horsley, Arnaud Monnard, Priyanka Singh, Tri Thanh Pham, David Salvador Garcia, Alexia Ferrand, Clemens Cabernard

    Centrosomes, the main microtubule organizing centers (MTOCs) of metazoan cells, contain an older “mother” and a younger “daughter” centriole. Stem cells either inherit the mother or daughter-centriole-containing centrosome, providing a possible mechanism for biased delivery of cell fate determinants. However, the mechanisms regulating centrosome asymmetry and biased centrosome segregation are unclear. Using 3D-structured illumination microscopy (3D-SIM) and live-cell imaging, we show in fly neural stem cells (neuroblasts) that the mitotic kinase Polo and its centriolar protein substrate Centrobin (Cnb) accumulate on the daughter centriole during mitosis, thereby generating molecularly distinct mother and daughter centrioles before interphase. Cnb’s asymmetric localization, potentially involving a direct relocalization mechanism, is regulated by Polo-mediated phosphorylation, whereas Polo’s daughter centriole enrichment requires both Wdr62 and Cnb. Based on optogenetic protein mislocalization experiments, we propose that the establishment of centriole asymmetry in mitosis primes biased interphase MTOC activity, necessary for correct spindle orientation.

    in PLoS Biology on August 06, 2020 09:00 PM.

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    Intact Brain Network Function in an Unresponsive Patient with COVID‐19

    Many patients with severe coronavirus disease 2019 (COVID‐19) remain unresponsive after surviving critical illness. Although several structural brain abnormalities have been described, their impact on brain function and implications for prognosis are unknown. Functional neuroimaging, which has prognostic significance, has yet to be explored in this population. Here we describe a patient with severe COVID‐19 who, despite prolonged unresponsiveness and structural brain abnormalities, demonstrated intact functional network connectivity, and weeks later recovered the ability to follow commands. When prognosticating for survivors of severe COVID‐19, clinicians should consider that brain networks may remain functionally intact despite structural injury and prolonged unresponsiveness. ANN NEUROL 2020

    in Annals of Neurology on August 06, 2020 04:26 PM.

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    Location and arrangement of campaniform sensilla in Drosophila melanogaster

    Location and arrangement of campaniform sensilla in Drosophila melanogaster

    Campaniform sensilla are a sensory system in insects that detect deformations of the exoskeleton. The comparison of front, middle, and hindleg sensilla reveals robust locations with a small amount of interindividual variability.


    Abstract

    Sensory systems provide input to motor networks on the state of the body and environment. One such sensory system in insects is the campaniform sensilla (CS), which detect deformations of the exoskeleton arising from resisted movements or external perturbations. When physical strain is applied to the cuticle, CS external structures are compressed, leading to transduction in an internal sensory neuron. In Drosophila melanogaster , the distribution of CS on the exoskeleton has not been comprehensively described. To investigate CS number, location, spatial arrangement, and potential differences between individuals, we compared the front, middle, and hind legs of multiple flies using scanning electron microscopy. Additionally, we imaged the entire body surface to confirm known CS locations. On the legs, the number and relative arrangement of CS varied between individuals, and single CS of corresponding segments showed characteristic differences between legs. This knowledge is fundamental for studying the relevance of cuticular strain information within the complex neuromuscular networks controlling posture and movement. This comprehensive account of all D. melanogaster CS helps set the stage for experimental investigations into their responsivity, sensitivity, and roles in sensory acquisition and motor control in a light‐weight model organism.

    in Journal of Comparative Neurology on August 06, 2020 12:53 PM.

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    Quantification of aromatase binding in the female human brain using [11C]cetrozole positron emission tomography

    Quantification of aromatase binding in the female human brain using [11C]cetrozole positron emission tomography

    Quantification of the binding of [11C]cetrozole to aromatase in the brain is best done using the two‐tissue reversible compartment model, or the simplified reference tissue model with the cerebellum as reference region. Receptor parametric mapping and Logan reference tissue model are suitable for parametric mapping. One hour of data acquisition is sufficient for the quantification.


    Abstract

    Aromatase, the enzyme that in the brain converts testosterone and androstenedione to estradiol and estrone, respectively, is a putative key factor in psychoneuroendocrinology. In vivo assessment of aromatase was performed to evaluate tracer kinetic models and optimal scan duration, for quantitative analysis of the aromatase positron emission tomography (PET) ligand [11C]cetrozole. Anatomical magnetic resonance and 90‐min dynamic [11C]cetrozole PET‐CT scans were performed on healthy women. Volume of interest (VOI)‐based analyses with a plasma‐input function were performed using the single‐tissue and two‐tissue (2TCM) reversible compartment models and plasma‐input Logan analysis. Additionally, the simplified reference tissue model (SRTM), Logan reference tissue model (LRTM), and standardized uptake volume ratio model, with cerebellum as reference region, were evaluated. Parametric images were generated and regionally averaged voxel values were compared with VOI‐based analyses of the reference tissue models. The optimal reference model was used for evaluation of a decreased scan duration. Differences between the plasma‐input‐ and reference tissue‐based methods and comparisons between scan durations were assessed by linear regression. The [11C]cetrozole time–activity curves were best described by the 2TCM. SRTM nondisplaceable binding potential (BPND), with cerebellum as reference region, can be used to estimate [11C]cetrozole binding and generated robust and quantitatively accurate results for a reduced scan duration of 60 min. Receptor parametric mapping, a basis function implementation of SRTM, as well as LRTM, produced quantitatively accurate parametric images, showing BPND at the voxel level. As PET tracer, [11C]cetrozole can be employed for relatively short brain scans to measure aromatase binding using a reference tissue‐based approach.

    in Journal of Neuroscience Research on August 06, 2020 11:39 AM.

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    Neuronal vector coding in spatial cognition

    Nature Reviews Neuroscience, Published online: 06 August 2020; doi:10.1038/s41583-020-0336-9

    A number of spatially selective neurons that encode an animal’s distance and direction from environmental features have been proposed by theoretical studies and experimentally identified. Andrej Bicanski and Neil Burgess summarize our current understanding of vector coding cells and describe their contribution to spatial cognition.

    in Nature Reviews on August 06, 2020 12:00 AM.

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    Daily briefing: Last of their kind, the tuatara genome reveals why this reptile is so remarkable

    Nature, Published online: 06 August 2020; doi:10.1038/d41586-020-02344-y

    The first tuatara genome sheds light on our reptile ancestors and epidemiologists predict the future of the coronavirus pandemic.

    in Nature on August 06, 2020 12:00 AM.

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    The trials of global research under the coronavirus

    Nature, Published online: 06 August 2020; doi:10.1038/d41586-020-02326-0

    Researchers share how they have adapted fieldwork and collaborations in the face of travel bans and closed borders.

    in Nature on August 06, 2020 12:00 AM.

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    Ultra-fluorescent dyes give objects an eye-popping glow

    Nature, Published online: 06 August 2020; doi:10.1038/d41586-020-02323-3

    Crystals of physically distanced dye molecules fluoresce brilliantly in a rainbow of colours.

    in Nature on August 06, 2020 12:00 AM.

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    NSF grant changes raise alarm about commitment to basic research

    Nature, Published online: 06 August 2020; doi:10.1038/d41586-020-02272-x

    The US National Science Foundation’s new focus on computer science could also put already-under-represented groups at a disadvantage, critics say.

    in Nature on August 06, 2020 12:00 AM.

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    Pharmacodynamic Biomarkers for Emerging LRRK2 Therapeutics

    Genetic studies have identified variants in the LRRK2 gene as important components of Parkinson’s disease (PD) pathobiology. Biochemical and emergent biomarker studies have coalesced around LRRK2 hyperactivation in disease. Therapeutics that diminish LRRK2 activity, either with small molecule kinase inhibitors or anti-sense oligonucleotides, have recently advanced to the clinic. Historically, there have been few successes in the development of therapies that might slow or halt the progression of neurodegenerative diseases. Over the past few decades of biomedical research, retrospective analyses suggest the broad integration of informative biomarkers early in development tends to distinguish successful pipelines from those that fail early. Herein, we discuss the biomarker regulatory process, emerging LRRK2 biomarker candidates, assays, underlying biomarker biology, and clinical integration.

    in Frontiers in Neuroscience: Neurodegeneration on August 06, 2020 12:00 AM.

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    Cross Talk Between Ferroptosis and Cerebral Ischemia

    Recently, ferroptosis has been revealed as a new form of regulated cell death. Distinct from apoptosis and necrosis, ferroptosis is evoked by iron-dependent lipid peroxidation. Furthermore, the metabolism of iron, lipids, and amino acids plays a significant regulatory role in ferroptosis, which can be reversed by glutathione peroxidase 4 and ferroptosis suppressor protein 1. Ferroptosis is implicated in the onset and development of numerous neurological diseases. Emerging studies have reported that ferroptosis induces and aggravates brain tissue damage following cerebral ischemia, whereas inhibition of ferroptosis dramatically attenuates induced damage. In this review, we have summarized the mechanistic relationship between ferroptosis and cerebral ischemia, including through iron overload, downregulation of glutathione peroxidase 4, and upregulation of lipid peroxidation. Although considerable attention has been paid to the effect of ferroptosis on cerebral ischemic injury, specific mechanisms need to be experimentally confirmed, including how cerebral ischemia induces ferroptosis and how ferroptosis deteriorates cerebral ischemia.

    in Frontiers in Neuroscience: Neurodegeneration on August 06, 2020 12:00 AM.

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    Blood-Brain Barrier: More Contributor to Disruption of Central Nervous System Homeostasis Than Victim in Neurological Disorders

    The blood-brain barrier (BBB) is a dynamic but solid shield in the cerebral microvascular system. It plays a pivotal role in maintaining central nervous system (CNS) homeostasis by regulating the exchange of materials between the circulation and the brain and protects the neural tissue from neurotoxic components as well as pathogens. Here, we discuss the development of the BBB in physiological conditions and then focus on the role of the BBB in cerebrovascular disease, including acute ischemic stroke and intracerebral hemorrhage, and neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Finally, we summarize recent advancements in the development of therapies targeting the BBB and outline future directions and outstanding questions in the field. We propose that BBB dysfunction not only results from, but is causal in the pathogenesis of neurological disorders; the BBB is more a contributor to the disruption of CNS homeostasis than a victim in neurological disorders.

    in Frontiers in Neuroscience: Neurodegeneration on August 06, 2020 12:00 AM.

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    Sleep Disturbances and Sleep Disordered Breathing Impair Cognitive Performance in Parkinson’s Disease

    Background

    Sleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson’s disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance.

    Objective

    This post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD.

    Methods

    Twenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients’ subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated.

    Results

    We did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, P = 0.020, unpaired two-sided t-test).

    Conclusion

    Sleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.

    in Frontiers in Neuroscience: Neurodegeneration on August 06, 2020 12:00 AM.

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    Economical Assessment of Working Memory and Response Inhibition in ADHD Using a Combined n-back/Nogo Paradigm: An ERP Study

    The development of cognitive interventions in attention-deficit/hyperactivity disorder (ADHD) often requires the assessment of multiple cognitive functions. However, experimental settings consisting of various tasks are particularly strenuous for patients and can thus result in poor data quality. For the economical assessment of working memory and response inhibition, this study aims to validate a combined n-back/nogo paradigm by comparing it to single task versions and to demonstrate its applicability for ADHD research. Twenty-five healthy individuals and 34 ADHD patients between 9 and 16 years participated in this event-related potential (ERP) study. Healthy controls underwent single task versions of a 2-back working memory task and a go/nogo response inhibition task as well as the introduced combined 2-back/nogo task. This combined task demonstrated a comparable ERP structure for working memory and response inhibition aspects as single task versions. Behaviorally, higher working memory performance during the combined paradigm indicated lower task difficulty, while high correlations between combined and single task versions still indicated valid working memory measures. For response inhibition performance, different task versions resulted in similar outcomes. The application of the combined n-back/nogo paradigm in ADHD patients revealed the expected working memory and response inhibition deficits, increased omission errors, reaction times, and standard deviation of reaction time, as well as diminished n-back P3 and nogo P3 amplitudes. We conclude that the combined n-back/nogo task is an effective paradigm for the economical assessment of working memory and response inhibition deficits in ADHD on a behavioral and neurophysiological level.

    in Frontiers in Human Neuroscience on August 06, 2020 12:00 AM.

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    Predicting Motor Imagery Performance From Resting-State EEG Using Dynamic Causal Modeling

    Motor imagery-based brain–computer interfaces (MI-BCIs) send commands to a computer using the brain activity registered when a subject imagines—but does not perform—a given movement. However, inconsistent MI-BCI performance occurs in variations of brain signals across subjects and experiments; this is considered to be a significant problem in practical BCI. Moreover, some subjects exhibit a phenomenon referred to as “BCI-inefficiency,” in which they are unable to generate brain signals for BCI control. These subjects have significant difficulties in using BCI. The primary goal of this study is to identify the connections of the resting-state network that affect MI performance and predict MI performance using these connections. We used a public database of MI, which includes the results of psychological questionnaires and pre-experimental resting-state taken over two sessions on different days. A dynamic causal model was used to calculate the coupling strengths between brain regions with directionality. Specifically, we investigated the motor network in resting-state, including the dorsolateral prefrontal cortex, which performs motor planning. As a result, we observed a significant difference in the connectivity strength from the supplementary motor area to the right dorsolateral prefrontal cortex between the low- and high-MI performance groups. This coupling, measured in the resting-state, is significantly stronger in the high-MI performance group than the low-MI performance group. The connection strength is positively correlated with MI-BCI performance (Session 1: r = 0.54; Session 2: r = 0.42). We also predicted MI performance using linear regression based on this connection (r-squared = 0.31). The proposed predictors, based on dynamic causal modeling, can develop new strategies for improving BCI performance. These findings can further our understanding of BCI-inefficiency and help BCI users to lower costs and save time.

    in Frontiers in Human Neuroscience on August 06, 2020 12:00 AM.

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    Emergence of Stable Synaptic Clusters on Dendrites Through Synaptic Rewiring

    The connectivity structure of neuronal networks in cortex is highly dynamic. This ongoing cortical rewiring is assumed to serve important functions for learning and memory. We analyze in this article a model for the self-organization of synaptic inputs onto dendritic branches of pyramidal cells. The model combines a generic stochastic rewiring principle with a simple synaptic plasticity rule that depends on local dendritic activity. In computer simulations, we find that this synaptic rewiring model leads to synaptic clustering, that is, temporally correlated inputs become locally clustered on dendritic branches. This empirical finding is backed up by a theoretical analysis which shows that rewiring in our model favors network configurations with synaptic clustering. We propose that synaptic clustering plays an important role in the organization of computation and memory in cortical circuits: we find that synaptic clustering through the proposed rewiring mechanism can serve as a mechanism to protect memories from subsequent modifications on a medium time scale. Rewiring of synaptic connections onto specific dendritic branches may thus counteract the general problem of catastrophic forgetting in neural networks.

    in Frontiers in Computational Neuroscience on August 06, 2020 12:00 AM.

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    New Optical Tools to Study Neural Circuit Assembly in the Retina

    During development, neurons navigate a tangled thicket of thousands of axons and dendrites to synapse with just a few specific targets. This phenomenon termed wiring specificity, is critical to the assembly of neural circuits and the way neurons manage this feat is only now becoming clear. Recent studies in the mouse retina are shedding new insight into this process. They show that specific wiring arises through a series of stages that include: directed axonal and dendritic growth, the formation of neuropil layers, positioning of such layers, and matching of co-laminar synaptic partners. Each stage appears to be directed by a distinct family of recognition molecules, suggesting that the combinatorial expression of such family members might act as a blueprint for retinal connectivity. By reviewing the evidence in support of each stage, and by considering their underlying molecular mechanisms, we attempt to synthesize these results into a wiring model which generates testable predictions for future studies. Finally, we conclude by highlighting new optical methods that could be used to address such predictions and gain further insight into this fundamental process.

    in Frontiers in Neural Circuits on August 06, 2020 12:00 AM.

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    Developmentally Regulated Rebound Depolarization Enhances Spike Timing Precision in Auditory Midbrain Neurons

    The inferior colliculus (IC) is an auditory midbrain structure involved in processing biologically important temporal features of sounds. The responses of IC neurons to these temporal features reflect an interaction of synaptic inputs and neuronal biophysical properties. One striking biophysical property of IC neurons is the rebound depolarization produced following membrane hyperpolarization. To understand how the rebound depolarization is involved in spike timing, we made whole-cell patch clamp recordings from IC neurons in brain slices of P9–21 rats. We found that the percentage of rebound neurons was developmentally regulated. The precision of the timing of the first spike on the rebound increased when the neuron was repetitively injected with a depolarizing current following membrane hyperpolarization. The average jitter of the first spikes was only 0.5 ms. The selective T-type Ca2+ channel antagonist, mibefradil, significantly increased the jitter of the first spike of neurons in response to repetitive depolarization following membrane hyperpolarization. Furthermore, the rebound was potentiated by one to two preceding rebounds within a few hundred milliseconds. The first spike generated on the potentiated rebound was more precise than that on the non-potentiated rebound. With the addition of a calcium chelator, BAPTA, into the cell, the rebound potentiation no longer occurred, and the precision of the first spike on the rebound was not improved. These results suggest that the postinhibitory rebound mediated by T-type Ca2+ channel promotes spike timing precision in IC neurons. The rebound potentiation and precise spikes may be induced by increases in intracellular calcium levels.

    in Frontiers in Cellular Neuroscience on August 06, 2020 12:00 AM.

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    Insight Into the Role of Ferroptosis in Non-neoplastic Neurological Diseases

    Ferroptosis is an iron-dependent form of cell death characterized by the accumulation of intracellular lipid reactive oxygen species (ROS). Ferroptosis is significantly different from other types of cell death including apoptosis, autophagy, and necrosis, both in morphology and biochemical characteristics. The mechanisms that are associated with ferroptosis include iron metabolism, lipid oxidation, and other pathophysiological changes. Ferroptosis inducers or inhibitors can influence its occurrence through different pathways. Ferroptosis was initially discovered in tumors, though recent studies have confirmed that it is also closely related to a variety of neurological diseases including neurodegenerative disease [Alzheimer’s disease (AD), Parkinson’s disease (PD), etc.] and stroke. This article reviews the definition and characteristics of ferroptosis, the potential mechanisms associated with its development, inducers/inhibitors, and its role in non-neoplastic neurological diseases. We hope to provide a theoretical basis and novel treatment strategies for the treatment of central nervous system diseases by targeting ferroptosis.

    in Frontiers in Cellular Neuroscience on August 06, 2020 12:00 AM.

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    Effects of Lactate on One Class of Group III (CT3) Muscle Afferents

    A class of Group III muscle afferent neurons has branching sensory terminals in the connective tissue between layers of mouse abdominal muscles (“CT3 muscle afferents”). These sensory endings are both mechanosensitive and metabosensitive. In the present study, responses of CT3 afferents to lactate ions and changes in temperature were recorded. Raising muscle temperature from 32.7°C to 37°C had no consistent effects on CT3 afferent basal firing rate or responses to either von Frey hair stimulation or to an applied load. Superfusion with lactate ions (15 mM, pH 7.4) was associated with an increase in firing from 6 ± 0.7 Hz to 11.7 ± 6.7 Hz (14 units, n = 13, P < 0.05, P = 0.0484) but with considerable variability in the nature and latency of response. Reducing the concentration of extracellular divalent cations, which mimicked the chelating effects of lactate, did not increase firing. Raised concentrations of divalent cations (to compensate for chelation) did not block excitatory effects of lactate on CT3 afferents, suggesting that effects via ASIC3 were not involved. Messenger RNA for the G-protein coupled receptor, hydroxyl carboxylic acid receptor 1 (HCAR1) was detected in dorsal root ganglia and HCAR1-like immunoreactivity was present in spinal afferent nerve cell bodies retrogradely labeled from mouse abdominal muscles. HCAR1-like immunoreactivity was also present in axons in mouse abdominal muscles. This raises the possibility that some effects of lactate on group III muscle afferents may be mediated by HCAR1.

    in Frontiers in Cellular Neuroscience on August 06, 2020 12:00 AM.

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    Overview of General and Discriminating Markers of Differential Microglia Phenotypes

    Inflammatory processes and microglia activation accompany most of the pathophysiological diseases in the central nervous system. It is proven that glial pathology precedes and even drives the development of multiple neurodegenerative conditions. A growing number of studies point out the importance of microglia in brain development as well as in physiological functioning. These resident brain immune cells are divergent from the peripherally infiltrated macrophages, but their precise in situ discrimination is surprisingly difficult. Microglial heterogeneity in the brain is especially visible in their morphology and cell density in particular brain structures but also in the expression of cellular markers. This often determines their role in physiology or pathology of brain functioning. The species differences between rodent and human markers add complexity to the whole picture. Furthermore, due to activation, microglia show a broad spectrum of phenotypes ranging from the pro-inflammatory, potentially cytotoxic M1 to the anti-inflammatory, scavenging, and regenerative M2. A precise distinction of specific phenotypes is nowadays essential to study microglial functions and tissue state in such a quickly changing environment. Due to the overwhelming amount of data on multiple sets of markers that is available for such studies, the choice of appropriate markers is a scientific challenge. This review gathers, classifies, and describes known and recently discovered protein markers expressed by microglial cells in their different phenotypes. The presented microglia markers include qualitative and semi-quantitative, general and specific, surface and intracellular proteins, as well as secreted molecules. The information provided here creates a comprehensive and practical guide through the current knowledge and will facilitate the choosing of proper, more specific markers for detailed studies on microglia and neuroinflammatory mechanisms in various physiological as well as pathological conditions. Both basic research and clinical medicine need clearly described and validated molecular markers of microglia phenotype, which are essential in diagnostics, treatment, and prevention of diseases engaging glia activation.

    in Frontiers in Cellular Neuroscience on August 06, 2020 12:00 AM.

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    Stem Cells of the Aging Brain

    The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current in vivo and in vitro models of neurodegenerative diseases rarely consider this. Therefore, combining both aging research and appropriate interrogation of animal disease models towards the understanding of the disease and age-related stem cell failure is imperative to the discovery of new therapies. This review article will highlight the main intrinsic and extrinsic regulators of neural stem cell (NSC) aging and discuss how these factors impact normal homeostatic functions within the adult brain. We will consider established in vivo animal and in vitro human disease model systems, and then discuss the current and future trajectories of novel senotherapeutics that target aging NSCs to ameliorate brain disease.

    in Frontiers in Ageing Neuroscience on August 06, 2020 12:00 AM.

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    Evaluation of the Mini-Mental State Examination and the Montreal Cognitive Assessment for Predicting Post-stroke Cognitive Impairment During the Acute Phase in Chinese Minor Stroke Patients

    Objective: To assess the value of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) during acute phase in predicting post-stroke cognitive impairment (PSCI) at 3–6 months.

    Methods: We prospectively recruited 229 patients who had suffered their first-ever ischemic stroke. PSCI was determined in 104 of these patients by a comprehensive neuropsychological battery performed at 3–6 months. Receiver operating characteristic (ROC) curve analysis was then performed to compare the discriminatory ability of the MMSE and MoCA. Also, we applied a decision tree generated by the classification and regression tree methodology.

    Results: In total, 66 patients had PSCI when evaluated 3–6 months after the onset of minor stroke. Logistic regression analysis revealed that education, body mass index (BMI), and baseline MoCA scores were independently associated with PSCI. ROC curve analysis showed that the ability to predict PSCI was similar when compared between baseline MoCA scores [area under curve (AUC), 0.821; 95% confidence interval (CI), 0.743–0.898] and baseline MMSE scores (AUC, 0.809; 95% CI, 0.725–0.892, P = 0.75). Both MMSE and MoCA exhibited similar predictive values at their optimal cut-off points (MMSE ≤27; sensitivity, 0.682; specificity, 0.816; MoCA ≤21; sensitivity, 0.636; specificity, 0.895). Classification and regression tree-derived analysis yielded an AUC of 0.823 (sensitivity, 0.803; specificity, 0.842).

    Conclusion: When applied within 2 weeks of stroke, the MMSE and MoCA are both useful and have similar predictive value for PSCI 3–6 months after the onset of minor stroke.

    in Frontiers in Ageing Neuroscience on August 06, 2020 12:00 AM.

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    An Integrated Index: Engrams, Place Cells, and Hippocampal Memory

    Goode et al. interpret recent work on hippocampal anatomy, physiology, and behavior through the lens of the hippocampal indexing theory, suggesting that hippocampal engrams may serve as a memory index to permit flexible reinstatement of previous experience.

    in Neuron: In press on August 06, 2020 12:00 AM.

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    Selective Routing of Spatial Information Flow from Input to Output in Hippocampal Granule Cells

    Zhang et al. simultaneously measure subthreshold EPSP and suprathreshold AP activity in morphologically identified dentate gyrus GCs in mice during spatial navigation, using intracellular patch-clamp recording. Although only a minor fraction of GCs shows spatially tuned spiking, a major fraction receives spatially tuned synaptic input. Intrinsic excitability controls input-output conversion.

    in Neuron: In press on August 06, 2020 12:00 AM.

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    Reply to “Prior Dual Antiplatelet Therapy and Thrombolysis in Acute Stroke”

    in Annals of Neurology on August 05, 2020 05:09 PM.

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    Normal Pressure Hydrocephalus Associated with Alzheimer's Disease

    Objective

    The aim was to investigate whether neurodegenerative biomarkers in cerebrospinal fluid (CSF) differentiate patients with suspected normal pressure hydrocephalus (NPH) who respond to CSF drainage from patients who do not respond.

    Methods

    Data from 62 consecutive patients who presented with magnetic resonance imaging changes indicative of NPH were studied with regard to cognitive and gait functions before and after drainage of 40–50ml of CSF. Additionally, S100 protein, neuron‐specific enolase, β‐amyloid protein, tau protein and phospho‐tau were determined in CSF. Statistical analyses were carried out with ANOVA and multiple linear regression.

    Results

    Patients with CSF constellations typical for Alzheimer's disease (n = 28) improved significantly in cognitive and gait‐related functions after CSF drainage. In contrast, those patients without a CSF constellation typical for Alzheimer's disease (n = 34) did not improve in cognitive and gait‐related functions after CSF drainage. In addition, positive CSF biomarkers for Alzheimer's disease predicted these improvements.

    Interpretation

    Our data suggest an association between Alzheimer's disease and NPH changes, supporting the recently suggested dichotomy of a neurodegenerative NPH and a true idiopathic NPH, with the latter appearing to be rare. ANN NEUROL 2020

    in Annals of Neurology on August 05, 2020 05:05 PM.

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    Non‐motor symptoms in Parkinson´s disease are reduced by nabilone

    Objective

    To assess the efficacy and safety of nabilone, a synthetic tetrahydrocannabinol analogue, as a treatment for non‐motor symptoms (NMS) in Parkinson´s Disease (PD).

    Methods

    This was a phase II placebo‐controlled, double‐blind, parallel‐group, enriched enrollment randomized withdrawal trial at the Medical University Innsbruck. A random sample of 47 PD patients with stable motor disease and disturbing NMS defined by a score of ≥4 points on the Movement Disorder Society‐Unified PD Rating Scale‐I (MDS‐UPDRS‐I) underwent open‐label nabilone titration (0.25mg once daily‐1mg twice daily, Phase 1). Responders were randomized 1:1 to continue with nabilone or switch to placebo for four weeks (Phase 2). The primary efficacy criterion was the change of the MDS‐UPDRS‐I between randomization and week four. Safety was analyzed in all patients who received at least one nabilone dose.

    Results

    Between October 2017 and July 2019, 19 patients received either nabilone (median dose=0.75mg) or placebo. At week four, mean change of the MDS‐UPDRS‐I was 2.63 (95%CI 1.53‐3.74, p=0.002, effect size=1.15) in the placebo versus 1.00 (95%CI ‐0.16‐2.16, p=0.280, effect size=0.42) in the nabilone‐group (difference:1.63, 95%CI 0.09‐3.18, p=0.030, effect size=0.66). Seventy‐seven percent of patients had adverse events (AEs) during open‐label titration, most of them were transient. In the double‐blind phase, similar proportions of patients in each group had AEs (42% placebo‐group, 32% nabilone‐group). There were no serious AEs.

    Interpretation

    Our results highlight the potential efficacy of nabilone for PD patients with disturbing NMS, which appears to be driven by positive effects on anxious mood and night‐time sleep problems.

    Trial registry: ClinicalTrials.gov (NCT03769896) and EudraCT (2017‐000192‐86)

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on August 05, 2020 04:43 PM.

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    Anticoagulation Timing in Cardioembolic Stroke and Recurrent Event Risk

    Objective

    Guidelines recommend initiating anticoagulation within 4 to 14 days after cardioembolic stroke. Data supporting this did not account for key factors potentially affecting the decision to initiate anticoagulation, such as infarct size, hemorrhagic transformation, or high‐risk features on echocardiography.

    Methods

    We pooled data from stroke registries of 8 comprehensive stroke centers across the United States. We included consecutive patients admitted with ischemic stroke and atrial fibrillation. The primary predictor was timing of initiating anticoagulation (0–3 days, 4–14 days, or >14 days), and outcomes were recurrent stroke/transient ischemic attack/systemic embolism, symptomatic intracerebral hemorrhage (sICH), and major extracranial hemorrhage (ECH) within 90 days.

    Results

    Among 2,084 patients, 1,289 met the inclusion criteria. The combined endpoint occurred in 10.1% (n = 130) subjects (87 ischemic events, 20 sICH, and 29 ECH). Overall, there was no significant difference in the composite endpoint between the 3 groups (0–3 days: 10.3%, 64/617; 4–14 days: 9.7%, 52/535; >14 days: 10.2%, 14/137; p = 0.933). In adjusted models, patients started on anticoagulation between 4 and 14 days did not have a lower rate of sICH (vs 0–3 days; odds ratio [OR] = 1.49, 95% confidence interval [CI] = 0.50–4.43), nor did they have a lower rate of recurrent ischemic events (vs >14 days; OR = 0.76, 95% CI = 0.36–1.62, p = 0.482).

    Interpretation

    In this multicenter real‐world cohort, the recommended (4–14 days) time frame to start oral anticoagulation was not associated with reduced ischemic and hemorrhagic outcomes. Randomized trials are required to determine the optimal timing of anticoagulation initiation. ANN NEUROL 2020

    in Annals of Neurology on August 05, 2020 03:08 PM.

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    Correcting molecular transition rates measured by single-molecule force spectroscopy for limited temporal resolution

    Author(s): David R. Jacobson and Thomas T. Perkins

    Equilibrium free-energy-landscape parameters governing biomolecular folding can be determined from nonequilibrium force-induced unfolding by measuring the rates k for transitioning back and forth between states as a function of force F. However, bias in the observed forward and reverse rates is intr...


    [Phys. Rev. E 102, 022402] Published Wed Aug 05, 2020

    in Physical Review E: Biological physics on August 05, 2020 10:00 AM.

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    Mitochondrial cristae modeled as an out-of-equilibrium membrane driven by a proton field

    Author(s): Nirbhay Patil, Stéphanie Bonneau, Fréderic Joubert, Anne-Florence Bitbol, and Hélène Berthoumieux

    As the places where most of the fuel of the cell, namely, ATP, is synthesized, mitochondria are crucial organelles in eukaryotic cells. The shape of the invaginations of the mitochondria inner membrane, known as a crista, has been identified as a signature of the energetic state of the organelle. Ho...


    [Phys. Rev. E 102, 022401] Published Wed Aug 05, 2020

    in Physical Review E: Biological physics on August 05, 2020 10:00 AM.

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    Author Correction: Analysis of the Human Protein Atlas Image Classification competition

    Nature Methods, Published online: 05 August 2020; doi:10.1038/s41592-020-0937-2

    Author Correction: Analysis of the Human Protein Atlas Image Classification competition

    in Nature Methods on August 05, 2020 12:00 AM.

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    SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2622-0

    SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness

    in Nature on August 05, 2020 12:00 AM.

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    Position-specific oxidation of miR-1 encodes cardiac hypertrophy

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2586-0

    The 8-oxoguanine modification of the microRNA miR-1 results in redirected recognition and silencing of target genes and leads to cardiac hypertrophy in mice.

    in Nature on August 05, 2020 12:00 AM.

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    Dichotomous engagement of HDAC3 activity governs inflammatory responses

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2576-2

    During the activation of mouse macrophages by lipopolysaccharides, histone deacetylase 3 controls inflammatory responses by both repressing and activating gene transcription depending on its differential association with transcription factors.

    in Nature on August 05, 2020 12:00 AM.

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    Mucosal or systemic microbiota exposures shape the B cell repertoire

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2564-6

    A mouse model of systemic versus mucosal exposure to microbial taxa reveals that the former provokes a flexible B cell response with a diverse immunoglobulin repertoire, whereas the latter generates a more-restricted response.

    in Nature on August 05, 2020 12:00 AM.

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    Rescue of oxytocin response and social behaviour in a mouse model of autism

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2563-7

    An autism-associated mutation in Nlgn3 results in impaired oxytocin signalling in dopaminergic neurons and altered social behavioural responses in mice, and treatment with an inhibitor of MAP kinase-interacting kinases rescues these phenotypes.

    in Nature on August 05, 2020 12:00 AM.

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    Zoonotic host diversity increases in human-dominated ecosystems

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2562-8

    Wildlife communities in human-managed ecosystems contain proportionally more species that share human pathogens, and at a higher abundance, than undisturbed habitats, suggesting that landscape transformation creates increasing opportunities for contact between humans and potential hosts of human disease.

    in Nature on August 05, 2020 12:00 AM.

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    The tuatara genome reveals ancient features of amniote evolution

    Nature, Published online: 05 August 2020; doi:10.1038/s41586-020-2561-9

    The approximately 5-Gb tuatara (Sphenodon punctatus) genome assembly provides a resource for analysing amniote evolution, and highlights the imperative for meaningful cultural engagement with Indigenous communities in genome-sequencing endeavours.

    in Nature on August 05, 2020 12:00 AM.

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    Non-genomic Actions of Methylprednisolone Differentially Influence GABA and Glutamate Release From Isolated Nerve Terminals of the Rat Hippocampus

    Corticosteroids exert a dual role in eukaryotic cells through their action via (1) intracellular receptors (slow genomic responses), or (2) membrane-bound receptors (fast non-genomic responses). Highly vulnerable regions of the brain, like the hippocampus, express high amounts of corticosteroid receptors, yet their actions on ionic currents and neurotransmitters release are still undefined. Here, we investigated the effect of methylprednisolone (MP) on GABA and glutamate (Glu) release from isolated nerve terminals of the rat hippocampus. MP favored both spontaneous and depolarization-evoked [14C]Glu release from rat hippocampal nerve terminals, without affecting [3H]GABA outflow. Facilitation of [14C]Glu release by MP is mediated by a Na+-dependent Ca2+-independent non-genomic mechanism relying on the activation of membrane-bound glucocorticoid (GR) and mineralocorticoid (MR) receptors sensitive to their antagonists mifepristone and spironolactone, respectively. The involvement of Na+-dependent high-affinity EAAT transport reversal was inferred by blockage of MP-induced [14C]Glu release by DL-TBOA. Depolarization-evoked [3H]GABA release in the presence of MP was partially attenuated by the selective P2X7 receptor antagonist A-438079, but this compound did not affect the release of [14C]Glu. Data indicate that MP differentially affects GABA and glutamate release from rat hippocampal nerve terminals via fast non-genomic mechanisms putatively involving the activation of membrane-bound corticosteroid receptors. Facilitation of Glu release strengthen previous assumptions that MP may act as a cognitive enhancer in rats, while crosstalk with ATP-sensitive P2X7 receptors may promote a therapeutically desirable GABAergic inhibitory control during paroxysmal epileptic crisis that might be particularly relevant when extracellular Ca2+ levels decrease below the threshold required for transmitter release.

    in Frontiers in Molecular Neuroscience on August 05, 2020 12:00 AM.

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    LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness

    Mutations in the LAMA2 gene affect the production of the α2 subunit of laminin-211 (= merosin) and result in either partial or complete laminin-211 deficiency. Complete merosin deficiency is typically associated with a more severe congenital muscular dystrophy (CMD), clinically manifested by hypotonia and weakness at birth, the development of contractures of large joints, and progressive respiratory involvement. Muscle atrophy and severe weakness typically prevent independent ambulation. Partial merosin deficiency is mostly manifested by later onset limb-girdle weakness and joint contractures so that independent ambulation is typically achieved. Collectively, complete and partial merosin deficiency is referred to as LAMA2-related dystrophies (LAMA2-RDs) and represents one of the most common forms of congenital muscular dystrophies worldwide. LAMA2-RDs are classically characterized by both central and peripheral nervous system involvement with abnormal appearing white matter (WM) on brain MRI and dystrophic appearing muscle on muscle biopsy as well as creatine kinase (CK) levels commonly elevated to >1,000 IU/L. Next-generation sequencing (NGS) has greatly improved diagnostic abilities for LAMA2-RD, and the majority of patients with merosin deficiency carry recessive pathogenic variants in the LAMA2 gene. The existence of multiple animal models for LAMA2-RDs has helped to advance our understanding of laminin-211 and has been instrumental in preclinical research progress and translation to clinical trials. The first clinical trial for the LAMA2-RDs was a phase 1 pharmacokinetic and safety study of the anti-apoptotic compound omigapil, based on preclinical studies performed in the dyW/dyW and dy2J/dy2J mouse models. This phase 1 study enabled the collection of pulmonary and motor outcome measures and also provided the opportunity for investigating exploratory outcome measures including muscle ultrasound, muscle MRI and serum, and urine biomarker collection. Natural history studies, including a five-year prospective natural history and comparative outcome measures study in patients with LAMA2-RD, have helped to better delineate the natural history and identify viable outcome measures. Plans for further clinical trials for LAMA2-RDs are presently in progress, highlighting the necessity of identifying adequate, disease-relevant biomarkers, capable of reflecting potential therapeutic changes, in addition to refining the clinical outcome measures and time-to-event trajectory analysis of affected patients.

    in Frontiers in Molecular Neuroscience on August 05, 2020 12:00 AM.

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    Gut-Brain Axis in the Early Postnatal Years of Life: A Developmental Perspective

    Emerging evidence suggests that alterations in the development of the gastrointestinal (GI) tract during the early postnatal period can influence brain development and vice-versa. It is increasingly recognized that communication between the GI tract and brain is mainly driven by neural, endocrine, immune, and metabolic mediators, collectively called the gut-brain axis (GBA). Changes in the GBA mediators occur in response to the developmental changes in the body during this period. This review provides an overview of major developmental events in the GI tract and brain in the early postnatal period and their parallel developmental trajectories under physiological conditions. Current knowledge of GBA mediators in context to brain function and behavioral outcomes and their synthesis and metabolism (site, timing, etc.) is discussed. This review also presents hypotheses on the role of the GBA mediators in response to the parallel development of the GI tract and brain in infants.

    in Frontiers in Integrative Neuroscience on August 05, 2020 12:00 AM.

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    Punishment Feedback Impairs Memory and Changes Cortical Feedback-Related Potentials During Motor Learning

    Reward and punishment have demonstrated dissociable effects on motor learning and memory, which suggests that these reinforcers are differently processed by the brain. To test this possibility, we use electroencephalography to record cortical neural activity after the presentation of reward and punishment feedback during a visuomotor rotation task. Participants were randomly placed into Reward, Punishment, or Control groups and performed the task under different conditions to assess the adaptation (learning) and retention (memory) of the motor task. These conditions featured an incongruent position between the cursor and the target, with the cursor trajectory, rotated 30° counterclockwise, requiring the participant to adapt their movement to hit the target. Feedback based on error magnitude was provided during the Adaptation condition in the form of a positive number (Reward) or negative number (Punishment), each representing a monetary gain or loss, respectively. No reinforcement or visual feedback was provided during the No Vision condition (retention). Performance error and event-related potentials (ERPs) time-locked to feedback presentation were calculated for each participant during both conditions. Punishment feedback reduced performance error and promoted faster learning during the Adaptation condition. In contrast, punishment feedback increased performance error during the No Vision condition compared to Control and Reward groups, which suggests a diminished motor memory. Moreover, the Punishment group showed a significant decrease in the amplitude of ERPs during the No Vision condition compared to the Adaptation condition. The amplitude of ERPs did not change in the other two groups. These results suggest that punishment feedback impairs motor retention by altering the neural processing involved in memory encoding. This study provides a neurophysiological underpinning for the dissociative effects of punishment feedback on motor learning.

    in Frontiers in Human Neuroscience on August 05, 2020 12:00 AM.

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    SARS-CoV-2 Dissemination Through Peripheral Nerves Explains Multiple Organ Injury

    Coronavirus disease (CoVID-19), caused by recently identified severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2), is characterized by inconsistent clinical presentations. While many infected individuals remain asymptomatic or show mild respiratory symptoms, others develop severe pneumonia or even respiratory distress syndrome. SARS-CoV-2 is reported to be able to infect the lungs, the intestines, blood vessels, the bile ducts, the conjunctiva, macrophages, T lymphocytes, the heart, liver, kidneys, and brain. More than a third of cases displayed neurological involvement, and many severely ill patients developed multiple organ infection and injury. However, less than 1% of patients had a detectable level of SARS-CoV-2 in the blood, raising a question of how the virus spreads throughout the body. We propose that nerve terminals in the orofacial mucosa, eyes, and olfactory neuroepithelium act as entry points for the brain invasion, allowing SARS-CoV-2 to infect the brainstem. By exploiting the subcellular membrane compartments of infected cells, a feature common to all coronaviruses, SARS-CoV-2 is capable to disseminate from the brain to periphery via vesicular axonal transport and passive diffusion through axonal endoplasmic reticula, causing multiple organ injury independently of an underlying respiratory infection. The proposed model clarifies a wide range of clinically observed phenomena in CoVID-19 patients, such as neurological symptoms unassociated with lung pathology, protracted presence of the virus in samples obtained from recovered patients, exaggerated immune response, and multiple organ failure in severe cases with variable course and dynamics of the disease. We believe that this model can provide novel insights into CoVID-19 and its long-term sequelae, and establish a framework for further research.

    in Frontiers in Cellular Neuroscience on August 05, 2020 12:00 AM.

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    Role of Chondroitin Sulfation Following Spinal Cord Injury

    Traumatic spinal cord injury produces long-term neurological damage, and presents a significant public health problem with nearly 18,000 new cases per year in the U.S. The injury results in both acute and chronic changes in the spinal cord, ultimately resulting in the production of a glial scar, consisting of multiple cells including fibroblasts, macrophages, microglia, and reactive astrocytes. Within the scar, there is an accumulation of extracellular matrix (ECM) molecules—primarily tenascins and chondroitin sulfate proteoglycans (CSPGs)—which are considered to be inhibitory to axonal regeneration. In this review article, we discuss the role of CSPGs in the injury response, especially how sulfated glycosaminoglycan (GAG) chains act to inhibit plasticity and regeneration. This includes how sulfation of GAG chains influences their biological activity and interactions with potential receptors. Comprehending the role of CSPGs in the inhibitory properties of the glial scar provides critical knowledge in the much-needed production of new therapies.

    in Frontiers in Cellular Neuroscience on August 05, 2020 12:00 AM.

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    Fear Priming: A Method for Examining Postural Strategies Associated With Fear of Falling

    Fear of falling influences postural strategies used for balance, and is key in the maintenance of independent living and quality of life as adults age. However, there is a distinct need for methodology that aims to specifically address and prime fear under dynamic conditions, and to better determine the role of fear in movement preparation. This preliminary study investigated how fear priming influences fear of falling in young and older individuals, and assessed how changes in fear of falling map to movement behavior. Young (21.5 ± 1.7 years, n = 10) and older (58.1 ± 2.2 years) participants matched for height, weight, and sex were repeatedly exposed to four different and incrementally challenging laboratory-based slipping perturbations during a self-initiated, goal-directed step and reach task. Both younger and older cohorts showed similar heightened perceptions in fear of falling after fear priming, and changes in peak joint excursions including reduced ankle flexion, and increased lumbar flexion after fear priming. Age-related changes were only evident in total mediolateral center of mass displacement, with younger participants showing greater displacement after fear priming. Despite clear differences in preparatory muscle onsets relative to reach onset seen in older participants, muscle timings or co-contraction indices were not significantly different. Methods utilizing repeated exposure to varying increases of a slip-based postural challenge can successfully prime fear of falling in individuals, regardless of age.

    in Frontiers in Ageing Neuroscience on August 05, 2020 12:00 AM.

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    Principles of Corticocortical Communication: Proposed Schemes and Design Considerations

    Nearly all brain functions involve routing neural activity among a distributed network of areas. Understanding this routing requires more than a description of interareal anatomical connectivity: it requires understanding what controls the flow of signals through interareal circuitry and how this communication might be modulated to allow flexible behavior. Here we review proposals of how communication, particularly between visual cortical areas, is instantiated and modulated, highlighting recent work that offers new perspectives.

    in Trends in Neurosciences: In press on August 05, 2020 12:00 AM.

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    Parent TRAP: Discriminating Infant Cries Requires a Higher-Order Auditory Association Area in Mice

    A circuit understanding of how perception links to response requires integrating neural connectivity, activity, and behavior. In this issue of Neuron, Tasaka et al. (2020) target neurons activated by ultrasonic pup vocalizations and discover a functional synaptic network embedded through acoustically selective TeA neurons that help link the calls to a discriminative maternal behavioral response.

    in Neuron: Current Issue on August 05, 2020 12:00 AM.

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    Young Neurons Tickle Memory during REM Sleep

    Memory formation is a dynamic process and sleep is part of it. Consolidation of memories relies on finely orchestrated brain activities occurring during the post-learning sleep period. In this issue of Neuron, Kumar and colleagues provide evidence that the activity of adult-born hippocampal neurons during REM sleep is critical for the consolidation of episodic memory.

    in Neuron: Current Issue on August 05, 2020 12:00 AM.

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    Precision Neuroimaging Opens a New Chapter of Neuroplasticity Experimentation

    Characterizing the brain’s ability to adapt to changing environments has been at the forefront of neuroscience for decades. In this issue of Neuron, Newbold et al. (2020) build on this neuroplasticity work using precision neuroimaging and arm casting to unmask previously unknown pulses of spontaneous activity.

    in Neuron: Current Issue on August 05, 2020 12:00 AM.

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    Dialogue Across Chasm: Are Psychology and Neurophysiology Incompatible?

    To establish a genuine scientific discourse, we must accept a long due departure from the habit of neatly arranging things in a hierarchy where “macroscopic” psychological mystery awaits explanation in terms of “microscopic” neural objects. Instead, a relational scientific methodology is wanted, accompanied by a dialogic mode of conversation between the disciplines.

    in Neuron: In press on August 05, 2020 12:00 AM.

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    Selective Mesoaccumbal Pathway Inactivation Affects Motivation but Not Reinforcement-Based Learning in Macaques

    Vancraeyenest et al. reversibly inactivated the pathway from the VTA to the NAc using a double-infection viral vector approach in macaques. This mainly affected dopaminergic projections and resulted in increased functional connectivity, especially pronounced in fronto-temporal circuits. Surprisingly, reinforcement-based learning remained unaffected, contrary to motivational behavior requiring high effort.

    in Neuron: In press on August 05, 2020 12:00 AM.

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    Molecular Crux of Hair Cell Mechanotransduction Machinery

    Although 62 years have elapsed since the first report of hereditary deafness in a mouse strain, the molecular mechanism of hair cell mechanotransduction remains elusive. Three recent studies present crucial insights into the molecular crux of hair cell mechanotransduction machinery.

    in Neuron: Current Issue on August 05, 2020 12:00 AM.

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    Vesicle Pools of Memory at Mossy Fiber Synapses

    In this issue of Neuron, Vandael et al. (2020) reveal that post-tetanic potentiation at dentate gyrus mossy fiber synapses is induced by natural activity patterns. This plasticity is mediated by an increase in readily releasable vesicle pool size and is extended in the absence of activity, forming a “pool engram.”

    in Neuron: Current Issue on August 05, 2020 12:00 AM.

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    Predicting precision grip grasp locations on three-dimensional objects

    by Lina K. Klein, Guido Maiello, Vivian C. Paulun, Roland W. Fleming

    We rarely experience difficulty picking up objects, yet of all potential contact points on the surface, only a small proportion yield effective grasps. Here, we present extensive behavioral data alongside a normative model that correctly predicts human precision grasping of unfamiliar 3D objects. We tracked participants’ forefinger and thumb as they picked up objects of 10 wood and brass cubes configured to tease apart effects of shape, weight, orientation, and mass distribution. Grasps were highly systematic and consistent across repetitions and participants. We employed these data to construct a model which combines five cost functions related to force closure, torque, natural grasp axis, grasp aperture, and visibility. Even without free parameters, the model predicts individual grasps almost as well as different individuals predict one another’s, but fitting weights reveals the relative importance of the different constraints. The model also accurately predicts human grasps on novel 3D-printed objects with more naturalistic geometries and is robust to perturbations in its key parameters. Together, the findings provide a unified account of how we successfully grasp objects of different 3D shape, orientation, mass, and mass distribution.

    in PLoS Computational Biology on August 04, 2020 09:00 PM.

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    Identification of regenerative processes in neonatal spinal cord injury in the opossum (Monodelphis domestica): A transcriptomic study

    Identification of regenerative processes in neonatal spinal cord injury in the opossum (Monodelphis domestica): A transcriptomic study

    In opossums, spinal injury early in development results in spontaneous axon growth through the injury, but this regeneration diminishes with maturity until it is lost entirely. Analysis of the postinjury transcriptomes suggests that there is a more complex transcriptomic response in nonregenerating cords, suggesting a stronger influence of non‐neuronal cells in the outcome after injury, and suggesting that a prolonged immune response may be inhibitory to spinal cord regeneration.


    Abstract

    This study investigates the response to spinal cord injury in the gray short‐tailed opossum (Monodelphis domestica ). In opossums spinal injury early in development results in spontaneous axon growth through the injury, but this regenerative potential diminishes with maturity until it is lost entirely. The mechanisms underlying this regeneration remain unknown. RNA sequencing was used to identify differential gene expression in regenerating (SCI at postnatal Day 7, P7SCI) and nonregenerating (SCI at Day 28, P28SCI) cords +1d, +3d, and +7d after complete spinal transection, compared to age‐matched controls. Genes showing significant differential expression (log2FC ≥ 1, Padj ≤ 0.05) were used for downstream analysis. Across all time‐points 233 genes altered expression after P7SCI, and 472 genes altered expression after P28SCI. One hundred and forty‐seven genes altered expression in both injury ages (63% of P7SCI data set). The majority of changes were gene upregulations. Gene ontology overrepresentation analysis in P7SCI gene‐sets showed significant overrepresentations only in immune‐associated categories, while P28SCI gene‐sets showed overrepresentations in these same immune categories, along with other categories such as “cell proliferation,” “cell adhesion,” and “apoptosis.” Cell‐type–association analysis suggested that, regardless of injury age, injury‐associated gene transcripts were most strongly associated with microglia and endothelial cells, with strikingly fewer astrocyte, oligodendrocyte and neuron‐related genes, the notable exception being a cluster of mostly downregulated oligodendrocyte‐associated genes in the P7SCI + 7d gene‐set. Our findings demonstrate a more complex transcriptomic response in nonregenerating cords, suggesting a strong influence of non‐neuronal cells in the outcome after injury and providing the largest survey yet of the transcriptomic changes occurring after SCI in this model.

    in Journal of Comparative Neurology on August 04, 2020 07:00 PM.

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    Polysialic acid in the rat brainstem and thoracolumbar spinal cord: Distribution, cellular location, and comparison with mouse

    Polysialic acid in the rat brainstem and thoracolumbar spinal cord: Distribution, cellular location, and comparison with mouse

    Distribution of polysialic acid (polySia) immunoreactivity in the adult rat brainstem (a) and thoracolumbar spinal cord (b–e). Discrete neural regions express the glycan, including the nucleus of solitary tract, Sp5C, A1 region (a) and dorsal horn and lateral horn (b) where choline acetyltransferase positive sympathetic preganglionic neurons are often coated with polySia (c–e).


    Abstract

    Polysialic acid (polySia), a homopolymer of α2,8‐linked glycans, is a posttranslational modification on a few glycoproteins, most commonly in the brain, on the neural cell adhesion molecule. Most research in the adult central nervous system has focused on its expression in higher brain regions, where its distribution coincides with regions known to exhibit high levels of synaptic plasticity. In contrast, scant attention has been paid to the expression of polySia in the hindbrain. The main aims of the study were to examine the distribution of polySia immunoreactivity in the brainstem and thoracolumbar spinal cord, to compare the distribution of polySia revealed by two commercial antibodies commonly used for its investigation, and to compare labeling in the rat and mouse. We present a comprehensive atlas of polySia immunoreactivity: we report that polySia labeling is particularly dense in the dorsal tegmentum, medial vestibular nuclei and lateral parabrachial nucleus, and in brainstem regions associated with autonomic function, including the dorsal vagal complex, A5, rostral ventral medulla, A1, and midline raphe, as well as sympathetic preganglionic neurons in the spinal cord and central targets of primary sensory afferents (nucleus of the solitary tract, spinal trigeminal nucleus, and dorsal horn [DH]). Ultrastructural examination showed labeling was present predominantly on the plasma membrane/within the extracellular space/in or on astrocytes. Labeling throughout the brainstem and spinal cord were very similar for the two antibodies and was eliminated by the polySia‐specific sialidase, Endo‐NF. Similar patterns of distribution were found in rat and mouse brainstem with differences evident in DH.

    in Journal of Comparative Neurology on August 04, 2020 07:00 PM.

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    Melatonin alters neuronal architecture and increases cysteine‐rich protein 1 signaling in the male mouse hippocampus

    Melatonin alters neuronal architecture and increases cysteine‐rich protein 1 signaling in the male mouse hippocampus

    Exogenous melatonin significantly alters hippocampal neuronal micromorphometry, increases cysteine‐rich protein 1 (crp‐1) expression, and improves memory retention in mice. These findings expand our knowledge about the beneficial effects of melatonin on hippocampal neurons, and implicates alterations of structural neuroplasticity and crp‐1 upregulation as possible key players in this process of cognitive function improvement.


    Abstract

    Neuronal plasticity describes changes in structure, function, and connections of neurons. The hippocampus, in particular, has been shown to exhibit considerable plasticity regarding both physiological and morphological functions. Melatonin, a hormone released by the pineal gland, promotes cell survival and dendrite maturation of neurons in the newborn brain and protects against neurological disorders. In this study, we investigated the effect of exogenous melatonin on neuronal architecture and its possible mechanism in the hippocampus of adult male C57BL/6 mice. Melatonin treatment significantly increased the total length and complexity of dendrites in the apical and basal cornu ammonis (CA) 1 and in the dentate gyrus in mouse hippocampi. Spine density in CA1 apical dendrites was increased, but no significant differences in other subregions were observed. In primary cultured hippocampal neurons, the length and arborization of neurites were significantly augmented by melatonin treatment. Additionally, western blot and immunohistochemical analyses in both in vivo and in vitro systems revealed significant increases in the level of cysteine‐rich protein 1 (crp‐1) protein, which is known to be involved in dendritic branching in mouse hippocampal neurons after melatonin treatment. Our results suggest that exogenous melatonin leads to significant alterations of neuronal micromorphometry in the adult hippocampus, possibly via crp‐1 signaling.

    in Journal of Neuroscience Research on August 04, 2020 06:24 PM.

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    Impaired intracellular trafficking of sodium‐dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington’s disease

    Impaired intracellular trafficking of sodium‐dependent vitamin C transporter 2 contributes to the redox imbalance in Huntington’s disease

    Extracellular ascorbic acid induces Ca2+ influx, stimulating sodium‐dependent vitamin C transporter 2 (SVCT2) anterograde trafficking in wild‐type cells. No ascorbic acid‐induced cytosolic Ca2+ increase was observed in Huntington's disease (HD) cells. Thus, SVCT2 would fail to reach the cellular surface, affecting ascorbic acid uptake in HD cells.


    Abstract

    Huntington's disease (HD) is a neurodegenerative disorder caused by a glutamine expansion at the first exon of the huntingtin gene. Huntingtin protein (Htt) is ubiquitously expressed and it is localized in several organelles, including endosomes. HD is associated with a failure in energy metabolism and oxidative damage. Ascorbic acid is a powerful antioxidant highly concentrated in the brain where it acts as a messenger, modulating neuronal metabolism. It is transported into neurons via the sodium‐dependent vitamin C transporter 2 (SVCT2). During synaptic activity, ascorbic acid is released from glial reservoirs to the extracellular space, inducing an increase in SVCT2 localization at the plasma membrane. Here, we studied SVCT2 trafficking and localization in HD. SVCT2 is decreased at synaptic terminals in YAC128 male mice. Using cellular models for HD (STHdhQ7 and STHdhQ111 cells), we determined that SVCT2 trafficking through secretory and endosomal pathways is altered in resting conditions. We observed Golgi fragmentation and SVCT2/Htt‐associated protein‐1 mis‐colocalization. Additionally, we observed altered ascorbic acid‐induced calcium signaling that explains the reduced SVCT2 translocation to the plasma membrane in the presence of extracellular ascorbic acid (active conditions) described in our previous results. Therefore, SVCT2 trafficking to the plasma membrane is altered in resting and active conditions in HD, explaining the redox imbalance observed during early stages of the disease.

    in Journal of Neuroscience Research on August 04, 2020 06:10 PM.

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    Reply to “Chronic traumatic encephalopathy and primary age‐related tauopathy”

    in Annals of Neurology on August 04, 2020 04:19 PM.

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    Correction to Supporting Information for Zadra et al., Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer [SI Correction]

    MEDICAL SCIENCES Correction to Supporting Information for “Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer,” by Giorgia Zadra, Caroline F. Ribeiro, Paolo Chetta, Yeung Ho, Stefano Cacciatore, Xueliang Gao, Sudeepa Syamala, Clyde Bango, Cornelia Photopoulos, Ying Huang, Svitlana Tyekucheva, Debora C. Bastos, Jeremy Tchaicha, Brian...

    in PNAS on August 04, 2020 04:02 PM.

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    Correction for Tzafetas et al., The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease [Correction]

    MEDICAL SCIENCES, CHEMISTRY Correction for “The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease,” by Menelaos Tzafetas, Anita Mitra, Maria Paraskevaidi, Zsolt Bodai, Ilkka Kalliala, Sarah Bowden, Konstantinos Lathouras, Francesca Rosini, Marcell Szasz, Adele Savage, Julia Balog, James McKenzie, Deirdre Lyons, Phillip Bennett, David...

    in PNAS on August 04, 2020 04:02 PM.

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    Correction for Pearson et al., Securing timelines in the ancient Mediterranean using multiproxy annual tree-ring data [Correction]

    ANTHROPOLOGY, CHEMISTRY Correction for “Securing timelines in the ancient Mediterranean using multiproxy annual tree-ring data,” by Charlotte Pearson, Matthew Salzer, Lukas Wacker, Peter Brewer, Adam Sookdeo, and Peter Kuniholm, which was first published March 30, 2020; 10.1073/pnas.1917445117 (Proc. Natl. Acad. Sci. U.S.A. 117, 8410–8415). The authors note that an earlier...

    in PNAS on August 04, 2020 04:02 PM.

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    Thermodynamic energetics underlying genomic instability and whole-genome doubling in cancer [Chemistry]

    Genomic instability contributes to tumorigenesis through the amplification and deletion of cancer driver genes. DNA copy number (CN) profiling of ensembles of tumors allows a thermodynamic analysis of the profile for each tumor. The free energy of the distribution of CNs is found to be a monotonically increasing function of...

    in PNAS on August 04, 2020 04:02 PM.

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    A mechanism-aware and multiomic machine-learning pipeline characterizes yeast cell growth [Biophysics and Computational Biology]

    Metabolic modeling and machine learning are key components in the emerging next generation of systems and synthetic biology tools, targeting the genotype–phenotype–environment relationship. Rather than being used in isolation, it is becoming clear that their value is maximized when they are combined. However, the potential of integrating these two frameworks...

    in PNAS on August 04, 2020 04:02 PM.

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    Allosteric deactivation of PIFs and EIN3 by microproteins in light control of plant development [Plant Biology]

    Buried seedlings undergo dramatic developmental transitions when they emerge from soil into sunlight. As central transcription factors suppressing light responses, PHYTOCHROME-INTERACTING FACTORs (PIFs) and ETHYLENE-INSENSITIVE 3 (EIN3) actively function in darkness and must be promptly repressed upon light to initiate deetiolation. Microproteins are evolutionarily conserved small single-domain proteins that act...

    in PNAS on August 04, 2020 04:02 PM.

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    Tonoplast-localized Ca2+ pumps regulate Ca2+ signals during pattern-triggered immunity in Arabidopsis thaliana [Plant Biology]

    One of the major events of early plant immune responses is a rapid influx of Ca2+ into the cytosol following pathogen recognition. Indeed, changes in cytosolic Ca2+ are recognized as ubiquitous elements of cellular signaling networks and are thought to encode stimulus-specific information in their duration, amplitude, and frequency. Despite...

    in PNAS on August 04, 2020 04:02 PM.

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    Light modulates the gravitropic responses through organ-specific PIFs and HY5 regulation of LAZY4 expression in Arabidopsis [Plant Biology]

    Light and gravity are two key environmental factors that control plant growth and architecture. However, the molecular basis of the coordination of light and gravity signaling in plants remains obscure. Here, we report that two classes of transcription factors, PHYTOCHROME INTERACTING FACTORS (PIFs) and ELONGATED HYPOCOTYL5 (HY5), can directly bind...

    in PNAS on August 04, 2020 04:02 PM.

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    Induced proximity of a TIR signaling domain on a plant-mammalian NLR chimera activates defense in plants [Plant Biology]

    Plant and animal intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors detect pathogen-derived molecules and activate defense. Plant NLRs can be divided into several classes based upon their N-terminal signaling domains, including TIR (Toll-like, Interleukin-1 receptor, Resistance protein)- and CC (coiled-coil)-NLRs. Upon ligand detection, mammalian NAIP and NLRC4 NLRs oligomerize, forming...

    in PNAS on August 04, 2020 04:02 PM.

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    TNNT2 mutations in the tropomyosin binding region of TNT1 disrupt its role in contractile inhibition and stimulate cardiac dysfunction [Physiology]

    Muscle contraction is regulated by the movement of end-to-end-linked troponin−tropomyosin complexes over the thin filament surface, which uncovers or blocks myosin binding sites along F-actin. The N-terminal half of troponin T (TnT), TNT1, independently promotes tropomyosin-based, steric inhibition of acto-myosin associations, in vitro. Recent structural models additionally suggest TNT1 may...

    in PNAS on August 04, 2020 04:02 PM.

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    Redistribution of metabolic resources through astrocyte networks mitigates neurodegenerative stress [Neuroscience]

    In the central nervous system, glycogen-derived bioenergetic resources in astrocytes help promote tissue survival in response to focal neuronal stress. However, our understanding of the extent to which these resources are mobilized and utilized during neurodegeneration, especially in nearby regions that are not actively degenerating, remains incomplete. Here we modeled...

    in PNAS on August 04, 2020 04:02 PM.

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    V1 neurons encode the perceptual compensation of false torsion arising from Listing’s law [Neuroscience]

    We try to deploy the retinal fovea to optimally scrutinize an object of interest by directing our eyes to it. The horizontal and vertical components of eye positions acquired by goal-directed saccades are determined by the object’s location. However, the eccentric eye positions also involve a torsional component, which according...

    in PNAS on August 04, 2020 04:02 PM.

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    Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans [Neuroscience]

    Humans display reproducible sex differences in cognition and behavior, which may partly reflect intrinsic sex differences in regional brain organization. However, the consistency, causes and consequences of sex differences in the human brain are poorly characterized and hotly debated. In contrast, recent studies in mice—a major model organism for studying...

    in PNAS on August 04, 2020 04:02 PM.

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    A connectomics approach to understanding a retinal disease [Neuroscience]

    Macular telangiectasia type 2 (MacTel), a late-onset macular degeneration, has been linked to a loss in the retina of Müller glial cells and the amino acid serine, synthesized by the Müller cells. The disease is confined mainly to a central retinal region called the MacTel zone. We have used electron...

    in PNAS on August 04, 2020 04:02 PM.

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    Human cytomegalovirus protein pUL36: A dual cell death pathway inhibitor [Microbiology]

    Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of intrinsic, innate, and adaptive viral immune evasion. Here, we employed multiplexed tandem mass tag-based proteomics to characterize host proteins targeted for degradation late during HCMV infection. This approach revealed that mixed lineage kinase domain-like protein (MLKL), a key...

    in PNAS on August 04, 2020 04:02 PM.

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    FOXO transcription factors activate alternative major immediate early promoters to induce human cytomegalovirus reactivation [Microbiology]

    Human progenitor cells (HPCs) support human cytomegalovirus (HCMV) latency, and their differentiation along the myeloid lineage triggers cellular cues that drive reactivation. A key step during HCMV reactivation in latently infected HPCs is reexpression of viral major immediate early (MIE) genes. We recently determined that the major immediate early promoter...

    in PNAS on August 04, 2020 04:02 PM.

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    Fc-mediated effector function contributes to the in vivo antiviral effect of an HIV neutralizing antibody [Microbiology]

    Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor...

    in PNAS on August 04, 2020 04:02 PM.

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    Morphological profiling of tubercle bacilli identifies drug pathways of action [Microbiology]

    Morphological profiling is a method to classify target pathways of antibacterials based on how bacteria respond to treatment through changes to cellular shape and spatial organization. Here we utilized the cell-to-cell variation in morphological features of Mycobacterium tuberculosis bacilli to develop a rapid profiling platform called Morphological Evaluation and Understanding...

    in PNAS on August 04, 2020 04:02 PM.

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    The gain-of-function allele bamAE470K bypasses the essential requirement for BamD in {beta}-barrel outer membrane protein assembly [Microbiology]

    The outer membrane (OM) of gram-negative bacteria confers innate resistance to toxins and antibiotics. Integral β-barrel outer membrane proteins (OMPs) function to establish and maintain the selective permeability of the OM. OMPs are assembled into the OM by the β-barrel assembly machine (BAM), which is composed of one OMP—BamA—and four...

    in PNAS on August 04, 2020 04:02 PM.

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    Wide lag time distributions break a trade-off between reproduction and survival in bacteria [Microbiology]

    Many microorganisms face a fundamental trade-off between reproduction and survival: Rapid growth boosts population size but makes microorganisms sensitive to external stressors. Here, we show that starved bacteria encountering new resources can break this trade-off by evolving phenotypic heterogeneity in lag time. We quantify the distribution of single-cell lag times...

    in PNAS on August 04, 2020 04:02 PM.

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    Nanoparticles presenting clusters of CD4 expose a universal vulnerability of HIV-1 by mimicking target cells [Microbiology]

    CD4-based decoy approaches against HIV-1 are attractive options for long-term viral control, but initial designs, including soluble CD4 (sCD4) and CD4-Ig, were ineffective. To evaluate a therapeutic that more accurately mimics HIV-1 target cells compared with monomeric sCD4 and dimeric CD4-Ig, we generated virus-like nanoparticles that present clusters of membrane-associated...

    in PNAS on August 04, 2020 04:02 PM.

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    Molecular basis of Coxsackievirus A10 entry using the two-in-one attachment and uncoating receptor KRM1 [Microbiology]

    KREMEN1 (KRM1) has been identified as a functional receptor for Coxsackievirus A10 (CV-A10), a causative agent of hand-foot-and-mouth disease (HFMD), which poses a great threat to infants globally. However, the underlying mechanisms for the viral entry process are not well understood. Here we determined the atomic structures of different forms...

    in PNAS on August 04, 2020 04:02 PM.

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    Yin Yang 1 is a potent activator of human T lymphotropic virus type 1 LTR-driven gene expression via RNA binding [Microbiology]

    Yin Yang 1 (YY1) is a DNA-binding transcription factor that either activates or represses gene expression. YY1 has previously been implicated in the transcriptional silencing of many retroviruses by binding to DNA sequences in the U3 region of the viral long terminal repeat (LTR). We here show that YY1 overexpression...

    in PNAS on August 04, 2020 04:02 PM.

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    Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA [Microbiology]

    A scalable approach for quantifying intact HIV-1 proviruses is critical for basic research and clinical trials directed at HIV-1 cure. The intact proviral DNA assay (IPDA) is a novel approach to characterizing the HIV-1 reservoir, focusing on the genetic integrity of individual proviruses independent of transcriptional status. It uses multiplex...

    in PNAS on August 04, 2020 04:02 PM.

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    Subdomain cryo-EM structure of nodaviral replication protein A crown complex provides mechanistic insights into RNA genome replication [Microbiology]

    For positive-strand RNA [(+)RNA] viruses, the major target for antiviral therapies is genomic RNA replication, which occurs at poorly understood membrane-bound viral RNA replication complexes. Recent cryoelectron microscopy (cryo-EM) of nodavirus RNA replication complexes revealed that the viral double-stranded RNA replication template is coiled inside a 30- to 90-nm invagination...

    in PNAS on August 04, 2020 04:02 PM.

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    High-throughput discovery of phage receptors using transposon insertion sequencing of bacteria [Microbiology]

    As the most abundant microbes on Earth, novel bacteriophages (phages; bacteria-specific viruses) are readily isolated from environmental samples. However, it remains challenging to characterize phage–bacteria interactions, such as the host receptor(s) phages bind to initiate infection. Here, we tested whether transposon insertion sequencing (INSeq) could be used to identify bacterial...

    in PNAS on August 04, 2020 04:02 PM.

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    Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects [Medical Sciences]

    Huntington’s disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms. It is caused by expansion of a cytosine–adenine–guanine triplet in the N-terminal domain of exon 1 in the huntingtin (HTT) gene that codes for an expanded polyglutamine stretch in the protein product which becomes aggregation...

    in PNAS on August 04, 2020 04:02 PM.

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    Microbial exposure drives polyclonal expansion of innate {gamma}{delta} T cells immediately after birth [Immunology and Inflammation]

    Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how γδ T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children...

    in PNAS on August 04, 2020 04:02 PM.

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    Fetal public V{gamma}9V{delta}2 T cells expand and gain potent cytotoxic functions early after birth [Immunology and Inflammation]

    Vγ9Vδ2 T cells are a major human blood γδ T cell population that respond in a T cell receptor (TCR)-dependent manner to phosphoantigens which are generated by a variety of microorganisms. It is not clear how Vγ9Vδ2 T cells react toward the sudden microbial exposure early after birth. We found...

    in PNAS on August 04, 2020 04:02 PM.

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    Bacterial immunotherapy for cancer induces CD4-dependent tumor-specific immunity through tumor-intrinsic interferon-{gamma} signaling [Immunology and Inflammation]

    Bacillus Calmette–Guérin (BCG) immunotherapy for bladder cancer is the only bacterial cancer therapy approved for clinical use. Although presumed to induce T cell-mediated immunity, whether tumor elimination depends on bacteria-specific or tumor-specific immunity is unknown. Herein we show that BCG-induced bladder tumor elimination requires CD4 and CD8 T cells, although...

    in PNAS on August 04, 2020 04:02 PM.

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    Ethical Justifications for Pandemic Rationing Strategies

    in Annals of Neurology on August 04, 2020 03:09 PM.

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    Neurologists' Duties in Planning for Triage of Critical Care Resources during the COVID‐19 Pandemic

    in Annals of Neurology on August 04, 2020 03:03 PM.

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    The entorhinal cortex of the monkey: VI. Organization of projections from the hippocampus, subiculum, presubiculum, and parasubiculum

    The entorhinal cortex of the monkey: VI. Organization of projections from the hippocampus, subiculum, presubiculum, and parasubiculum

    Projections from hippocampal fields CA1 and the subiculum to the entorhinal cortex are topographically organized. Projections from the presubiculum preferentially distribute to the caudal half of the entorhinal cortex and thus provides a potential indicator for a primate homologue of the medial entorhinal cortex as defined in rodents.


    ABSTRACT

    The organization of projections from the macaque monkey hippocampus, subiculum, presubiculum, and parasubiculum to the entorhinal cortex was analyzed using anterograde and retrograde tracing techniques. Projections exclusively originate in the CA1 field of the hippocampus and in the subiculum, presubiculum, and parasubiculum. The CA1 and subicular projections terminate most densely in Layers V and VI of the entorhinal cortex, with sparser innervation of the deep portion of Layers III and II. Entorhinal projections from CA1 and the subiculum are topographically organized such that a rostrocaudal axis of origin is related to a medial‐to‐lateral axis of termination. A proximodistal axis of origin in CA1 and distoproximal axis in subiculum are related to a rostrocaudal axis of termination in the entorhinal cortex. The presubiculum sends a dense, bilateral projection to caudal parts of the entorhinal cortex. This projection terminates most densely in Layer III with sparser termination in Layers I, II, and V. The same parts of entorhinal cortex receive a dense projection from the parasubiculum. This projection terminates in Layers III and II. Both presubicular and parasubicular projections demonstrate the same longitudinal topographic organization as the projections from CA1 and the subiculum. These studies demonstrate that: (a) hippocampal and subicular inputs to the entorhinal cortex in the monkey are organized similar to those described in nonprimate species; (b) the topographic organization of the projections from the hippocampus and subicular areas matches that of the reciprocal projections from the entorhinal cortex to the hippocampus and the subicular areas.

    in Journal of Comparative Neurology on August 04, 2020 08:20 AM.

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    An ultracold junction

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1015-5

    An ultracold junction

    in Nature Physics on August 04, 2020 12:00 AM.

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    Unequal equals

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1014-6

    Unequal equals

    in Nature Physics on August 04, 2020 12:00 AM.

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    Test your theory

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1013-7

    Test your theory

    in Nature Physics on August 04, 2020 12:00 AM.

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    Lost and found

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1012-8

    Lost and found

    in Nature Physics on August 04, 2020 12:00 AM.

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    Spins sense fields

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1011-9

    Spins sense fields

    in Nature Physics on August 04, 2020 12:00 AM.

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    Black physicists matter

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1010-x

    The persistent under-representation of Black physicists is a systemic problem that requires will, money and long-term commitment to be solved.

    in Nature Physics on August 04, 2020 12:00 AM.

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    The unifying role of topology

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-1001-y

    The unifying role of topology

    in Nature Physics on August 04, 2020 12:00 AM.

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    A spectral unit

    Nature Physics, Published online: 04 August 2020; doi:10.1038/s41567-020-0997-3

    Giacomo Prando summarizes the troubled history of the radian, a unit with the odd property of appearing and disappearing seemingly at will in dimensional formulas.

    in Nature Physics on August 04, 2020 12:00 AM.

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    Effects of Cortical Cooling on Activity Across Layers of the Rat Barrel Cortex

    Moderate cortical cooling is known to suppress slow oscillations and to evoke persistent cortical activity. However, the cooling-induced changes in electrical activity across cortical layers remain largely unknown. Here, we performed multi-channel local field potential (LFP) and multi-unit activity (MUA) recordings with linear silicone probes through the layers of single cortical barrel columns in urethane-anesthetized rats under normothermia (38°C) and during local cortical surface cooling (30°C). During cortically generated slow oscillations, moderate cortical cooling decreased delta wave amplitude, delta-wave occurrence, the duration of silent states, and delta wave-locked MUA synchronization. Moderate cortical cooling increased total time spent in the active state and decreased total time spent in the silent state. Cooling-evoked changes in the MUA firing rate in cortical layer 5 (L5) varied from increase to decrease across animals, and the polarity of changes in L5 MUA correlated with changes in total time spent in the active state. The decrease in temperature reduced MUA firing rates in all other cortical layers. Sensory-evoked MUA responses also decreased during cooling through all cortical layers. The cooling-dependent slowdown was detected at the fast time-scale with a decreased frequency of sensory-evoked high-frequency oscillations (HFO). Thus, moderate cortical cooling suppresses slow oscillations and desynchronizes neuronal activity through all cortical layers, and is associated with reduced firing across all cortical layers except L5, where cooling induces variable and non-consistent changes in neuronal firing, which are common features of the transition from slow-wave synchronization to desynchronized activity in the barrel cortex.

    in Frontiers in Systems Neuroscience on August 04, 2020 12:00 AM.

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    Fentanyl Inhibits Air Puff-Evoked Sensory Information Processing in Mouse Cerebellar Neurons Recorded in vivo

    Aim: To examine the effects of fentanyl, a potent mu-opioid receptor (MOR) agonist, on-air puff-evoked responses in Purkinje cells (PCs), and molecular layer interneurons (MLIs) using in vivo patch-clamp recordings in anesthetized mice.

    Methods: Male mice 6–8 weeks-old were anesthetized and fixed on a custom-made stereotaxic frame. The cerebellar surface was exposed and perfused with oxygenated artificial cerebrospinal fluid (ACSF). Patch-clamp recordings in the cell-attached mode were obtained from PCs and MLIs. Facial stimulation by air-puff of the ipsilateral whisker pad was performed through a pressurized injection system. Fentanyl citrate, CTOP, and H-89 dissolved in ACSF were perfused onto the cerebellar surface.

    Results: Fentanyl significantly inhibited the amplitude and area under the curve (AUC) of sensory stimulation-evoked inhibitory responses in PCs. Although fentanyl did not influence the frequency of simple spikes (SSs), it decreased the pause of SS. The IC50 of the fentanyl-induced suppression of the P1 response amplitude was 5.53 μM. The selective MOR antagonist CTOP abolished fentanyl-induced inhibitory responses in PCs. However, the application of CTOP alone increased the amplitude, AUC of P1, and the pause of SS. Notably, fentanyl significantly inhibited the tactile-evoked response of MLIs but did not affect their spontaneous firing. The fentanyl-induced decrease of inhibitory responses in PCs was partially prevented by a PKA inhibitor, H-89.

    Conclusions: These results suggest that fentanyl binds to MORs in MLIs to reduce GABAergic neurotransmission in MLI-PC projections and one potential mechanism is via modulation of the cAMP-PKA pathway.

    in Frontiers in Systems Neuroscience on August 04, 2020 12:00 AM.

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    Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease

    Alzheimer’s disease (AD) is the most common type of senile dementia, characterized by neurofibrillary tangle and amyloid plaque in brain pathology. Major efforts in AD drug were devoted to the interference with the production and accumulation of amyloid-β peptide (Aβ), which plays a causal role in the pathogenesis of AD. Aβ is generated from amyloid precursor protein (APP), by consecutive cleavage by β-secretase and γ-secretase. Therefore, β-secretase and γ-secretase inhibition have been the focus for AD drug discovery efforts for amyloid reduction. Here, we review β-secretase inhibitors and γ-secretase inhibitors/modulators, and their efficacies in clinical trials. In addition, we discussed the novel concept of specifically targeting the γ-secretase substrate APP. Targeting amyloidogenic processing of APP is still a fundamentally sound strategy to develop disease-modifying AD therapies and recent advance in γ-secretase/APP complex structure provides new opportunities in designing selective inhibitors/modulators for AD.

    in Frontiers in Molecular Neuroscience on August 04, 2020 12:00 AM.

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    Collapsin Response Mediator Protein 2 and Endophilin2 Coordinate Regulation of AMPA Receptor GluA1 Subunit Recycling

    The dynamic trafficking of AMPA receptors (AMPARs), which enables the endocytosis, recycling, and exocytosis of AMPARs, is crucial for synaptic plasticity. Endophilin2, which directly interacts with the GluA1 subunit of AMPARs, plays an important role in AMPAR endocytosis. Collapsin response mediator protein 2 (CRMP2) promotes the maturation of the dendritic spine and can transfer AMPARs to the membrane. Although the mechanisms of AMPAR endocytosis and exocytosis are well known, the exact molecular mechanisms underlying AMPAR recycling remain unclear. Here, we report a unique interaction between CRMP2 and endophilin2. Our results showed that overexpression of CRMP2 and endophilin2 increased the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs) and modestly enhanced AMPAR levels in hippocampal neurons. Furthermore, the CRMP2 and endophilin2 overexpression phenotype failed to occur when the interaction between these two proteins was inhibited. Further analysis revealed that this interaction was regulated by CRMP2 phosphorylation. The phosphorylation of CRMP2 inhibited its interaction with endophilin2; this was mainly affected by the phosphorylation of Thr514 and Ser518 by glycogen synthase kinase (GSK) 3β. CRMP2 phosphorylation increased degradation and inhibited the surface expression of AMPAR GluA1 subunits in cultured hippocampal neurons. However, the dephosphorylation of CRMP2 inhibited degradation and promoted the surface expression of AMPAR GluA1 subunits in cultured hippocampal neurons. Taken together, our data demonstrated that the interaction between CRMP2 and endophilin2 was conductive to the recycling of AMPA receptor GluA1 subunits in hippocampal neurons.

    in Frontiers in Molecular Neuroscience on August 04, 2020 12:00 AM.

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    Assessing the Effects of Continuous Theta Burst Stimulation Over the Dorsolateral Prefrontal Cortex on Human Cognition: A Systematic Review

    Theta burst stimulation is increasingly growing in popularity as a non-invasive method of moderating corticospinal networks. Theta burst stimulation uses gamma frequency trains applied at the rhythm of theta, thus, mimicking theta–gamma coupling involved in cognitive processes. The dorsolateral prefrontal cortex has been found to play a crucial role in numerous cognitive processes. Here, we include 25 studies for review to determine the cognitive effects of continuous theta burst stimulation over the dorsolateral prefrontal cortex; 20 of these studies are healthy participant and five are patient (pharmacotherapy-resistant depression) studies. Due to the heterogeneous nature of the included studies, only a descriptive approach is used and meta-analytics ruled out. The cognitive effect is measured on various cognitive domains: attention, working memory, planning, language, decision making, executive function, and inhibitory and cognitive control. We conclude that continuous theta burst stimulation over the dorsolateral prefrontal cortex mainly inhibits cognitive performance. However, in some instances, it can lead to improved performance by inhibiting the effect of distractors or other competing irrelevant cognitive processes. To be precise, continuous theta burst stimulation over the right dorsolateral prefrontal cortex impaired attention, inhibitory control, planning, and goal-directed behavior in decision making but also improved decision making by reducing impulsivity. Conversely, continuous theta burst stimulation over the left dorsolateral prefrontal cortex impaired executive function, working, auditory feedback regulation, and cognitive control but accelerated the planning, decision-making process. These findings constitute a useful contribution to the literature on the cognitive effects of continuous theta burst stimulation over the dorsolateral prefrontal cortex.

    in Frontiers in Integrative Neuroscience on August 04, 2020 12:00 AM.

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    Abnormal Spontaneous Neural Activity in Parkinson’s Disease With “pure” Apathy

    Background

    Apathy is one of the most common non-motor symptoms of Parkinson’s disease (PD). However, its pathophysiology remains unclear.

    Methods

    We analyzed resting-state functional magnetic resonance imaging (MRI) data acquired at a 3.0T MRI scanner using the amplitude of low-frequency fluctuation (ALFF) metric in 20 de novo, drug-naïve, non-demented PD patients with apathy (PD-A), 26 PD patients without apathy (PD-NA) without comorbidity of depressive or anxious symptoms, and 23 matched healthy control (HC) subjects.

    Results

    We found that the ALFF decreased significantly in the bilateral nucleus accumbens, dorsal anterior cingulate cortex (ACC), and left dorsolateral prefrontal cortex in patients with PD-A compared to patients with PD-NA and HC subjects. Furthermore, apathy severity was negatively correlated with the ALFF in the bilateral nucleus accumbens and dorsal ACC in the pooled patients with PD.

    Conclusion

    The present study characterized the functional pattern of changes in spontaneous neural activity in patients with PD-A. With the aim to better elucidate the pathophysiological mechanisms responsible for these changes, this study controlled for the potentially confounding effects of dopaminergic medication, depression, anxiety, and global cognitive impairment. The findings of the current study add to the literature by highlighting potential abnormalities in mesocorticolimbic pathways involved in the development of apathy in PD.

    in Frontiers in Neuroscience: Neurodegeneration on August 04, 2020 12:00 AM.

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    TRP Channels Role in Pain Associated With Neurodegenerative Diseases

    Transient receptor potential (TRP) are cation channels expressed in both non-excitable and excitable cells from diverse tissues, including heart, lung, and brain. The TRP channel family includes 28 isoforms activated by physical and chemical stimuli, such as temperature, pH, osmotic pressure, and noxious stimuli. Recently, it has been shown that TRP channels are also directly or indirectly activated by reactive oxygen species. Oxidative stress plays an essential role in neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, and TRP channels are involved in the progression of those diseases by mechanisms involving changes in the crosstalk between Ca2+ regulation, oxidative stress, and production of inflammatory mediators. TRP channels involved in nociception include members of the TRPV, TRPM, TRPA, and TRPC subfamilies that transduce physical and chemical noxious stimuli. It has also been reported that pain is a complex issue in patients with Alzheimer’s and Parkinson’s diseases, and adequate management of pain in those conditions is still in discussion. TRPV1 has a role in neuroinflammation, a critical mechanism involved in neurodegeneration. Therefore, some studies have considered TRPV1 as a target for both pain treatment and neurodegenerative disorders. Thus, this review aimed to describe the TRP-dependent mechanism that can mediate pain sensation in neurodegenerative diseases and the therapeutic approach available to palliate pain and neurodegenerative symptoms throughout the regulation of these channels.

    in Frontiers in Neuroscience: Neurodegeneration on August 04, 2020 12:00 AM.

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    MR Imaging of SCA3/MJD

    Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive autosomal dominantly inherited cerebellar ataxia characterized by the aggregation of polyglutamine-expanded protein within neuronal nuclei in the brain, which can lead to brain damage that precedes the onset of clinical manifestations. Magnetic resonance imaging (MRI) techniques such as morphometric MRI, diffusion tensor imaging (DTI), functional magnetic resonance imaging (fMRI), and magnetic resonance spectroscopy (MRS) have gained increasing attention as non-invasive and quantitative methods for the assessment of structural and functional alterations in clinical SCA3/MJD patients as well as preclinical carriers. Morphometric MRI has demonstrated typical patterns of atrophy or volume loss in the cerebellum and brainstem with extensive lesions in some supratentorial areas. DTI has detected widespread microstructural alterations in brain white matter, which indicate disrupted brain anatomical connectivity. Task-related fMRI has presented unusual brain activation patterns within the cerebellum and some extracerebellar tissue, reflecting the decreased functional connectivity of these brain regions in SCA3/MJD subjects. MRS has revealed abnormal neurochemical profiles, such as the levels or ratios of N-acetyl aspartate, choline, and creatine, in both clinical cases and preclinical cases before the alterations in brain anatomical structure. Moreover, a number of studies have reported correlations of MR imaging alterations with clinical and genetic features. The utility of these MR imaging techniques can help to identify preclinical SCA3/MJD carriers, monitor disease progression, evaluate response to therapeutic interventions, and illustrate the pathophysiological mechanisms underlying the occurrence, development, and prognosis of SCA3/MJD.

    in Frontiers in Neuroscience: Neurodegeneration on August 04, 2020 12:00 AM.

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    Self-Selection of Interesting Occupation Facilitates Cognitive Response to the Task: An Event-Related Potential Study

    Introduction: In this study, we examined whether the self-selection of occupations of interest affects reaction times (RTs) and cognitive processing by using the Aid for Decision-making in Occupation Choice (ADOC) and event-related potentials (ERP). We also assessed the relationship of these with psychological indicators.

    Method: We extracted 78 occupations from the ADOC in consideration of the subjects’ age, and three conditions were set: (1) self-selection of an interesting occupation; (2) self-selection of a disliked occupation; and (3) forced selection. The RT task was executed under their conditions during which ERP was measured. We compared the P300 component of ERP in these conditions. Moreover, we examined the association of cognitive processing and degree of satisfaction and performance concerning occupation, with psychological indicators.

    Results: P300 amplitude at Fz significantly increased in the self-selection of an interesting occupation. P300 amplitude at Pz was significantly positively correlated with the occupational satisfaction score.

    Conclusion: Self-selection of interesting occupations in the ADOC resulted in increased attention resource allocation by increasing motivation. Further, there was a positive correlation between satisfaction concerning the occupation and attention of resource allocation. Therefore, occupational therapists should know which occupations the patients consider interesting and help them to select by themselves, thus enhancing their satisfaction after consultation. These interventions may contribute to promoting motivation and cognitive processing.

    in Frontiers in Human Neuroscience on August 04, 2020 12:00 AM.

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    Adolescent Substance Use and the Brain: Behavioral, Cognitive and Neuroimaging Correlates

    Adolescence is an important ontogenetic period that is characterized by behaviors such as enhanced novelty-seeking, impulsivity, and reward preference, which can give rise to an increased risk for substance use. While substance use rates in adolescence are generally on a decline, the current rates combined with emerging trends, such as increases in e-cigarette use, remain a significant public health concern. In this review, we focus on the neurobiological divergences associated with adolescent substance use, derived from a cross-sectional, retrospective, and longitudinal studies, and highlight how the use of these substances during adolescence may relate to behavioral and neuroimaging-based outcomes. Identifying and understanding the associations between adolescent substance use and changes in cognition, mental health, and future substance use risk may assist our understanding of the consequences of drug exposure during this critical window.

    in Frontiers in Human Neuroscience on August 04, 2020 12:00 AM.

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    Being in the Past and Perform the Future in a Virtual World: VR Applications to Assess and Enhance Episodic and Prospective Memory in Normal and Pathological Aging

    The process of aging commonly features a gradual deterioration in cognitive performance and, in particular, the decline of memory. Despite the increased longevity of the world’s population, the prevalence of neurodegenerative conditions, such as dementia, continues to be a major burden on public health, and consequently, the latest research has been focused on memory and aging. Currently, the failure of episodic and Prospective memory (PM) is one of the main complaints in the elderly, considered among the early symptoms of dementia. It is therefore increasingly important to define more clearly the boundaries between normal and pathological aging. Recently, researchers have begun to build and apply Virtual Environments (VE) to the explicit purpose of better understanding the performance of episodic and PM in complex and realistic contexts, with the perspective of further developing effective training procedures that depend on reliable cognitive assessment methods. Virtual technology offers higher levels of realism than “pen and paper” testing and at the same time more experimental control than naturalistic settings. In this mini-review article, we examine the outcomes of recently available studies on virtual reality technology applications developed for the assessment and improvement of episodic and/or PM. To consider the latest technology, we selected 29 articles that have been published in the last 10 years. These documents show that VR-based technologies can provide a valid basis for screening and treatment and, through increased sensory stimulation and enriched environments reproducing the scenarios of everyday life, could represent effective stimulating experiences even in pathological aging.

    in Frontiers in Human Neuroscience on August 04, 2020 12:00 AM.

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    Admittance Method for Estimating Local Field Potentials Generated in a Multi-Scale Neuron Model of the Hippocampus

    Significant progress has been made toward model-based prediction of neral tissue activation in response to extracellular electrical stimulation, but challenges remain in the accurate and efficient estimation of distributed local field potentials (LFP). Analytical methods of estimating electric fields are a first-order approximation that may be suitable for model validation, but they are computationally expensive and cannot accurately capture boundary conditions in heterogeneous tissue. While there are many appropriate numerical methods of solving electric fields in neural tissue models, there isn't an established standard for mesh geometry nor a well-known rule for handling any mismatch in spatial resolution. Moreover, the challenge of misalignment between current sources and mesh nodes in a finite-element or resistor-network method volume conduction model needs to be further investigated. Therefore, using a previously published and validated multi-scale model of the hippocampus, the authors have formulated an algorithm for LFP estimation, and by extension, bidirectional communication between discretized and numerically solved volume conduction models and biologically detailed neural circuit models constructed in NEURON. Development of this algorithm required that we assess meshes of (i) unstructured tetrahedral and grid-based hexahedral geometries as well as (ii) differing approaches for managing the spatial misalignment of current sources and mesh nodes. The resulting algorithm is validated through the comparison of Admittance Method predicted evoked potentials with analytically estimated LFPs. Establishing this method is a critical step toward closed-loop integration of volume conductor and NEURON models that could lead to substantial improvement of the predictive power of multi-scale stimulation models of cortical tissue. These models may be used to deepen our understanding of hippocampal pathologies and the identification of efficacious electroceutical treatments.

    in Frontiers in Computational Neuroscience on August 04, 2020 12:00 AM.

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    Overall Survival Prediction in Glioblastoma With Radiomic Features Using Machine Learning

    Glioblastoma is a WHO grade IV brain tumor, which leads to poor overall survival (OS) of patients. For precise surgical and treatment planning, OS prediction of glioblastoma (GBM) patients is highly desired by clinicians and oncologists. Radiomic research attempts at predicting disease prognosis, thus providing beneficial information for personalized treatment from a variety of imaging features extracted from multiple MR images. In this study, first-order, intensity-based volume and shape-based and textural radiomic features are extracted from fluid-attenuated inversion recovery (FLAIR) and T1ce MRI data. The region of interest is further decomposed with stationary wavelet transform with low-pass and high-pass filtering. Further, radiomic features are extracted on these decomposed images, which helped in acquiring the directional information. The efficiency of the proposed algorithm is evaluated on Brain Tumor Segmentation (BraTS) challenge training, validation, and test datasets. The proposed approach achieved 0.695, 0.571, and 0.558 on BraTS training, validation, and test datasets. The proposed approach secured the third position in BraTS 2018 challenge for the OS prediction task.

    in Frontiers in Computational Neuroscience on August 04, 2020 12:00 AM.

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    Maternal Immune Activation Affects Hippocampal Excitatory and Inhibitory Synaptic Transmission in Offspring From an Early Developmental Period to Adulthood

    One of the risk factors for schizophrenia is maternal infection. We have previously shown that Polyriboinosinic-polyribocytidylic acid (poly I:C) induced maternal immune activation in mice caused histological changes in the hippocampal CA1 area of offspring during the developmental period and impaired sensorimotor gating in offspring during adulthood, resulting in behavioral changes. However, it remains unclear how maternal immune activation functionally impacts the hippocampal neuronal activity of offspring. We studied the effect of prenatal poly I:C treatment on synaptic transmission of hippocampal CA1 pyramidal cells in postnatal and adult offspring. Treatment with poly I:C diminished excitatory and enhanced inhibitory (GABAergic) synaptic transmission on pyramidal cells in adult offspring. During the early developmental period, we still observed that treatment with poly I:C decreased excitatory synaptic transmission and potentially increased GABAergic synaptic transmission, which was uncovered under a condition of high extracellular potassium-activated neurons. In conclusion, we demonstrate that maternal immune activation decreased excitatory and increased inhibitory synaptic transmission on hippocampal pyramidal cells from an early developmental period to adulthood, which could result in net inhibition in conjunction with poor functional organization and integration of hippocampal circuits.

    in Frontiers in Cellular Neuroscience on August 04, 2020 12:00 AM.

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    What Have Advances in Transcriptomic Technologies Taught us About Human White Matter Pathologies?

    For a long time, post-mortem analysis of human brain pathologies has been purely descriptive, limiting insight into the pathological mechanisms. However, starting in the early 2000s, next-generation sequencing (NGS) and the routine application of bulk RNA-sequencing and microarray technologies have revolutionized the usefulness of post-mortem human brain tissue. This has allowed many studies to provide novel mechanistic insights into certain brain pathologies, albeit at a still unsatisfying resolution, with masking of lowly expressed genes and regulatory elements in different cell types. The recent rapid evolution of single-cell technologies has now allowed researchers to shed light on human pathologies at a previously unreached resolution revealing further insights into pathological mechanisms that will open the way for the development of new strategies for therapies. In this review article, we will give an overview of the incremental information that single-cell technologies have given us for human white matter (WM) pathologies, summarize which single-cell technologies are available, and speculate where these novel approaches may lead us for pathological assessment in the future.

    in Frontiers in Cellular Neuroscience on August 04, 2020 12:00 AM.

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    FGF5 Regulates Schwann Cell Migration and Adhesion

    The fibroblast growth factor (FGF) family polypeptides play key roles in promoting tissue regeneration and repair. FGF5 is strongly up-regulated in Schwann cells of the peripheral nervous system following injury; however, a role for FGF5 in peripheral nerve regeneration has not been shown up to now. In this report, we examined the expression of FGF5 and its receptors FGFR1-4 in Schwann cells of the mouse sciatic nerve following injury, and then measured the effects of FGF5 treatment upon cultured primary rat Schwann cells. By microarray and mRNA sequencing data analysis, RT-PCR, qPCR, western blotting and immunostaining, we show that FGF5 is highly up-regulated in Schwann cells of the mouse distal sciatic nerve following injury, and FGFR1 and FGFR2 are highly expressed in Schwann cells of the peripheral nerve both before and following injury. Using cultured primary rat Schwann cells, we show that FGF5 inhibits ERK1/2 MAP kinase activity but promotes rapid Schwann cell migration and adhesion via the upregulation of N-cadherin. Thus, FGF5 is an autocrine regulator of Schwann cells to regulate Schwann cell migration and adhesion.

    in Frontiers in Cellular Neuroscience on August 04, 2020 12:00 AM.

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    Streptozotocin Induces Alzheimer’s Disease-Like Pathology in Hippocampal Neuronal Cells via CDK5/Drp1-Mediated Mitochondrial Fragmentation

    Aberrant brain insulin signaling plays a critical role in the pathology of Alzheimer’s disease (AD). Mitochondrial dysfunction plays a role in the progression of AD, with excessive mitochondrial fission in the hippocampus being one of the pathological mechanisms of AD. However, the molecular mechanisms underlying the progression of AD and mitochondrial fragmentation induced by aberrant brain insulin signaling in the hippocampal neurons are poorly understood. Therefore, we investigated the molecular mechanistic signaling associated with mitochondrial dynamics using streptozotocin (STZ), a diabetogenic compound, in the hippocampus cell line, HT-22 cells. In this metabolic dysfunctional cellular model, hallmarks of AD such as neuronal apoptosis, synaptic loss, and tau hyper-phosphorylation are induced by STZ. We found that in the mitochondrial fission protein Drp1, phosphorylation is increased in STZ-treated HT-22 cells. We also determined that inhibition of mitochondrial fragmentation suppresses STZ-induced AD-like pathology. Furthermore, we found that phosphorylation of Drp1 was induced by CDK5, and inhibition of CDK5 suppresses STZ-induced mitochondrial fragmentation and AD-like pathology. Therefore, these findings indicate that mitochondrial morphology and functional regulation may be a strategy of potential therapeutic for treating abnormal metabolic functions associated with the pathogenesis of AD.

    in Frontiers in Cellular Neuroscience on August 04, 2020 12:00 AM.

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    That’s a Wrap! Molecular Drivers Governing Neuronal Nogo Receptor-Dependent Myelin Plasticity and Integrity

    Myelin is a dynamic membrane that is important for coordinating the fast propagation of action potentials along small or large caliber axons (0.1–10 μm) some of which extend the entire length of the spinal cord. Due to the heterogeneity of electrical and energy demands of the variable neuronal populations, the axo-myelinic and axo-glial interactions that regulate the biophysical properties of myelinated axons also vary in terms of molecular interactions at the membrane interfaces. An important topic of debate in neuroscience is how myelin is maintained and modified under neuronal control and how disruption of this control (due to disease or injury) can initiate and/or propagate neurodegeneration. One of the key molecular signaling cascades that have been investigated in the context of neural injury over the past two decades involves the myelin-associated inhibitory factors (MAIFs) that interact with Nogo receptor 1 (NgR1). Chief among the MAIF superfamily of molecules is a reticulon family protein, Nogo-A, that is established as a potent inhibitor of neurite sprouting and axon regeneration. However, an understated role for NgR1 is its ability to control axo-myelin interactions and Nogo-A specific ligand binding. These interactions may occur at axo-dendritic and axo-glial synapses regulating their functional and dynamic membrane domains. The current review provides a comprehensive analysis of how neuronal NgR1 can regulate myelin thickness and plasticity under normal and disease conditions. Specifically, we discuss how NgR1 plays an important role in regulating paranodal and juxtaparanodal domains through specific signal transduction cascades that are important for microdomain molecular architecture and action potential propagation. Potential therapeutics designed to target NgR1-dependent signaling during disease are being developed in animal models since interference with the involvement of the receptor may facilitate neurological recovery. Hence, the regulatory role played by NgR1 in the axo-myelinic interface is an important research field of clinical significance that requires comprehensive investigation.

    in Frontiers in Cellular Neuroscience on August 04, 2020 12:00 AM.

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    Substantia Nigra Hyperechogenicity Reflects the Progression of Dopaminergic Neurodegeneration in 6-OHDA Rat Model of Parkinson’s Disease

    Parkinson’s disease (PD) is the second most common neurodegenerative disease, and there is still no effective way to stop its progress. Therefore, early detection is crucial for the prevention and the treatment of Parkinson’s disease. The current diagnosis of Parkinson’s disease, however, mainly depends on the symptoms, so it is necessary to establish a reliable imaging modality for PD diagnosis and its progression monitoring. Other studies and our previous ones demonstrated that substantia nigra hyperechogenicity (SNH) was detected by transcranial sonography (TCS) in the ventral midbrain of PD patients, and SNH is regarded as a characteristic marker of PD. The present study aimed to explore whether SNH could serve as a reliable imaging modality to monitor the progression of dopaminergic neurodegeneration of PD. The results revealed that the size of SNH was positively related with the degree of dopaminergic neuron death in PD animal models. Furthermore, we revealed that microglia activation contributed to the SNH formation in substantia nigra (SN) in PD models. Taken together, this study suggests that SNH through TCS is a promising imaging modality to monitor the progression of dopaminergic neurodegeneration of PD.

    in Frontiers in Cellular Neuroscience on August 04, 2020 12:00 AM.

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    Estradiol Replacement at the Critical Period Protects Hippocampal Neural Stem Cells to Improve Cognition in APP/PS1 Mice

    It has been suggested that there is a critical window for estrogen replacement therapy (ERT) in postmenopausal women with Alzheimer’s disease (AD); however, supporting evidence is lacking. To address this issue, we investigated the effective period for estradiol (E2) treatment using a mouse model of AD. Four-month-old female APPswe/PSEN1dE9 (APP/PS1) mice were ovariectomized (OVX) and treated with E2 for 2 months starting at the age of 4 months (early period), 6 months (mid-period), or 8 months (late period). We then evaluated hippocampal neurogenesis, β-amyloid (Aβ) accumulation, telomerase activity, and hippocampal-dependent behavior. Compared to age-matched wild type mice, APP/PS1 mice with intact ovaries showed increased proliferation of hippocampal neural stem cells (NSCs) at 8 months of age and decreased proliferation of NSCs at 10 months of age; meanwhile, Aβ accumulation progressively increased with age, paralleling the reduced survival of immature neurons. OVX-induced depletion of E2 in APP/PS1 mice resulted in elevated Aβ levels accompanied by elevated p75 neurotrophin receptor (p75NTR) expression and increased NSC proliferation at 6 months of age, which subsequently declined; accelerated reduction of immature neurons starting from 6 months of age, and reduced telomerase activity and worsened memory performance at 10 months of age. Treatment with E2 in the early period post-OVX, rather than in the mid or late period, abrogated these effects, and p75NTR inhibition reduced the overproliferation of NSCs in 6-month-old OVX-APP/PS1 mice. Thus, E2 deficiency in young APP/PS1 mice exacerbates cognitive deficits and depletes the hippocampal NSC pool in later life; this can be alleviated by E2 treatment in the early period following OVX, which prevents Aβ/p75NTR-induced NSC overproliferation and preserves telomerase activity.

    in Frontiers in Ageing Neuroscience on August 04, 2020 12:00 AM.

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    Progress of RAGE Molecular Imaging in Alzheimer’s Disease

    Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by senile plaques (SPs), which are caused by amyloid beta (Aβ) deposition and neurofibrillary tangles (NFTs) of abnormal hyperphosphorylated tau protein. The receptor for advanced glycation end products (RAGE) binds to advanced glycation end products deposited during vascular dysfunction. Alzheimer’s disease may occur when RAGE binds to Aβ and releases reactive oxygen species, further exacerbating Aβ deposition and eventually leading to SPs and NFTs. As it is involved in early AD, RAGE may be considered as a more potent biomarker than Aβ. Positron emission tomography provides valuable information regarding the underlying pathological processes of AD many years before the appearance of clinical symptoms. Thus, to further reveal the role of RAGE in AD pathology and for early diagnosis of AD, a tracer that targets RAGE is needed. In this review, we first describe the early diagnosis of AD and then summarize the interaction between RAGE and Aβ and Tau that is required to induce AD pathology, and finally focus on RAGE-targeting probes, highlighting the potential of RAGE to be used as an effective target. The development of RAGE probes is expected to aid in AD diagnosis and treatment.

    in Frontiers in Ageing Neuroscience on August 04, 2020 12:00 AM.

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    Viral Vectors for Neural Circuit Mapping and Recent Advances in Trans-synaptic Anterograde Tracers

    Xu et al. review the viruses that have been used for neural circuit mapping and provide a primer on currently applied anterograde and retrograde viral tracers with practical guidance on experimental uses.

    in Neuron: In press on August 04, 2020 12:00 AM.

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    Ipa1 Is an RNA Polymerase II Elongation Factor that Facilitates Termination by Maintaining Levels of the Poly(A) Site Endonuclease Ysh1

    (Cell Reports 26, 1919–1933.e1–e5; February 12, 2019)

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1

    Bratkowski et al. describe cryo-EM structures of autoinhibited and active SARM1, an axon-enriched, injury-activated NADase. Structure-function studies elucidate the mode of autoinhibition and SARM1 activity regulation. The authors provide mechanistic insight into SARM1’s regulation by the local metabolic environment, laying the foundation for future SARM1-based therapies to treat neurological diseases.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Single-Cell RNA Profiling Reveals Adipocyte to Macrophage Signaling Sufficient to Enhance Thermogenesis

    Henriques et al. show an alternative pathway to enhance thermogenesis through an adipocyte cAMP/PKA axis in denervated iWAT. Signals emanating from this pathway generate M2-type macrophages associated with iWAT browning.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    RGS6 Mediates Effects of Voluntary Running on Adult Hippocampal Neurogenesis

    Gao et al. use translational profiling to unveil genome-wide intrinsic molecular changes in adult-born hippocampal neurons that contribute to voluntary running-enhanced adult neurogenesis. The molecular mediators identified, such as RGS6, are necessary for accelerated neuronal maturation and improved learning and memory in running mice.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    K13-Mediated Reduced Susceptibility to Artemisinin in Plasmodium falciparum Is Overlaid on a Trait of Enhanced DNA Damage Repair

    Southeast Asia (SEA) has been the breeding ground for malaria drug resistance, including resistance to artemisinin, the first-line anti-malarial drug. In this study, Xiong et al. find a relationship between DNA damage repair and artemisinin resistance in SEA, leading to insights on the establishment and spread of current artemisinin resistance.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest

    Tsabar et al. show that a subset of cells switches from oscillatory to sustained p53 dynamics more than 24 h after irradiation-induced DNA damage. Switching is maximal at intermediate radiation doses, requires escape from irradiation-induced cell cycle arrest, and is facilitated by caspase-2-PIDDosome-mediated degradation of p53’s inhibitor MDM2.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Inhibition of MEK1/2 Forestalls the Onset of Acquired Resistance to Entrectinib in Multiple Models of NTRK1-Driven Cancer

    Vaishnavi et al. present two novel tissue-of-origin mouse models of transformation and describe a mechanistic rationale for why vertical, combined pathway inhibition of TRKA with MEK inhibition can significantly delay the onset of acquired resistance in numerous mouse models driven by an NTRK1 fusion.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin

    Boontanrart et al. model the cellular stress that occurs upon loss of β-globin in human erythroid cells. Decreased β-globin attenuates the eIF2aP-ATF4 pathway, resulting in increased fetal γ-globin. ATF4 regulates the MYB γ-globin repressor via binding at the HBS1L-MYB intergenic enhancer.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Sialyl-LewisX Glycoantigen Is Enriched on Cells with Persistent HIV Transcription during Therapy

    Cell-surface glycans play a critical role in cell functions and fate. Nevertheless, the relevance of host glycosylation to HIV persistence is unknown. Colomb et al. characterized the cell-surface glycomes of HIV-infected cells during therapy and identified glycomic signatures of these cells that may affect cell trafficking and therefore HIV persistence.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Macrophage K63-Linked Ubiquitination of YAP Promotes Its Nuclear Localization and Exacerbates Atherosclerosis

    Liu et al. show that IL-1β-TRAF6 signaling triggers K63-linked ubiquitination of YAP in macrophages, which results in enhanced YAP stability and nuclear translocation, induces pro-inflammatory gene expression, and exacerbates atherosclerosis.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Altered MICOS Morphology and Mitochondrial Ion Homeostasis Contribute to Poly(GR) Toxicity Associated with C9-ALS/FTD

    G4C2 repeat expansion in C9ORF72 is the most common genetic cause of ALS. Repeat-encoded poly(GR) is believed to contribute to disease, albeit with not fully defined mechanisms. Li et al. show that poly(GR) targets the MICOS complex, causing mitochondrial toxicity. Manipulating MICOS is beneficial in animal models and patient cells.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Nicotinamide Mononucleotide Supplementation Reverses the Declining Quality of Maternally Aged Oocytes

    Miao et al. find that in vivo supplementation of the NAD+ precursor nicotinamide mononucleotide (NMN) effectively improves the quality of maternally aged oocytes by restoring their mitochondrial function and enhancing meiotic competency, fertilization ability, and subsequent embryonic development potential. This study provides a potential strategy to improve the reproductive outcome of women of advanced maternal age.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    In Vivo Estimates of Liver Metabolic Flux Assessed by 13C-Propionate and 13C-Lactate Are Impacted by Tracer Recycling and Equilibrium Assumptions

    Prior studies of in vivo liver metabolism using 13C tracers have produced divergent estimates of Krebs cycle and anaplerotic fluxes. Hasenour et al. present findings that are critical for interpreting experiments with two widely used metabolic tracers and introduce modeling strategies to improve isotope-based determination of liver metabolic fluxes.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency

    Gatti et al. demonstrate that the enzyme TRIP12 is a PAR-targeted ubiquitin ligase (PTUbL), which regulates PARP1 turnover. TRIP12 and PARP1 are inversely correlated in human cancers, and loss of TRIP12 leads to increased PARP inhibitor-induced PARP trapping, replication-associated DNA damage, and amplifies PARP inhibitor-induced cancer cell death.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    EllipTrack: A Global-Local Cell-Tracking Pipeline for 2D Fluorescence Time-Lapse Microscopy

    Tian et al. present a cell-tracking pipeline called EllipTrack that is optimized for modern, multi-day, high-throughput 2D fluorescent time-lapse movies. EllipTrack produces nearly error-free cell lineages for the cell lines tested and represents an improvement over existing tools for hard-to-track cells such as cancer cells.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Tousled-Like Kinases Suppress Innate Immune Signaling Triggered by Alternative Lengthening of Telomeres

    Segura-Bayona et al. find the Tousled-like kinases (TLKs) maintain chromatin at repetitive genome elements and telomeres. TLK depletion results in heterochromatin desilencing and induction of alternative lengthening of telomeres (ALT), robustly activating cGAS-STING-TBK1-mediated innate immune responses. This suggests TLKs represent a druggable vulnerability in ALT+ and chromosomally unstable tumor cells.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Stromal Cell-Contact Dependent PI3K and APRIL Induced NF-κB Signaling Prevent Mitochondrial- and ER Stress Induced Death of Memory Plasma Cells

    In this study, Cornelis et al. address the molecular mechanisms underlying the survival of murine memory plasma cells in the bone marrow. The authors provide evidence that direct contact to stromal cells and exogenous APRIL provide resilience to mitochondrial and endoplasmic stress, respectively, synergistically promoting plasma cell survival.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Immune Monitoring Reveals Fusion Peptide Priming to Imprint Cross-Clade HIV-Neutralizing Responses with a Characteristic Early B Cell Signature

    Immune monitoring of B cells in response to vaccination can enable early insights, even in the absence of serum neutralization. Cheng et al. observe an early B cell signature in NHPs predictive of the vaccine outcome, with priming of HIV FP imprinting cross-clade neutralizing FP-directed vaccine responses.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Molecular Transducers of Human Skeletal Muscle Remodeling under Different Loading States

    Stokes et al. identify and validate a core set of genes that are regulated in proportion to the magnitude of muscle protein turnover with loading. Several of these genes correlate with muscle growth only at their 3′ or 5′ untranslated region, and a subset directly influences protein synthesis in vitro.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis

    GPR35 is associated with IBD, but how GPR35 may influence macrophage-mediated intestinal homeostasis remains unclear. Using zebrafish and mice genetic tools, Kaya and colleagues have identified that LPA triggers GPR35 activity and that loss of macrophage GPR35 signaling confers intrinsic dysfunctions with effects on cytokine production and intestinal homeostasis.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    A Trio of Active Zone Proteins Comprised of RIM-BPs, RIMs, and Munc13s Governs Neurotransmitter Release

    Brockmann et al. show that the functional interactions of the presynaptic scaffolds RIM, RBP, and Munc13 are more profound than previously envisioned. RBP2, for instance, primes synaptic vesicles via Munc13-1 at the expense of presynaptic Ca2+-channel function and, consequently, affects short term plasticity.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Marginal Zone Formation Requires ACKR3 Expression on B Cells

    ACKR3 expression marks two distinct marginal zone B cell populations. Radice et al. demonstrate that the receptor is required to form a proper marginal zone and to establish the correct microarchitecture of mouse spleen, which is necessary for an effective early immune response to T-independent antigens.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting

    Tan et al. identify the E3-ligase MARCH6 as an important regulator of endothelial sprouting angiogenesis, owing to its ability to degrade the cholesterol biosynthetic enzyme SQLE. The study highlights that adequate SQLE levels are a critical determinant of maintaining endothelial junctions and proper sprouting angiogenesis.

    in Cell Reports: Current Issue on August 04, 2020 12:00 AM.

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    Flexible neural connectivity under constraints on total connection strength

    by Gabriel Koch Ocker, Michael A. Buice

    Neural computation is determined by neurons’ dynamics and circuit connectivity. Uncertain and dynamic environments may require neural hardware to adapt to different computational tasks, each requiring different connectivity configurations. At the same time, connectivity is subject to a variety of constraints, placing limits on the possible computations a given neural circuit can perform. Here we examine the hypothesis that the organization of neural circuitry favors computational flexibility: that it makes many computational solutions available, given physiological constraints. From this hypothesis, we develop models of connectivity degree distributions based on constraints on a neuron’s total synaptic weight. To test these models, we examine reconstructions of the mushroom bodies from the first instar larva and adult Drosophila melanogaster. We perform a Bayesian model comparison for two constraint models and a random wiring null model. Overall, we find that flexibility under a homeostatically fixed total synaptic weight describes Kenyon cell connectivity better than other models, suggesting a principle shaping the apparently random structure of Kenyon cell wiring. Furthermore, we find evidence that larval Kenyon cells are more flexible earlier in development, suggesting a mechanism whereby neural circuits begin as flexible systems that develop into specialized computational circuits.

    in PLoS Computational Biology on August 03, 2020 09:00 PM.

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    Multiplexing information flow through dynamic signalling systems

    by Giorgos Minas, Dan J. Woodcock, Louise Ashall, Claire V. Harper, Michael R. H. White, David A. Rand

    We consider how a signalling system can act as an information hub by multiplexing information arising from multiple signals. We formally define multiplexing, mathematically characterise which systems can multiplex and how well they can do it. While the results of this paper are theoretical, to motivate the idea of multiplexing, we provide experimental evidence that tentatively suggests that the NF-κB transcription factor can multiplex information about changes in multiple signals. We believe that our theoretical results may resolve the apparent paradox of how a system like NF-κB that regulates cell fate and inflammatory signalling in response to diverse stimuli can appear to have the low information carrying capacity suggested by recent studies on scalar signals. In carrying out our study, we introduce new methods for the analysis of large, nonlinear stochastic dynamic models, and develop computational algorithms that facilitate the calculation of fundamental constructs of information theory such as Kullback–Leibler divergences and sensitivity matrices, and link these methods to new theory about multiplexing information. We show that many current models such as those of the NF-κB system cannot multiplex effectively and provide models that overcome this limitation using post-transcriptional modifications.

    in PLoS Computational Biology on August 03, 2020 09:00 PM.

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    Combining hypoxia-activated prodrugs and radiotherapy <i>in silico</i>: Impact of treatment scheduling and the intra-tumoural oxygen landscape

    by Sara Hamis, Mohammad Kohandel, Ludwig J. Dubois, Ala Yaromina, Philippe Lambin, Gibin G. Powathil

    Hypoxia-activated prodrugs (HAPs) present a conceptually elegant approach to not only overcome, but better yet, exploit intra-tumoural hypoxia. Despite being successful in vitro and in vivo, HAPs are yet to achieve successful results in clinical settings. It has been hypothesised that this lack of clinical success can, in part, be explained by the insufficiently stringent clinical screening selection of determining which tumours are suitable for HAP treatments. Taking a mathematical modelling approach, we investigate how tumour properties and HAP-radiation scheduling influence treatment outcomes in simulated tumours. The following key results are demonstrated in silico: (i) HAP and ionising radiation (IR) monotherapies may attack tumours in dissimilar, and complementary, ways. (ii) HAP-IR scheduling may impact treatment efficacy. (iii) HAPs may function as IR treatment intensifiers. (iv) The spatio-temporal intra-tumoural oxygen landscape may impact HAP efficacy. Our in silico framework is based on an on-lattice, hybrid, multiscale cellular automaton spanning three spatial dimensions. The mathematical model for tumour spheroid growth is parameterised by multicellular tumour spheroid (MCTS) data.

    in PLoS Computational Biology on August 03, 2020 09:00 PM.

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    Optimising efficacy of antibiotics against systemic infection by varying dosage quantities and times

    by Andy Hoyle, David Cairns, Iona Paterson, Stuart McMillan, Gabriela Ochoa, Andrew P. Desbois

    Mass production and use of antibiotics has led to the rise of resistant bacteria, a problem possibly exacerbated by inappropriate and non-optimal application. Antibiotic treatment often follows fixed-dose regimens, with a standard dose of antibiotic administered equally spaced in time. But are such fixed-dose regimens optimal or can alternative regimens be designed to increase efficacy? Yet, few mathematical models have aimed to identify optimal treatments based on biological data of infections inside a living host. In addition, assumptions to make the mathematical models analytically tractable limit the search space of possible treatment regimens (e.g. to fixed-dose treatments). Here, we aimed to address these limitations by using experiments in a Galleria mellonella (insect) model of bacterial infection, to create a fully parametrised mathematical model of a systemic Vibrio infection. We successfully validated this model with biological experiments, including treatments unseen by the mathematical model. Then, by applying artificial intelligence, this model was used to determine optimal antibiotic dosage regimens to treat the host to maximise survival while minimising total antibiotic used. As expected, host survival increased as total quantity of antibiotic applied during the course of treatment increased. However, many of the optimal regimens tended to follow a large initial ‘loading’ dose followed by doses of incremental reductions in antibiotic quantity (dose ‘tapering’). Moreover, application of the entire antibiotic in a single dose at the start of treatment was never optimal, except when the total quantity of antibiotic was very low. Importantly, the range of optimal regimens identified was broad enough to allow the antibiotic prescriber to choose a regimen based on additional criteria or preferences. Our findings demonstrate the utility of an insect host to model antibiotic therapies in vivo and the approach lays a foundation for future regimen optimisation for patient and societal benefits.

    in PLoS Computational Biology on August 03, 2020 09:00 PM.

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    Task-evoked activity quenches neural correlations and variability across cortical areas

    by Takuya Ito, Scott L. Brincat, Markus Siegel, Ravi D. Mill, Biyu J. He, Earl K. Miller, Horacio G. Rotstein, Michael W. Cole

    Many large-scale functional connectivity studies have emphasized the importance of communication through increased inter-region correlations during task states. In contrast, local circuit studies have demonstrated that task states primarily reduce correlations among pairs of neurons, likely enhancing their information coding by suppressing shared spontaneous activity. Here we sought to adjudicate between these conflicting perspectives, assessing whether co-active brain regions during task states tend to increase or decrease their correlations. We found that variability and correlations primarily decrease across a variety of cortical regions in two highly distinct data sets: non-human primate spiking data and human functional magnetic resonance imaging data. Moreover, this observed variability and correlation reduction was accompanied by an overall increase in dimensionality (reflecting less information redundancy) during task states, suggesting that decreased correlations increased information coding capacity. We further found in both spiking and neural mass computational models that task-evoked activity increased the stability around a stable attractor, globally quenching neural variability and correlations. Together, our results provide an integrative mechanistic account that encompasses measures of large-scale neural activity, variability, and correlations during resting and task states.

    in PLoS Computational Biology on August 03, 2020 09:00 PM.

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    Heritable gene expression variability and stochasticity govern clonal heterogeneity in circadian period

    by K. L. Nikhil, Sandra Korge, Achim Kramer

    A ubiquitous feature of the circadian clock across life forms is its organization as a network of cellular oscillators, with individual cellular oscillators within the network often exhibiting considerable heterogeneity in their intrinsic periods. The interaction of coupling and heterogeneity in circadian clock networks is hypothesized to influence clock’s entrainability, but our knowledge of mechanisms governing period heterogeneity within circadian clock networks remains largely elusive. In this study, we aimed to explore the principles that underlie intercellular period variation in circadian clock networks (clonal period heterogeneity). To this end, we employed a laboratory selection approach and derived a panel of 25 clonal cell populations exhibiting circadian periods ranging from 22 to 28 h. We report that a single parent clone can produce progeny clones with a wide distribution of circadian periods, and this heterogeneity, in addition to being stochastically driven, has a heritable component. By quantifying the expression of 20 circadian clock and clock-associated genes across our clone panel, we found that inheritance of expression patterns in at least three clock genes might govern clonal period heterogeneity in circadian clock networks. Furthermore, we provide evidence suggesting that heritable epigenetic variation in gene expression regulation might underlie period heterogeneity.

    in PLoS Biology on August 03, 2020 09:00 PM.

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    Cell–substrate adhesion drives Scar/WAVE activation and phosphorylation by a Ste20-family kinase, which controls pseudopod lifetime

    by Shashi Prakash Singh, Peter A. Thomason, Sergio Lilla, Matthias Schaks, Qing Tang, Bruce L. Goode, Laura M. Machesky, Klemens Rottner, Robert H. Insall

    The Scar/WAVE complex is the principal catalyst of pseudopod and lamellipod formation. Here we show that Scar/WAVE’s proline-rich domain is polyphosphorylated after the complex is activated. Blocking Scar/WAVE activation stops phosphorylation in both Dictyostelium and mammalian cells, implying that phosphorylation modulates pseudopods after they have been formed, rather than controlling whether they are initiated. Unexpectedly, phosphorylation is not promoted by chemotactic signaling but is greatly stimulated by cell:substrate adhesion and diminished when cells deadhere. Phosphorylation-deficient or phosphomimetic Scar/WAVE mutants are both normally functional and rescue the phenotype of knockout cells, demonstrating that phosphorylation is dispensable for activation and actin regulation. However, pseudopods and patches of phosphorylation-deficient Scar/WAVE last substantially longer in mutants, altering the dynamics and size of pseudopods and lamellipods and thus changing migration speed. Scar/WAVE phosphorylation does not require ERK2 in Dictyostelium or mammalian cells. However, the MAPKKK homologue SepA contributes substantially—sepA mutants have less steady-state phosphorylation, which does not increase in response to adhesion. The mutants also behave similarly to cells expressing phosphorylation-deficient Scar, with longer-lived pseudopods and patches of Scar recruitment. We conclude that pseudopod engagement with substratum is more important than extracellular signals at regulating Scar/WAVE’s activity and that phosphorylation acts as a pseudopod timer by promoting Scar/WAVE turnover.

    in PLoS Biology on August 03, 2020 09:00 PM.

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    Selfing mutants link Ku proteins to mating type determination in <i>Tetrahymena</i>

    by I-Ting Lin, Meng-Chao Yao

    Recognition of self and nonself is important for outcrossing organisms, and different mating types establish the barrier against self-mating. In the unicellular ciliate T. thermophila, mating type determination requires complex DNA rearrangements at a single mat locus during conjugation to produce a type-specific gene pair (MTA and MTB) for 1 of 7 possible mating types. Surprisingly, we found that decreased expression of the DNA breakage-repair protein Ku80 at late stages of conjugation generated persistent selfing phenotype in the progeny. DNA analysis revealed multiple mating-type gene pairs as well as a variety of mis-paired, unusually arranged mating-type genes in these selfers that resemble some proposed rearrangement intermediates. They are found also in normal cells during conjugation and are lost after 10 fissions but are retained in Ku mutants. Silencing of TKU80 or TKU70-2 immediately after conjugation also generated selfing phenotype, revealing a hidden DNA rearrangement process beyond conjugation. Mating reactions between the mutant and normal cells suggest a 2-component system for self–nonself-recognition through MTA and MTB genes.

    in PLoS Biology on August 03, 2020 09:00 PM.

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    Down-regulation of a cytokine secreted from peripheral fat bodies improves visual attention while reducing sleep in <i>Drosophila</i>

    by Deniz Ertekin, Leonie Kirszenblat, Richard Faville, Bruno van Swinderen

    Sleep is vital for survival. Yet under environmentally challenging conditions, such as starvation, animals suppress their need for sleep. Interestingly, starvation-induced sleep loss does not evoke a subsequent sleep rebound. Little is known about how starvation-induced sleep deprivation differs from other types of sleep loss, or why some sleep functions become dispensable during starvation. Here, we demonstrate that down-regulation of the secreted cytokine unpaired 2 (upd2) in Drosophila flies may mimic a starved-like state. We used a genetic knockdown strategy to investigate the consequences of upd2 on visual attention and sleep in otherwise well-fed flies, thereby sidestepping the negative side effects of undernourishment. We find that knockdown of upd2 in the fat body (FB) is sufficient to suppress sleep and promote feeding-related behaviors while also improving selective visual attention. Furthermore, we show that this peripheral signal is integrated in the fly brain via insulin-expressing cells. Together, these findings identify a role for peripheral tissue-to-brain interactions in the simultaneous regulation of sleep quality and attention, to potentially promote adaptive behaviors necessary for survival in hungry animals.

    in PLoS Biology on August 03, 2020 09:00 PM.

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    Early‐onset parkinsonism is a manifestation of the PPP2R5D p.E200K mutation

    PPP2R5D‐ related neurodevelopmental disorder is characterized by a range of neurodevelopmental and behavioral manifestations. We report the association of early‐onset parkinsonism with the PPP2R5D p.E200K mutation. Clinical characterization and exome sequencing were performed on three patients, with postmortem neuropathologic examination for one patient. All patients had mild developmental delay and developed levodopa‐responsive parkinsonism between ages 25 to 40. The PPP2R5D c.598G>A (p.E200K) mutation was identified in all patients. Neuropathologic examination demonstrated uneven, focally severe neuronal loss and gliosis in the substantia nigra pars compacta, without Lewy bodies. Our findings suggest the PPP2R5D p.E200K mutation to be a possible new cause of early‐onset parkinsonism.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on August 03, 2020 07:46 PM.

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    Mapping the Insula with Stereo‐Electroencephalography: The Emergence of Semiology in Insula Lobe Seizures

    Objective

    Insula epilepsy is rare and can be evaluated effectively by Stereotactic intracerebral EEG (SEEG). Many previous studies of insulo‐opercular seizures have been unable to separate insular and opercular onset. With adequate sampling of the insula, this study shows this is possible.

    Methods

    We analyzed intrainsular dynamics and extrainsular propagation in 12 patients with “pure” insula epilepsy (n = 9) or insular and only deepest opercular involvement (n = 3) at seizure onset. Review of semiology defined clinical groups, agglomerative cluster, and principal component analysis of semiological features were performed. Quantitative epileptogenicity, and intrainsular and extrainsular propagation were computed via time frequency analysis and epileptogenicity mapping.

    Results

    Seizure onset patterns were heterogeneous; the seizure onset zone was focal. Seizure onset and first ictal change within insula functional subdivision correlated with aura and reflex component. No paninsular spread occurred; contralateral insular spread was very early. While the discharge was intrainsular, clinical signs related to aura or vegetative signs. Extrainsular propagation was early and related to the emergence of the majority of clinical signs. Cluster analysis found an anterior, intermediate, and posterior insula seizure onset group. The largest principal component separated anterior insula manifestations, including early hypermotor signs, early recovery, and no aura from posterior insula features of early dystonia, early tonic motor features, and sensorimotor aura.

    Interpretation

    Aura is vital to identifying seizure onset and relates to insula functional subdivision. Seizures are heterogenous; extrainsular propagation occurs early, accounting for most of the semiology. With adequate sampling, "pure" insula epilepsy can be identified and focal curative resection is possible. ANN NEUROL 2020

    in Annals of Neurology on August 03, 2020 07:00 PM.

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    Circulating metabolites differentiate acute ischemic stroke from stroke mimics

    Objective

    Early discrimination of patients with ischemic stroke (IS) from stroke mimics (SM) poses a diagnostic challenge. The circulating metabolome might reflect pathophysiological events related to acute IS. Here, we investigated the utility of early metabolic changes for differentiating IS from SM.

    Methods

    We performed untargeted metabolomics on serum samples obtained from patients with IS (N=508) and SM (N=349; defined by absence of a DWI positive lesion on MRI) who presented to hospital within 24 hours after symptom onset (median time from symptom onset to blood sampling= 3.3h; IQR: 1.6‐6.7h) and from neurologically normal controls (NC, N=112). We compared diagnostic groups in a discovery‐validation approach by applying multivariable linear regression models, machine learning techniques, and propensity score matching. We further performed a targeted look‐up of published metabolite sets.

    Results

    Levels of forty‐one metabolites were significantly associated with IS compared to NC. The top metabolites showing the highest value in separating IS from SM were asymmetrical and symmetrical dimethylarginine, pregnenolone sulfate, and adenosine. Together, these four metabolites differentiated patients with IS from SM with an AUC of 0.90 in the replication sample, which was superior to multimodal cranial computed tomography (AUC=0.80) obtained for routine diagnostics. They were further superior to previously published metabolite sets detected in our samples. All four metabolites returned to control levels by day 90.

    Interpretation

    A set of four metabolites with known biological effects relevant to stroke pathophysiology shows unprecedented utility to identify patients with IS upon hospital arrival thus encouraging further investigation including multicenter studies.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on August 03, 2020 03:20 PM.

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    Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

    Estrogen receptor alpha, G‐protein coupled estrogen receptor 1, and aromatase: Developmental, sex, and region‐specific differences across the rat caudate–putamen, nucleus accumbens core and shell

    Rat striatal regions express nuclear estrogen receptor α and GPER‐1 early in development, while aromatase expression increases with age. (a–f) Caudate–putamen micrographs depicting ERα positive cells or lack thereof females P3 (a), P20 (b), and adult (c); males P3 (d), P20 (e), and adult (f). Examples of ERα positive cells are marked by small white arrows.


    Abstract

    Sex steroid hormones such as 17β‐estradiol (estradiol) regulate neuronal function by binding to estrogen receptors (ERs), including ERα and GPER1, and through differential production via the enzyme aromatase. ERs and aromatase are expressed across the nervous system, including in the striatal brain regions. These regions, comprising the nucleus accumbens core, shell, and caudate–putamen, are instrumental for a wide‐range of functions and disorders that show sex differences in phenotype and/or incidence. Sex‐specific estrogen action is an integral component for generating these sex differences. A distinctive feature of the striatal regions is that in adulthood neurons exclusively express membrane but not nuclear ERs. This long‐standing finding dominates models of estrogen action in striatal regions. However, the developmental etiology of ER and aromatase cellular expression in female and male striatum is unknown. This omission in knowledge is important to address, as developmental stage influences cellular estrogenic mechanisms. Thus, ERα, GPER1, and aromatase cellular immunoreactivity was assessed in perinatal, prepubertal, and adult female and male rats. We tested the hypothesis that ERα, GPER1, and aromatase exhibits sex, region, and age‐specific differences, including nuclear expression. ERα exhibits nuclear expression in all three striatal regions before adulthood and disappears in a region‐ and sex‐specific time‐course. Cellular GPER1 expression decreases during development in a region‐ but not sex‐specific time‐course, resulting in extranuclear expression by adulthood. Somatic aromatase expression presents at prepuberty and increases by adulthood in a region‐ but not sex‐specific time‐course. These data indicate that developmental period exerts critical sex‐specific influences on striatal cellular estrogenic mechanisms.

    in Journal of Comparative Neurology on August 03, 2020 08:50 AM.

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    Projections from the dorsomedial division of the bed nucleus of the Stria terminalis to hypothalamic nuclei in the mouse

    Projections from the dorsomedial division of the bed nucleus of the Stria terminalis to hypothalamic nuclei in the mouse

    Neurons of the dorsomedial division of the bed nucleus of the stria terminalis (BNSTdm) project onto hypothalamic nuclei including the paraventricular (PVH), dorsomedial (DMH), arcuate (ARH) nuclei and the lateral hypothalamic area (LHA). In particular, BNSTdm neurons innervate proopiomelanocortin (POMC), agouti‐related peptide (AgRP), melanin‐concentrating hormone (MCH) and orexin (ORX) expressing neurons of the ARH and the LHA, respectively.


    Abstract

    As stressful environment is a potent modulator of feeding, we seek in the present work to decipher the neuroanatomical basis for an interplay between stress and feeding behaviors. For this, we combined anterograde and retrograde tracing with immunohistochemical approaches to investigate the patterns of projections between the dorsomedial division of the bed nucleus of the stria terminalis (BNST), well connected to the amygdala, and hypothalamic structures such as the paraventricular (PVH) and dorsomedial (DMH), the arcuate (ARH) nuclei and the lateral hypothalamic areas (LHA) known to control feeding and motivated behaviors. We particularly focused our study on afferences to proopiomelanocortin (POMC), agouti‐related peptide (AgRP), melanin‐concentrating‐hormone (MCH) and orexin (ORX) neurons characteristics of the ARH and the LHA, respectively. We found light to intense innervation of all these hypothalamic nuclei. We particularly showed an innervation of POMC, AgRP, MCH and ORX neurons by the dorsomedial and dorsolateral divisions of the BNST. Therefore, these results lay the foundation for a better understanding of the neuroanatomical basis of the stress‐related feeding behaviors.

    in Journal of Comparative Neurology on August 03, 2020 08:48 AM.

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    Light sheet microscopy of the gerbil cochlea

    Light sheet microscopy of the gerbil cochlea

    Light sheet microcopy is used to map frequency along the basilar membrane within intact cochleae, retaining spatial orientation and relationships with internal and external structural landmarks. Three‐dimensional measures of how frequency domains relate to one another gives insight into how the geometric organization of the cochlea may influence its physiology.


    Abstract

    Light sheet fluorescence microscopy (LSFM) provides a rapid and complete three‐dimensional image of the cochlea. The method retains anatomical relationships—on a micrometer scale—between internal structures such as hair cells, basilar membrane (BM), and modiolus with external surface structures such as the round and oval windows. Immunolabeled hair cells were used to visualize the spiraling BM in the intact cochlea without time intensive dissections or additional histological processing; yet material prepared for LSFM could be rehydrated, the BM dissected out and reimaged at higher resolution with the confocal microscope. In immersion‐fixed material, details of the cochlear vasculature were seen throughout the cochlea. Hair cell counts (both inner and outer) as well as frequency maps of the BM were comparable to those obtained by other methods, but with the added dimension of depth. The material provided measures of angular, linear, and vector distance between characteristic frequency regions along the BM. Thus, LSFM provides a unique ability to rapidly image the entire cochlea in a manner applicable to model and interpret physiological results. Furthermore, the three‐dimensional organization of the cochlea can be studied at the organ and cellular level with LSFM, and this same material can be taken to the confocal microscope for detailed analysis at the subcellular level.

    in Journal of Comparative Neurology on August 03, 2020 08:33 AM.

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    High-fat food biases hypothalamic and mesolimbic expression of consummatory drives

    Nature Neuroscience, Published online: 03 August 2020; doi:10.1038/s41593-020-0684-9

    Mazzone and Liang-Guallpa et al. demonstrate that consuming high-fat foods rapidly and durably tunes parallel brain circuits to drive intake of a high-fat diet while devaluing a nutritionally balanced, standard diet even under states of intense hunger.

    in Nature Neuroscience on August 03, 2020 12:00 AM.

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    Astrocytes contribute to remote memory formation by modulating hippocampal–cortical communication during learning

    Nature Neuroscience, Published online: 03 August 2020; doi:10.1038/s41593-020-0679-6

    Kol et al. show that the foundation of remote memory is formed during acquisition by the massive recruitment of ACC-projecting CA1 neurons. Remote memory acquisition involves projection-specific effects of astrocytes on CA1-to-ACC neuronal communication.

    in Nature Neuroscience on August 03, 2020 12:00 AM.

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    Starring role for astrocytes in memory

    Nature Neuroscience, Published online: 03 August 2020; doi:10.1038/s41593-020-0678-7

    Following learning, memories for events are reorganized in a time-dependent manner in distributed hippocampal–cortical networks. While previous studies have focused on neural contributions to this process of systems consolidation, a new study by Kol et al. reveals that astrocytes play crucial modulatory roles in the formation of remote memories.

    in Nature Neuroscience on August 03, 2020 12:00 AM.

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    Active dendritic currents gate descending cortical outputs in perception

    Nature Neuroscience, Published online: 03 August 2020; doi:10.1038/s41593-020-0677-8

    The authors showed that the ‘moment of perception’ is causally related to dendritic activity in subcortically projecting layer 5 pyramidal neurons that project to the higher-order thalamus, superior colliculus and striatum.

    in Nature Neuroscience on August 03, 2020 12:00 AM.

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    Rational design and implementation of a chemically inducible heterotrimerization system

    Nature Methods, Published online: 03 August 2020; doi:10.1038/s41592-020-0913-x

    Chemically inducible trimerization tools based on split FRB or FKBP with full-length FKBP or FRB, respectively, expand the chemogenetics toolbox. Their efficiency and fast kinetics enable new types of protein manipulation in live cells.

    in Nature Methods on August 03, 2020 12:00 AM.

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    High-sensitivity and high-specificity biomechanical imaging by stimulated Brillouin scattering microscopy

    Nature Methods, Published online: 03 August 2020; doi:10.1038/s41592-020-0882-0

    Stimulated Brillouin scattering microscopy overcomes the trade-off between acquisition speed and spectral resolution in spontaneous Brillouin scattering microscopy and allows visualization of elasticity and viscosity, as shown in C. elegans.

    in Nature Methods on August 03, 2020 12:00 AM.

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    Diversity and function of corticopetal and corticofugal GABAergic projection neurons

    Nature Reviews Neuroscience, Published online: 03 August 2020; doi:10.1038/s41583-020-0344-9

    Increasing evidence indicates that some cortical neurons that send long-range projections to distant brain regions are GABAergic. In this Review, Melzer and Monyer examine recent progress in the identification and function of these neurons.

    in Nature Reviews on August 03, 2020 12:00 AM.

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    Fast spin-flip enables efficient and stable organic electroluminescence from charge-transfer states

    Nature Photonics, Published online: 03 August 2020; doi:10.1038/s41566-020-0668-z

    An organic molecule, 5Cz-TRZ, with multiple donor units supports fast reverse intersystem crossing, allowing fabrication of high-performance organic light-emitting diodes.

    in Nature Photomics on August 03, 2020 12:00 AM.

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    Organic light emitters exhibiting very fast reverse intersystem crossing

    Nature Photonics, Published online: 03 August 2020; doi:10.1038/s41566-020-0667-0

    An organic molecule, TpAT-tFFO, which is designed to support rapid reverse intersystem crossing allows the fabrication of efficient organic light-emitting diodes.

    in Nature Photomics on August 03, 2020 12:00 AM.

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    Adaptation Modulates Spike-Phase Coupling Tuning Curve in the Rat Primary Auditory Cortex

    Adaptation is an important mechanism that causes a decrease in the neural response both in terms of local field potentials (LFP) and spiking activity. We previously showed this reduction effect in the tuning curve of the primary auditory cortex. Moreover, we revealed that a repeated stimulus reduces the neural response in terms of spike-phase coupling (SPC). In the current study, we examined the effect of adaptation on the SPC tuning curve. To this end, employing the phase-locking value (PLV) method, we estimated the spike-LFP coupling. The data was obtained by a simultaneous recording from four single-electrodes in the primary auditory cortex of 15 rats. We first investigated whether the neural system may use spike-LFP phase coupling in the primary auditory cortex to encode sensory information. Secondly, we investigated the effect of adaptation on this potential SPC tuning. Our data showed that the coupling between spikes’ times and the LFP phase in beta oscillations represents sensory information (different stimulus frequencies), with an inverted bell-shaped tuning curve. Furthermore, we showed that adaptation to a specific frequency modulates SPC tuning curve of the adapter and its neighboring frequencies. These findings could be useful for interpretation of feature representation in terms of SPC and the underlying neural mechanism of adaptation.

    in Frontiers in Systems Neuroscience on August 03, 2020 12:00 AM.

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    Foveal Therapy in Blue Cone Monochromacy: Predictions of Visual Potential From Artificial Intelligence

    Novel therapeutic approaches for treating inherited retinal degenerations (IRDs) prompt a need to understand which patients with impaired vision have the anatomical potential to gain from participation in a clinical trial. We used supervised machine learning to predict foveal function from foveal structure in blue cone monochromacy (BCM), an X-linked congenital cone photoreceptor dysfunction secondary to mutations in the OPN1LW/OPN1MW gene cluster. BCM patients with either disease-associated large deletion or missense mutations were studied and results compared with those from subjects with other forms of IRD and various degrees of preserved central structure and function. A machine learning technique was used to associate foveal sensitivities and best-corrected visual acuities to foveal structure in IRD patients. Two random forest (RF) models trained on IRD data were applied to predict foveal function in BCM. A curve fitting method was also used and results compared with those of the RF models. The BCM and IRD patients had a comparable range of foveal structure. IRD patients had peak sensitivity at the fovea. Machine learning could successfully predict foveal sensitivity (FS) results from segmented or un-segmented optical coherence tomography (OCT) input. Application of machine learning predictions to BCM at the fovea showed differences between predicted and measured sensitivities, thereby defining treatment potential. The curve fitting method provided similar results. Given a measure of visual acuity (VA) and foveal outer nuclear layer thickness, the question of how many lines of acuity would represent the best efficacious result for each BCM patient could be answered. We propose that foveal vision improvement potential in BCM is predictable from retinal structure using machine learning and curve fitting approaches. This should allow estimates of maximal efficacy in patients being considered for clinical trials and also guide decisions about dosing.

    in Frontiers in Neuroscience: Neurodegeneration on August 03, 2020 12:00 AM.

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    HIF-1α Mediates TRAIL-Induced Neuronal Apoptosis via Regulating DcR1 Expression Following Traumatic Brain Injury

    Background: Neuronal apoptosis involved in secondary injury following traumatic brain injury (TBI) significantly contributes to the poor outcomes of patients with TBI. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis of tumor cells. Hypoxia factor (HIF) 1α is a controversial factor that mediates the neuronal apoptotic pathway. Herein, we hypothesize that HIF-1α may mediate the TRAIL-induced neuronal apoptosis after TBI.

    Methods: We used Western blots and immunofluorescence to study the expression and cell localization of TRAIL and death receptor 5 (DR5) after TBI in rats. Soluble DR5 (sDR5) administration was used to block the TRAIL-induced neuronal death and neural deficits. HIF-1α inhibitor 2ME and agonist DMOG were used to study the role of HIF-1α in TRAIL-induced neuronal death. Meanwhile, HIF-1α siRNA was used to investigate the role of HIF-1α in TRAIL-induced neuronal death in vitro.

    Results: The expressions of microglia-located TRAIL and neuron-located DR5 were significantly upregulated after TBI. sDR5 significantly attenuated TRAIL-induced neuronal apoptosis and neurological deficits. 2ME decreased neuronal apoptosis, lesion area, and brain edema and improved neurological function via increased expression of TRAIL decoy receptor 1 (DcR1), which inhibited TRAIL-induced apoptosis after TBI. The administration of DMOG produced the opposite effect than did 2ME. Similarly, HIF-1α siRNA attenuated TRAIL-induced neuronal death via increased DcR1 expression in vitro.

    Conclusion: Our findings suggested that the TRAIL/DR5 signaling pathway plays an important role after neuronal apoptosis after TBI. HIF-1α mediates TRAIL-induced neuronal apoptosis by regulating DcR1 expression following TBI.

    in Frontiers in Cellular Neuroscience on August 03, 2020 12:00 AM.

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    Frequency of Spinocerebellar Ataxia type 1, 2, 3,6 and 7 and clinical profile of Spinocerebellar Ataxia type 3 in Malaysia

    Spinocerebellar ataxias (SCA) are highly heterogenous group of neurodegenerative diseases causing progressive cerebellar dysfunction. We report the first description of relative frequencies of the common SCA m...

    in Cerebellum and Ataxias on August 03, 2020 12:00 AM.

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    Hypothalamic Interactions with Large-Scale Neural Circuits Underlying Reinforcement Learning and Motivated Behavior

    Biological agents adapt behavior to support the survival needs of the individual and the species. In this review we outline the anatomical, physiological, and computational processes that support reinforcement learning (RL). We describe two circuits in the primate brain that are linked to specific aspects of learning and goal-directed behavior. The ventral circuit, that includes the amygdala, ventral medial prefrontal cortex, and ventral striatum, has substantial connectivity with the hypothalamus.

    in Trends in Neurosciences: In press on August 03, 2020 12:00 AM.

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    The effects of low intensity focused ultrasonic stimulation on dorsal root ganglion neurons and Schwann cells in vitro

    The effects of low intensity focused ultrasonic stimulation on dorsal root ganglion neurons and Schwann cells in vitro

    Ultrasonic neuromodulation of peripheral nerve cells.


    Abstract

    Satisfactory treatment of peripheral nerve injury (PNI) faces difficulties owing to the intrinsic biological barriers in larger injuries and invasive surgical interventions. Injury gaps >3 cm have low chances of full motor and sensory recovery, and the unmet need for PNI repair techniques which increase the likelihood of functional recovery while limiting invasiveness motivate this work. Building upon prior work in ultrasound stimulation (US) of dorsal root ganglion (DRG) neurons, the effects of US on DRG neuron and Schwann cell (SC) cocultures were investigated to uncover the role of SCs in mediating the neuronal response to US in vitro . Acoustic intensity‐dependent alteration in selected neuromorphometrics of DRG neurons in coculture with SCs was observed in total outgrowth, primary neurites, and length compared to previously reported DRG monoculture in a calcium‐independent manner. SC viability and proliferation were not impacted by US. Conditioned medium studies suggest secreted factors from SCs subjected to US impact DRG neuron morphology. These findings advance the current understanding of mechanisms by which these cell types respond to US, which may lead to new noninvasive US therapies for treating PNI.

    in Journal of Neuroscience Research on August 02, 2020 05:03 PM.

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    Alertness Training Improves Spatial Bias and Functional Ability in Spatial Neglect

    Objective

    We conducted a multi‐site, randomized, double‐blinded controlled trial to examine the effectiveness of a digital health intervention targeting the intrinsic regulation of goal‐directed alertness in patients with chronic hemispatial neglect.

    Methods

    Forty‐nine participants with hemispatial neglect that demonstrated significant spatially biased attention following acquired brain injury were randomly assigned to the experimental attention remediation treatment or active control group. The participants engaged with the remotely administered interventions for twelve weeks. The primary outcome was spatial bias on the Posner cueing task (response time difference: left – right target trials). Secondary outcomes included functional abilities (measured via the Catherine Bergego scale and Barthel index), spatial cognition, executive function, quality of life and sleep. Assessments were conducted prior to and immediately following participation in the experimental intervention or control condition, and again after a three‐month no contact period.

    Results

    Compared with the active control group, the intervention group exhibited a significant improvement in the primary outcome—a reduction in spatially biased attention on the Posner cueing task (p=0.010, Cohen’s d=0.96)—as well as significant improvements in functional abilities as measured on the Catherine Bergego and Barthel indices (p=0.027, Cohen’s d=0.24).

    Interpretation

    Our results demonstrate that our attention training program was effective in improving the debilitating attention deficits common to hemispatial neglect. This benefit generalized to improvements in real‐world functional abilities. This safe, highly scalable and self‐administered treatment for hemispatial neglect may serve as a useful addition to the existing standard of care.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on August 02, 2020 02:13 PM.

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    Amyotrophic Lateral Sclerosis: Fuel for the Corticofugal Feud

    This commentary provides perspective on the report by Burg et al. that corticospinal motor neurons provoke corticofugal spread of motor neuron degeneration in ALS.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on August 02, 2020 01:53 PM.

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    Chronic traumatic encephalopathy and primary age‐related tauopathy

    in Annals of Neurology on August 02, 2020 01:39 PM.

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    Effects of IgLON5 antibodies on neuronal cytoskeleton: a link between autoimmunity and neurodegeneration

    Anti‐IgLON5 disease is a neurological disorder characterized by autoantibodies against IgLON5 and pathological evidence of neuronal‐specific tau accumulation. Here we report that patients' IgLON5 IgG, but not other cell‐surface antibodies, disrupt the cytoskeletal organization in cultured rat hippocampal neurons resulting in dystrophic neurites and axonal swelling. Adsorption of IgLON5 IgG with HEK293 cells expressing IgLON5 abrogated the indicated cytoskeletal changes. These findings along an increase of levels of neurofilaments in patients' CSF suggest that IgLON5 IgG, unlike other cell‐surface antibodies, disrupt neuronal cytoskeleton maintenance providing a link between autoimmunity and neurodegeneration.

    This article is protected by copyright. All rights reserved.

    in Annals of Neurology on August 02, 2020 01:33 PM.

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    Outcome measures from experimental traumatic brain injury in male rats vary with the complete temporal biomechanical profile of the injury event

    Outcome measures from experimental traumatic brain injury in male rats vary with the complete temporal biomechanical profile of the injury event

    Injury to the brain can vary greatly due to differences in the biomechanics of the traumatic event. This study demonstrates that the sequelae of neuronal loss and behavioral outcomes are related to the rate, peak, and impulse of the injury. Left: Neuronal degeneration for fast‐rate injury is lower than slow‐rate injuries. *p  < 0.05. Right: Chronic neuronal loss is equivalent across injury rates *p  < 0.05 compared to sham.


    Abstract

    Millions suffer a traumatic brain injury (TBI) each year wherein the outcomes associated with injury can vary greatly between individuals. This study postulates that variations in each biomechanical parameter of a head trauma lead to differences in histological and behavioral outcome measures that should be considered collectively in assessing injury. While trauma severity typically scales with the magnitude of injury, much less is known about the effects of rate and duration of the mechanical insult. In this study, a newly developed voice‐coil fluid percussion injury system was used to investigate the effects of injury rate and fluid percussion impulse on a collection of post‐injury outcomes in male rats. Collectively the data suggest a potential shift in the specificity and progression of neuronal injury and function rather than a general scaling of injury severity. While a faster, shorter fluid percussion first presents as a mild TBI, neuronal loss and some behavioral tasks were similar among the slower and faster fluid percussion injuries. This study concludes that the sequelae of neuronal degeneration and behavioral outcomes are related to the complete temporal profile of the fluid percussion and do not scale only with peak pressure.

    in Journal of Neuroscience Research on August 02, 2020 10:55 AM.

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    Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin‐4 treatment

    Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin‐4 treatment

    Insulin deficiency, rather than insulin resistance, induces AD‐like features in wild type and transgenic mice carrying amyloid β and tau genes. Treatment with Exendin‐4 ameliorates these features in an intervention paradigm when deficits were already present, reflecting the more likely scenario when patients will consult.


    Abstract

    Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side‐by‐side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin‐4 (Ex4) treatment in a mouse model of AD. Three–4‐month‐old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high‐fat diet (HFD). A second study was performed in TAPP‐STZ mice treated with Ex4, a long‐lasting analog of GLP‐1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12 weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT‐STZ and TAPP‐STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP‐STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes.

    in Journal of Neuroscience Research on August 01, 2020 07:39 PM.

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    Alpha‐Synuclein Oligomers and Neurofilament Light Chain in Spinal Fluid Differentiate Multiple System Atrophy from Lewy Body Synucleinopathies

    Objective

    To explore the role of alpha‐synuclein (αSyn) oligomers and neurofilament light chain (NFL) in cerebrospinal fluid (CSF) as markers of early multiple system atrophy (MSA) and to contrast findings with Lewy body synucleinopathies.

    Methods

    In a discovery cohort of well‐characterized early MSA patients (n = 24) and matched healthy controls (CON, n = 14), we utilized enzyme‐linked immunosorbent assay to measure NFL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF. We confirmed findings in a separate prospectively enrolled cohort of patients with early MSA (n = 38), Parkinson disease (PD, n = 16), and dementia with Lewy bodies (DLB, n = 13), and CON subjects (n = 15).

    Results

    In the discovery cohort, NFL was markedly elevated in MSA patients, with perfect separation from CON. αSyn‐PMCA was nonreactive in all CON, whereas all MSA samples were positive. In the confirmatory cohort, NFL again perfectly separated MSA from CON, and was significantly lower in PD and DLB compared to MSA. PMCA was again nonreactive in all CON, and positive in all but 2 MSA cases. All PD and all but 2 DLB samples were also positive for αSyn aggregates but with markedly different reaction kinetics from MSA; aggregation occurred later, but maximum fluorescence was higher, allowing for perfect separation of reactive samples between MSA and Lewy body synucleinopathies.

    Interpretation

    NFL and αSyn oligomers in CSF faithfully differentiate early MSA not only from CON but also from Lewy body synucleinopathies. The findings support the role of these markers as diagnostic biomarkers, and have important implications for understanding pathophysiologic mechanisms underlying the synucleinopathies. ANN NEUROL 2020

    in Annals of Neurology on August 01, 2020 02:48 PM.

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    Basic quantitative morphological methods applied to the central nervous system

    Basic quantitative morphological methods applied to the central nervous system

    Design‐based stereological methods allow the estimation of basic morphological parameters in representative samples of the sectioned central nervous system. Point probes can be used to estimate volume (illustrated for the Area Fraction Fractionator), line probes can be used to estimate surface area (illustrated for a vertical sections design), area probes can be used to estimate length (illustrated for the Spaceball probe), and volume probes must be used to estimate number (illustrated for the Disector). This review provides an introduction to how these methods solve problems associated with other quantitative approaches, how they are applied to histological material, how a sampling scheme can be designed and evaluated, and which practical problems need to be solved to generate the numbers that we will need to come to an understanding of central nervous system function.


    Abstract

    Generating numbers has become an almost inevitable task associated with studies of the morphology of the nervous system. Numbers serve a desire for clarity and objectivity in the presentation of results and are a prerequisite for the statistical evaluation of experimental outcomes. Clarity, objectivity, and statistics make demands on the quality of the numbers that are not met by many methods. This review provides a refresher of problems associated with generating numbers that describe the nervous system in terms of the volumes, surfaces, lengths, and numbers of its components. An important aim is to provide comprehensible descriptions of the methods that address these problems. Collectively known as design‐based stereology, these methods share two features critical to their application. First, they are firmly based in mathematics and its proofs. Second and critically underemphasized, an understanding of their mathematical background is not necessary for their informed and productive application. Understanding and applying estimators of volume, surface, length or number does not require more of an organizational mastermind than an immunohistochemical protocol. And when it comes to calculations, square roots are the gravest challenges to overcome. Sampling strategies that are combined with stereological probes are efficient and allow a rational assessment if the numbers that have been generated are “good enough.” Much may be unfamiliar, but very little is difficult. These methods can no longer be scapegoats for discrepant results but faithfully produce numbers on the material that is assessed. They also faithfully reflect problems that associated with the histological material and the anatomically informed decisions needed to generate numbers that are not only valid in theory. It is within reach to generate practically useful numbers that must integrate with qualitative knowledge to understand the function of neural systems.

    in Journal of Comparative Neurology on August 01, 2020 11:35 AM.

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    Reply to the Letter “ Covid‐19‐associated encephalopathy and cytokine‐mediated Neuroinflammation”

    in Annals of Neurology on August 01, 2020 10:30 AM.

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    Microchiropterans have a diminutive cerebral cortex, not an enlarged cerebellum, compared to megachiropterans and other mammals

    Microchiropterans have a diminutive cerebral cortex, not an enlarged cerebellum, compared to megachiropterans and other mammals

    Herculano‐Houzel et al. examine numbers of neurons in the brain of 13 bat species and find that the apparently “enlarged” cerebellum of small echolocating bats has the same proportion of brain neurons as other mammals, and is more likely simply the result of a diminutive cerebral cortex.


    Abstract

    Small echolocating bats are set apart from most other mammals by their relatively large cerebellum, a feature that has been associated to echolocation, as it is presumed to indicate a relatively enlarged number of neurons in the cerebellum in comparison to other brain structures. Here we quantify the neuronal composition of the cerebral cortex, cerebellum and remaining brain structures of seven species of large Pteropodid bats (formerly classified as megachiropterans), one of which echolocates, and six species of small bats (formerly classified as microchiropterans), all of which echolocate. This chiropteran data is compared to 60 mammalian species in our dataset to determine whether the relatively large cerebellum of the small echolocating bats, and possibly that of the echolocating Pteropodid, contains a relatively enlarged number of neurons. We find no evidence that the distribution of neurons differs between microchiropterans and megachiropterans, but our data indicate that microchiropterans, like the smallest shrew in our dataset, have diminutive cerebral cortices, which makes the cerebellum appear relatively large. We propose that, in agreement with the diminutive brain size of the earliest fossil mammals, this is a plesiomorphic, not a derived, feature of microchiropteran brains. The results of this study also reveal important neural characteristics related to the phylogenetic affinities and relationships of the chiropterans.

    in Journal of Comparative Neurology on August 01, 2020 10:10 AM.

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    Ocular Dominance Plasticity: molecular mechanisms revisited

    Ocular dominance plasticity (ODP) is a type of cortical plasticity operating in visual cortex of mammals that are endowed with binocular vision based on the competition‐driven disparity.

    Earlier, a molecular mechanism was proposed that catecholamines play an important role in the maintenance of ODP in kittens. Having survived the initial test, the hypothesis was further advanced to identify noradrenaline (NA) as a key factor that regulates ODP in the immature cortex. Later, the ODP‐promoting effect of NA is extended to the adult with age‐related limitations. Following the enhanced NA availability, the chain events downstream lead to the β‐adrenoreceptor‐induced cAMP accumulation, which in turn activates the protein kinase A. Eventually, the protein kinase translocates to the cell nucleus to activate cAMP responsive element binding protein (CREB). CREB is a cellular transcription factor that controls the transcription of various genes, underpinning neuronal plasticity and long‐term memory.

    In the advent of molecular genetics in that various types of new tools have become available with relative ease, ODP research has lightly adopted in the rodent model the original concepts and methodologies. Here, after briefly tracing the strategic maturation of our quest, the review moves to the later development of the field, with the emphasis placed around the following issues: 1) Are we testing ODP per s e? 2) What does monocular deprivation deprive of the immature cortex? 3) The critical importance of binocular competition, 4) What is the adult plasticity? 5) Excitation‐Inhibition balance in local circuits, and 6) Species differences in the animal models.

    This article is protected by copyright. All rights reserved.

    in Journal of Comparative Neurology on August 01, 2020 08:49 AM.

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    Subscription and Copyright Information

    in Trends in Neurosciences: Current Issue on August 01, 2020 12:00 AM.

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    Advisory Board and Contents

    in Trends in Neurosciences: Current Issue on August 01, 2020 12:00 AM.

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    Regional sequence expansion or collapse in heterozygous genome assemblies

    by Kathryn C. Asalone, Kara M. Ryan, Maryam Yamadi, Annastelle L. Cohen, William G. Farmer, Deborah J. George, Claudia Joppert, Kaitlyn Kim, Madeeha Froze Mughal, Rana Said, Metin Toksoz-Exley, Evgeny Bisk, John R. Bracht

    High levels of heterozygosity present a unique genome assembly challenge and can adversely impact downstream analyses, yet is common in sequencing datasets obtained from non-model organisms. Here we show that by re-assembling a heterozygous dataset with variant parameters and different assembly algorithms, we are able to generate assemblies whose protein annotations are statistically enriched for specific gene ontology categories. While total assembly length was not significantly affected by assembly methodologies tested, the assemblies generated varied widely in fragmentation level and we show local assembly collapse or expansion underlying the enrichment or depletion of specific protein functional groups. We show that these statistically significant deviations in gene ontology groups can occur in seemingly high-quality assemblies, and result from difficult-to-detect local sequence expansion or contractions. Given the unpredictable interplay between assembly algorithm, parameter, and biological sequence data heterozygosity, we highlight the need for better measures of assembly quality than N50 value, including methods for assessing local expansion and collapse.

    in PLoS Computational Biology on July 31, 2020 09:00 PM.

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    Cortical ignition dynamics is tightly linked to the core organisation of the human connectome

    by Samy Castro, Wael El-Deredy, Demian Battaglia, Patricio Orio

    The capability of cortical regions to flexibly sustain an “ignited” state of activity has been discussed in relation to conscious perception or hierarchical information processing. Here, we investigate how the intrinsic propensity of different regions to get ignited is determined by the specific topological organisation of the structural connectome. More specifically, we simulated the resting-state dynamics of mean-field whole-brain models and assessed how dynamic multi-stability and ignition differ between a reference model embedding a realistic human connectome, and alternative models based on a variety of randomised connectome ensembles. We found that the strength of global excitation needed to first trigger ignition in a subset of regions is substantially smaller for the model embedding the empirical human connectome. Furthermore, when increasing the strength of excitation, the propagation of ignition outside of this initial core–which is able to self-sustain its high activity–is way more gradual than for any of the randomised connectomes, allowing for graded control of the number of ignited regions. We explain both these assets in terms of the exceptional weighted core-shell organisation of the empirical connectome, speculating that this topology of human structural connectivity may be attuned to support enhanced ignition dynamics.

    in PLoS Computational Biology on July 31, 2020 09:00 PM.

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    Zinc protection of fertilized eggs is an ancient feature of sexual reproduction in animals

    by Katherine L. Wozniak, Rachel E. Bainbridge, Dominique W. Summerville, Maiwase Tembo, Wesley A. Phelps, Monica L. Sauer, Bennett W. Wisner, Madelyn E. Czekalski, Srikavya Pasumarthy, Meghan L. Hanson, Melania B. Linderman, Catherine H. Luu, Madison E. Boehm, Steven M. Sanders, Katherine M. Buckley, Daniel J. Bain, Matthew L. Nicotra, Miler T. Lee, Anne E. Carlson

    One of the earliest and most prevalent barriers to successful reproduction is polyspermy, or fertilization of an egg by multiple sperm. To prevent these supernumerary fertilizations, eggs have evolved multiple mechanisms. It has recently been proposed that zinc released by mammalian eggs at fertilization may block additional sperm from entering. Here, we demonstrate that eggs from amphibia and teleost fish also release zinc. Using Xenopus laevis as a model, we document that zinc reversibly blocks fertilization. Finally, we demonstrate that extracellular zinc similarly disrupts early embryonic development in eggs from diverse phyla, including Cnidaria, Echinodermata, and Chordata. Our study reveals that a fundamental strategy protecting human eggs from fertilization by multiple sperm may have evolved more than 650 million years ago.

    in PLoS Biology on July 31, 2020 09:00 PM.

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    Longitudinal connections and the organization of the temporal cortex in macaques, great apes, and humans

    by Lea Roumazeilles, Nicole Eichert, Katherine L. Bryant, Davide Folloni, Jerome Sallet, Suhas Vijayakumar, Sean Foxley, Benjamin C. Tendler, Saad Jbabdi, Colin Reveley, Lennart Verhagen, Lori B. Dershowitz, Martin Guthrie, Edmund Flach, Karla L. Miller, Rogier B. Mars

    The temporal association cortex is considered a primate specialization and is involved in complex behaviors, with some, such as language, particularly characteristic of humans. The emergence of these behaviors has been linked to major differences in temporal lobe white matter in humans compared with monkeys. It is unknown, however, how the organization of the temporal lobe differs across several anthropoid primates. Therefore, we systematically compared the organization of the major temporal lobe white matter tracts in the human, gorilla, and chimpanzee great apes and in the macaque monkey. We show that humans and great apes, in particular the chimpanzee, exhibit an expanded and more complex occipital–temporal white matter system; additionally, in humans, the invasion of dorsal tracts into the temporal lobe provides a further specialization. We demonstrate the reorganization of different tracts along the primate evolutionary tree, including distinctive connectivity of human temporal gray matter.

    in PLoS Biology on July 31, 2020 09:00 PM.

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    Continuing Clinical Research During Shelter‐in‐Place

    in Annals of Neurology on July 31, 2020 03:33 PM.

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    Content type revamp

    Nature Methods, Published online: 31 July 2020; doi:10.1038/s41592-020-0927-4

    We’ve made some recent updates to our various content type offerings at Nature Methods. Here is a cheat sheet.

    in Nature Methods on July 31, 2020 12:00 AM.

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    Trapping fluorescence in the soma

    Nature Methods, Published online: 31 July 2020; doi:10.1038/s41592-020-0923-8

    Tethering fluorescent proteins to ribosomes clears up background signals when imaging neural circuits.

    in Nature Methods on July 31, 2020 12:00 AM.

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    Mapping RNA–RNA interactions

    Nature Methods, Published online: 31 July 2020; doi:10.1038/s41592-020-0922-9

    RIC-seq enables in situ mapping of intra- and intermolecular RNA–RNA interactions.

    in Nature Methods on July 31, 2020 12:00 AM.

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    Multiplex fate mapping

    Nature Methods, Published online: 31 July 2020; doi:10.1038/s41592-020-0921-x

    barRNAseq allows detailed explorations of signaling pathways that control embryonic differentiation.

    in Nature Methods on July 31, 2020 12:00 AM.

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    Imaging single glycan molecules

    Nature Methods, Published online: 31 July 2020; doi:10.1038/s41592-020-0919-4

    Direct imaging of carbohydrates using electrospray ion beam deposition and scanning tunneling microscopy.

    in Nature Methods on July 31, 2020 12:00 AM.

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    Role of Ginkgolides in the Inflammatory Immune Response of Neurological Diseases: A Review of Current Literatures

    The inflammatory immune response (IIR) is a physiological or excessive systemic response, induced by inflammatory immune cells according to changes in the internal and external environments. An excessive IIR is the pathological basis for the generation and development of neurological diseases. Ginkgolides are one of the important medicinal ingredients in Ginkgo biloba. Many studies have verified that ginkgolides have anti-platelet-activating, anti-apoptotic, anti-oxidative, neurotrophic, and neuroimmunomodulatory effects. Inflammatory immunomodulation is mediated by inhibition of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways. They also inhibit the platelet-activating factor (PAF)-mediated signal transduction to attenuate the inflammatory response. Herein, we reviewed the studies on the roles of ginkgolides in inflammatory immunomodulation and suggested its potential role in novel treatments for neurological diseases.

    in Frontiers in Systems Neuroscience on July 31, 2020 12:00 AM.

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    Impacts of AD-Related ABCA7 and CLU Variants on Default Mode Network Connectivity in Healthy Middle-Age Adults

    Objective

    To investigate the impact of Alzheimer’s disease (AD)-related risk gene (ATP-binding cassette A7-ABCA7 and Clusterin-CLU) on the functional connectivity pattern of default mode network (DMN) in healthy middle-age adults.

    Methods

    A total of 147 healthy middle-aged volunteers were enrolled in this study. All subjects completed MRI scans, neuropsychological assessments, and AD-related genotyped analysis. All subjects were divided into high, middle and low risk groups according to the score of risk genotypes, which included CLU (rs11136000, rs2279590, rs9331888, and rs9331949) and ABCA7 (rs3764650 and rs4147929). The genetic effects of CLU, ABCA7, and CLU × ABCA7 on DMN functional connectivity pattern were further explored. Moreover, the genetic effect of Apolipoprotein ε4 (APOEε4) was also considered. Finally, correlation analysis was performed between the signals of brain regions with genetic effect and neuropsychological test scores.

    Results

    Compared with the low-risk group, the high-risk group of CLU showed decreased functional connectivity in posterior cingulate cortex (PCC) and the left middle frontal cortex (P < 0.05, GRF correction). As for the interaction between the CLU and ABCA7, all the subjects were divided into high, middle, and low risk group; the middle-risk group was divided into CLU and ABCA7-dominated middle-risk group. The function connectivity pattern of DMN among the three or four groups were distributed in the bilateral medial prefrontal cortex (MPFC) and bilateral superior frontal gyrus (SFG) (P < 0.05, GRF correction). When APOEε4 carriers were excluded, the CLU-predominant middle-risk group displayed the decreased functional connectivity in MPFC when compared with the low-risk group, while ABCA7-prodominant middle-risk group displayed decreased functional connectivity in cuneus when compared with the high-risk group (all P < 0.05, GRF correction). The z values of left middle frontal cortex were positively correlated with the scores of Serial Dotting Test (SDT) in high-risk group of CLU, while z values of MPFC and cuneus were positively correlated to the scores of Montreal Cognitive Assessment (MoCA) in low-risk group of three or four groups.

    Conclusion

    The functional connectivity of MPFC-PCC might be modulated by the interaction of CLU and ABCA7. Moreover, APOEε4 might be interacted with ABCA7 and CLU modulation in the middle-aged carriers.

    in Frontiers in Molecular Neuroscience on July 31, 2020 12:00 AM.

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    ApoER2: Functional Tuning Through Splicing

    Alternative splicing occurs in over 95% of protein-coding genes and contributes to the diversity of the human proteome. Apolipoprotein E receptor 2 (apoER2) is a critical modulator of neuronal development and synaptic plasticity in the brain and is enriched in cassette exon splicing events, in which functional exons are excluded from the final transcript. These alternative splicing events affect apoER2 function, as individual apoER2 exons tend to encode distinct protein functional domains. Although several apoER2 splice variants have been characterized, much work remains to understand how apoER2 splicing events modulate distinct apoER2 activities, including ligand binding specificity, synapse formation and plasticity. Additionally, little is known about how apoER2 splicing events are regulated. Often, alternative splicing events are regulated through the combinatorial action of RNA-binding proteins and other epigenetic mechanisms, however, the regulatory pathways corresponding to each specific exon are unknown in most cases. In this mini-review, we describe the structure of apoER2, highlight the unique functions of known isoforms, discuss what is currently known about the regulation of apoER2 splicing by RNA-binding proteins and pose new questions that will further our understanding of apoER2 splicing complexity.

    in Frontiers in Molecular Neuroscience on July 31, 2020 12:00 AM.

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    The P2X7 Receptor: Central Hub of Brain Diseases

    The P2X7 receptor is a cation channel activated by high concentrations of adenosine triphosphate (ATP). Upon long-term activation, it complexes with membrane proteins forming a wide pore that leads to cell death and increased release of ATP into the extracellular milieu. The P2X7 receptor is widely expressed in the CNS, such as frontal cortex, hippocampus, amygdala and striatum, regions involved in neurodegenerative diseases and psychiatric disorders. Despite P2X7 receptor functions in glial cells have been extensively studied, the existence and roles of this receptor in neurons are still controversially discussed. Regardless, P2X7 receptors mediate several processes observed in neuropsychiatric disorders and brain tumors, such as activation of neuroinflammatory response, stimulation of glutamate release and neuroplasticity impairment. Moreover, P2X7 receptor gene polymorphisms have been associated to depression, and isoforms of P2X7 receptors are implicated in neuropsychiatric diseases. In view of that, the P2X7 receptor has been proposed to be a potential target for therapeutic intervention in brain diseases. This review discusses the molecular mechanisms underlying P2X7 receptor-mediated signaling in neurodegenerative diseases, psychiatric disorders, and brain tumors. In addition, it highlights the recent advances in the development of P2X7 receptor antagonists that are able of penetrating the central nervous system.

    in Frontiers in Molecular Neuroscience on July 31, 2020 12:00 AM.

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    Delayed (21 Days) Post Stroke Treatment With RPh201, a Botany-Derived Compound, Improves Neurological Functional Recovery in a Rat Model of Embolic Stroke

    Background

    Despite the recent advances in the acute stroke care, treatment options for long-term disability are limited. RPh201 is a botany-derived bioactive compound that has been shown to exert beneficial effects in various experimental models of neural injury. The present study evaluated the effect of delayed RPh201 treatment on long term functional recovery after stroke.

    Methods

    Adult male Wistar rats subjected to embolic middle cerebral artery occlusion (MCAO) were randomized into the following experimental groups (n = 20/group): (1) RPh201 treatment, and (2) Vehicle (cottonseed oil). RPh201 (20 μl) or Vehicle were subcutaneously administered twice a week for 16 consecutive weeks starting at 21 days after MCAO. An array of behavioral tests was performed up to120 days after MCAO.

    Results

    Ischemic rats treated with RPh201 exhibited significant (p < 0.05) improvement of neurological function measured by adhesive removal test, foot-fault test, and modified neurological severity score at 90 and 120 days after MCAO. Immunohistochemistry analysis showed that RPh201 treatment robustly increased neurofilament heavy chain positive axons and myelin basic protein densities in the peri-infarct area by 61% and 31%, respectively, when compared to the Vehicle treatment, which were further confirmed by Western blot analysis. The RPh201 treatment did not reduce infarct volume.

    Conclusion

    Our data demonstrated that RPh201 has a therapeutic effect on improvement of functional recovery in male ischemic rats even when the treatment was initiated 21 days post stroke. Enhanced axonal and myelination densities by RPh201 in ischemic brain may contribute to improved stroke recovery.

    in Frontiers in Neuroscience: Neurodegeneration on July 31, 2020 12:00 AM.

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    Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

    Traumatic brain injury (TBI), a leading cause of morbidity worldwide, induces mechanical, persistent structural, and metabolic abnormalities in neurons and other brain-resident cells. The key pathological features of TBI include neuroinflammation, oxidative stress, excitotoxicity, and mitochondrial dysfunction. These pathological processes persist for a period of time after TBIs. Sirtuins are evolutionarily conserved nicotinamide-adenine dinucleotide (NAD+)-dependent deacetylases and mono-ADP-ribosyl transferases. The mammalian sirtuin family has seven members, referred to as Sirtuin (SIRT) 1–7. Accumulating evidence suggests that SIRT1 and SIRT3 play a neuroprotective role in TBI. Although the evidence is scant, considering the involvement of SIRT2, 4–7 in other brain injury models, they may also intervene in similar pathophysiology in TBI. Neurodegenerative diseases are generally accepted sequelae of TBI. It was found that TBI and neurodegenerative diseases have many similarities and overlaps in pathological features. Besides, sirtuins play some unique roles in some neurodegenerative diseases. Therefore, we propose that sirtuins might be a promising therapeutic target for both TBI and associated neurodegenerative diseases. In this paper, we review the neuroprotective effects of sirtuins on TBI as well as related neurodegeneration and discuss the therapeutic potential of sirtuin modulators.

    in Frontiers in Neuroscience: Neurodegeneration on July 31, 2020 12:00 AM.

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    Amyloid Beta Immunoreactivity in the Retinal Ganglion Cell Layer of the Alzheimer’s Eye

    Alzheimer’s disease (AD) is the most prevalent form of dementia, accounting for 60–70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-β (Aβ)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify Aβ in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of Aβ in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of Aβ in retinal wholemounts and to inform on future retinal image studies targeting Aβ. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal Aβ using immunohistochemistry, confocal microscopy, and quantitative image analysis. Aβ load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular Aβ retinal deposits were significantly higher in AD than controls. Mid-peripheral Aβ levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular Aβ was associated with lower NP score, while higher extracellular Aβ was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular Aβ as a surrogate measure of Aβ in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more Aβ deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging.

    in Frontiers in Neuroscience: Neurodegeneration on July 31, 2020 12:00 AM.

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    Anti-fatigue Performance in SSVEP-Based Visual Acuity Assessment: A Comparison of Six Stimulus Paradigms

    Purpose

    The occurrence of mental fatigue when users stare at stimuli is a critical problem in the implementation of steady-state visual evoked potential (SSVEP)-based visual acuity assessment, which may weaken the SSVEP amplitude and signal-to-noise ratio (SNR) and subsequently affect the results of visual acuity assessment. This study aimed to explore the anti-fatigue performance of six stimulus paradigms (reverse vertical sinusoidal gratings, reverse horizontal sinusoidal gratings, reverse vertical square-wave gratings, brief-onset vertical sinusoidal gratings, reversal checkerboards, and oscillating expansion–contraction concentric rings) in SSVEP acuity assessment.

    Methods

    Based on four indices of α + θ index, pupil diameter, National Aeronautics and Space Administration Task Load Index (NASA-TLX), and amplitude and SNR of SSVEPs, this study quantitatively evaluated mental fatigue in six SSVEP visual attention runs corresponding to six paradigms with 12 subjects.

    Results

    These indices of mental fatigue showed a good agreement. The results showed that the paradigm of motion expansion–contraction concentric rings had a superior anti-fatigue efficacy than the other five paradigms of conventional onset mode or pattern reversal mode during prolonged SSVEP experiment. The paradigm of brief-onset mode showed the lowest anti-fatigue efficacy, and the other paradigms of pattern reversal SSVEP paradigms showed a similar anti-fatigue efficacy, which was between motion expansion–contraction mode and onset mode.

    Conclusion

    This study recommended the paradigm of oscillating expansion–contraction concentric rings as the stimulation paradigm in SSVEP visual acuity because of its superior anti-fatigue efficacy.

    in Frontiers in Human Neuroscience on July 31, 2020 12:00 AM.

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    Improving the Cross-Subject Performance of the ERP-Based Brain–Computer Interface Using Rapid Serial Visual Presentation and Correlation Analysis Rank

    The brain–computer interface (BCI) is a system that is designed to provide communication channels to anyone through a computer. Initially, it was suggested to help the disabled, but actually had been proposed a wider range of applications. However, the cross-subject recognition in BCI systems is difficult to break apart from the individual specific characteristics, unsteady characteristics, and environmental specific characteristics, which also makes it difficult to develop highly reliable and highly stable BCI systems. Rapid serial visual presentation (RSVP) is one of the most recent spellers with a clean, unified background and a single stimulus, which may evoke event-related potential (ERP) patterns with less individual difference. In order to build a BCI system that allows new users to use it directly without calibration or with less calibration time, RSVP was employed as evoked paradigm, then correlation analysis rank (CAR) algorithm was proposed to improve the cross-individual classification and simultaneously use as less training data as possible. Fifty-eight subjects took part in the experiments. The flash stimulation time is 200 ms, and the off time is 100 ms. The P300 component was locked to the target representation by time. The results showed that RSVP could evoke more similar ERP patterns among subjects compared with matrix paradigm. Then, the included angle cosine was calculated and counted for averaged ERP waveform between each two subjects. The average matching number of all subjects was 6 for the matrix paradigm, while for the RSVP paradigm, the average matching number range was 20 when the threshold value was set to 0.5, more than three times as much larger, quantificationally indicating that ERP waveforms evoked by the RSVP paradigm produced smaller individual differences, and it is more favorable for cross-subject classification. Information transfer rates (ITR) were also calculated for RSVP and matrix paradigms, and the RSVP paradigm got the average ITR of 43.18 bits/min, which was 13% higher than the matrix paradigm. Then, the receiver operating characteristic (ROC) curve value was computed and compared using the proposed CAR algorithm and traditional random selection. The results showed that the proposed CAR got significantly better performance than the traditional random selection and got the best AUC value of 0.8, while the traditional random selection only achieved 0.65. These encouraging results suggest that with proper evoked paradigm and classification methods, it is feasible to get stable performance across subjects for ERP-based BCI. Thus, our findings provide a new approach to improve BCI performances.

    in Frontiers in Human Neuroscience on July 31, 2020 12:00 AM.

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    Exploring the Role of Action Consequences in the Handle-Response Compatibility Effect

    Previous research investigating handle-response compatibility effects with graspable objects used different categories of objects as stimuli, regardless of their specific, intrinsic characteristics. The current study explores whether different types of objects’ characteristics may elicit different types of spatial compatibility, that is, handle-response and response-effect compatibility as well as their potential interaction. In Experiment 1, objects having a graspable handle opposite to either a visible functional component (i.e., handle-function objects: a teapot) or a latent functional component (handle-only objects: a pitcher lacking the spout) were presented separately in different blocks. Both the handle and the goal-directed functional components of these objects were located on the horizontal axis. In Experiment 2, handle-only objects had a handle located on the horizontal axis and a latent functional component located on the vertical axis (e.g., a cup). In both experiments, participants were required to judge the material (plastic and metal) the object was made of. Results showed that the handle-response compatibility effect was sensitive to whether the actions consequences of object manipulation took place on the horizontal rather than on the vertical axis.

    in Frontiers in Human Neuroscience on July 31, 2020 12:00 AM.

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    Neural Processes Underlying Mirror-Induced Visual Illusion: An Activation Likelihood Estimation Meta-Analysis

    Introduction: Neuroimaging studies on neural processes associated with mirror-induced visual illusion (MVI) are growing in number. Previous systematic reviews on these studies used qualitative approaches.

    Objective: The present study conducted activation likelihood estimation (ALE) meta-analysis to locate the brain areas for unfolding the neural processes associated with the MVI.

    Method: We searched the CINAHL, MEDLINE, Scopus, and PubMed databases and identified eight studies (with 14 experiments) that met the inclusion criteria.

    Results: Contrasting with a rest condition, strong convergence in the bilateral primary and premotor areas and the inferior parietal lobule suggested top-down motor planning and execution. In addition, convergence was identified in the ipsilateral precuneus, cerebellum, superior frontal gyrus, and superior parietal lobule, clusters corresponding to the static hidden hand indicating self-processing operations, somatosensory processing, and motor control. When contrasting with an active movement condition, additional substantial convergence was revealed in visual-related areas, such as the ipsilateral cuneus, fusiform gyrus, middle occipital gyrus (visual area V2) and lingual gyrus, which mediate basic visual processing.

    Conclusions: To the best of our knowledge, the current meta-analysis is the first to reveal the visualization, mental rehearsal and motor-related processes underpinning the MVI and offers theoretical support on using MVI as a clinical intervention for post-stroke patients.

    in Frontiers in Human Neuroscience on July 31, 2020 12:00 AM.

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    Corrigendum: Does Transcranial Direct Current Stimulation (tDCS) Improve Disgust Regulation Through Imagery Rescripting?

    in Frontiers in Human Neuroscience on July 31, 2020 12:00 AM.

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    The Importance of Cerebellar Connectivity on Simulated Brain Dynamics

    The brain shows a complex multiscale organization that prevents a direct understanding of how structure, function and dynamics are correlated. To date, advances in neural modeling offer a unique opportunity for simulating global brain dynamics by embedding empirical data on different scales in a mathematical framework. The Virtual Brain (TVB) is an advanced data-driven model allowing to simulate brain dynamics starting from individual subjects’ structural and functional connectivity obtained, for example, from magnetic resonance imaging (MRI). The use of TVB has been limited so far to cerebral connectivity but here, for the first time, we have introduced cerebellar nodes and interconnecting tracts to demonstrate the impact of cerebro-cerebellar loops on brain dynamics. Indeed, the matching between the empirical and simulated functional connectome was significantly improved when including the cerebro-cerebellar loops. This positive result should be considered as a first step, since issues remain open about the best strategy to reconstruct effective structural connectivity and the nature of the neural mass or mean-field models generating local activity in the nodes. For example, signal processing is known to differ remarkably between cortical and cerebellar microcircuits. Tackling these challenges is expected to further improve the predictive power of functional brain activity simulations, using TVB or other similar tools, in explaining not just global brain dynamics but also the role of cerebellum in determining brain states in physiological conditions and in the numerous pathologies affecting the cerebro-cerebellar loops.

    in Frontiers in Cellular Neuroscience on July 31, 2020 12:00 AM.

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    Activated Oxytocin Neurons in the PVN-DVC Pathway in Asthmatic Rats

    Asthma is a heterogeneous disease, and the central nervous system (CNS) also participates in the pathogenesis of asthma. We previously reported the amygdala might regulate asthmatic attacks via projecting to the paraventricular hypothalamic nucleus (PVN). The dorsal vagal complex (DVC) is a crucial region that modulates respiratory. This study aimed to observe the activity in both PVN and DVC and the connection between PVN and DVC in asthmatic rats. Immunohistochemistry was conducted to observe the changes in Fos and oxytocin (OT) expression. Retrograde tracing using wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and double immunohistochemistry for OT and Fos was used to observe the HRP/OT/Fos positive neurons distribution in the PVN. The results showed that during an asthma attack, the Fos positive neurons increased in both PVN and DVC over time. The expression of OT positive neurons in PVN showed a similar trend in parallel to the c-Fos positive neurons in PVN. The HRP retrograde-labeled neurons were densely distributed in the medial and lateral subnucleus in the PVN. OT+/HRP+ and Fos+/OT+/HRP+ accounted for 18.14%, and 2.37% of HRP-labeled neurons, respectively. Our study showed PVN and DVC were activated and the expression of OT positive neurons in PVN were increased over time during an asthma attack. The existence of connection between PVN and DVC suggested the OT neurons in PVN might project to DVC which might be involved in the pathogenesis of asthma.

    in Frontiers in Neuroanatomy on July 31, 2020 12:00 AM.

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    Clinical and Oculomotor Correlates With Freezing of Gait in a Chinese Cohort of Parkinson’s Disease Patients

    Accumulating evidence suggests that freezing of gait (FOG) is a unique gait disturbance in Parkinson’s disease (PD), and its pathophysiology is not fully elucidated. The present study aims to investigate the clinical and oculomotor associations with FOG in Chinese PD patients. From Jan 2017 to Dec 2019, a total of 210 PD patients were consecutively registered for FOG evaluation based on item-3 of the Freezing of Gait Questionnaire (FOGQ). We explored the demographic, motor, and non-motor symptom differences in FOG positive (PD+FOG, n = 45) vs. negative (PD-FOG, n = 165) group. In addition, 40 PD patients and 37 healthy controls (HC) also underwent oculomotor test via videonystagmography (VNG). Visually guided saccade (VGS) latency, saccade accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of horizontal axis were compared among PD+FOG (n = 20), PD-FOG (n = 20), and HC (n = 37). Compared with PD-FOG, PD+FOG had longer disease duration, more severe motor symptoms, lower cognitive scores, more severe depressive and autonomic impairments, as well as higher daily levodopa equivalent dosage. FOG occurred more frequently in patients with wearing-off. VNG subgroup analysis demonstrated that PD+FOG had prolonged saccade latency and decreased saccade accuracy relative to PD-FOG or HC. SPEM gain at 0.1 and 0.2 Hz was also decreased in PD+FOG compared with HC. Furthermore, prolonged saccade latency was correlated with higher FOGQ scores in PD patients. Our results verify that PD with FOG patients suffer from more severe motor and non-motor symptoms, indicating more extensive neurodegeneration. Prolonged saccade latency could be a practical oculomotor parameter both for identification and progression of FOG in PD.

    in Frontiers in Ageing Neuroscience on July 31, 2020 12:00 AM.

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    MicroRNA-138 promotes neuroblastoma SH-SY5Y cell apoptosis by directly targeting DEK in Alzheimer’s disease cell model

    Alzheimer’s disease (AD) is a progressive neuro-degenerative disease with a major manifestation of dementia. MicroRNAs were reported to regulate the transcript expression in patients with Alzheimer’s disease (...

    in BMC Neuroscience on July 31, 2020 12:00 AM.

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    Emergent neutrality in consumer-resource dynamics

    by Rafael D’Andrea, Theo Gibbs, James P. O’Dwyer

    Neutral theory assumes all species and individuals in a community are ecologically equivalent. This controversial hypothesis has been tested across many taxonomic groups and environmental contexts, and successfully predicts species abundance distributions across multiple high-diversity communities. However, it has been critiqued for its failure to predict a broader range of community properties, particularly regarding community dynamics from generational to geological timescales. Moreover, it is unclear whether neutrality can ever be a true description of a community given the ubiquity of interspecific differences, which presumably lead to ecological inequivalences. Here we derive analytical predictions for when and why non-neutral communities of consumers and resources may present neutral-like outcomes, which we verify using numerical simulations. Our results, which span both static and dynamical community properties, demonstrate the limitations of summarizing distributions to detect non-neutrality, and provide a potential explanation for the successes of neutral theory as a description of macroecological pattern.

    in PLoS Computational Biology on July 30, 2020 09:00 PM.

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    ADP is the dominant controller of AMP-activated protein kinase activity dynamics in skeletal muscle during exercise

    by Ian F. Coccimiglio, David C. Clarke

    Exercise training elicits profound metabolic adaptations in skeletal muscle cells. A key molecule in coordinating these adaptations is AMP-activated protein kinase (AMPK), whose activity increases in response to cellular energy demand. AMPK activity dynamics are primarily controlled by the adenine nucleotides ADP and AMP, but how each contributes to its control in skeletal muscle during exercise is unclear. We developed and validated a mathematical model of AMPK signaling dynamics, and then applied global parameter sensitivity analyses with data-informed constraints to predict that AMPK activity dynamics are determined principally by ADP and not AMP. We then used the model to predict the effects of two additional direct-binding activators of AMPK, ZMP and Compound 991, further validating the model and demonstrating its applicability to understanding AMPK pharmacology. The relative effects of direct-binding activators can be understood in terms of four properties, namely their concentrations, binding affinities for AMPK, abilities to enhance AMPK phosphorylation, and the magnitudes of their allosteric activation of AMPK. Despite AMP’s favorable values in three of these four properties, ADP is the dominant controller of AMPK activity dynamics in skeletal muscle during exercise by virtue of its higher concentration compared to that of AMP.

    in PLoS Computational Biology on July 30, 2020 09:00 PM.

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    Electrical coupling controls dimensionality and chaotic firing of inferior olive neurons

    by Huu Hoang, Eric J. Lang, Yoshito Hirata, Isao T. Tokuda, Kazuyuki Aihara, Keisuke Toyama, Mitsuo Kawato, Nicolas Schweighofer

    We previously proposed, on theoretical grounds, that the cerebellum must regulate the dimensionality of its neuronal activity during motor learning and control to cope with the low firing frequency of inferior olive neurons, which form one of two major inputs to the cerebellar cortex. Such dimensionality regulation is possible via modulation of electrical coupling through the gap junctions between inferior olive neurons by inhibitory GABAergic synapses. In addition, we previously showed in simulations that intermediate coupling strengths induce chaotic firing of inferior olive neurons and increase their information carrying capacity. However, there is no in vivo experimental data supporting these two theoretical predictions. Here, we computed the levels of synchrony, dimensionality, and chaos of the inferior olive code by analyzing in vivo recordings of Purkinje cell complex spike activity in three different coupling conditions: carbenoxolone (gap junctions blocker), control, and picrotoxin (GABA-A receptor antagonist). To examine the effect of electrical coupling on dimensionality and chaotic dynamics, we first determined the physiological range of effective coupling strengths between inferior olive neurons in the three conditions using a combination of a biophysical network model of the inferior olive and a novel Bayesian model averaging approach. We found that effective coupling co-varied with synchrony and was inversely related to the dimensionality of inferior olive firing dynamics, as measured via a principal component analysis of the spike trains in each condition. Furthermore, for both the model and the data, we found an inverted U-shaped relationship between coupling strengths and complexity entropy, a measure of chaos for spiking neural data. These results are consistent with our hypothesis according to which electrical coupling regulates the dimensionality and the complexity in the inferior olive neurons in order to optimize both motor learning and control of high dimensional motor systems by the cerebellum.

    in PLoS Computational Biology on July 30, 2020 09:00 PM.

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    Quorum sensing via dynamic cytokine signaling comprehensively explains divergent patterns of effector choice among helper T cells

    by Edward C. Schrom II, Simon A. Levin, Andrea L. Graham

    In the animal kingdom, various forms of swarming enable groups of autonomous individuals to transform uncertain information into unified decisions which are probabilistically beneficial. Crossing scales from individual to group decisions requires dynamically accumulating signals among individuals. In striking parallel, the mammalian immune system is also a group of decentralized autonomous units (i.e. cells) which collectively navigate uncertainty with the help of dynamically accumulating signals (i.e. cytokines). Therefore, we apply techniques of understanding swarm behavior to a decision-making problem in the mammalian immune system, namely effector choice among CD4+ T helper (Th) cells. We find that incorporating dynamic cytokine signaling into a simple model of Th differentiation comprehensively explains divergent observations of this process. The plasticity and heterogeneity of individual Th cells, the tunable mixtures of effector types that can be generated in vitro, and the polarized yet updateable group effector commitment often observed in vivo are all explained by the same set of underlying molecular rules. These rules reveal that Th cells harness dynamic cytokine signaling to implement a system of quorum sensing. Quorum sensing, in turn, may confer adaptive advantages on the mammalian immune system, especially during coinfection and during coevolution with manipulative parasites. This highlights a new way of understanding the mammalian immune system as a cellular swarm, and it underscores the power of collectives throughout nature.

    in PLoS Computational Biology on July 30, 2020 09:00 PM.

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    Ten simple rules for reading a scientific paper

    by Maureen A. Carey, Kevin L. Steiner, William A. Petri Jr

    in PLoS Computational Biology on July 30, 2020 09:00 PM.

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    5-Formylcytosine landscapes of human preimplantation embryos at single-cell resolution

    by Yun Gao, Lin Li, Peng Yuan, Fan Zhai, Yixin Ren, Liying Yan, Rong Li, Ying Lian, Xiaohui Zhu, Xinglong Wu, Kehkooi Kee, Lu Wen, Jie Qiao, Fuchou Tang

    Epigenetic dynamics, such as DNA methylation and chromatin accessibility, have been extensively explored in human preimplantation embryos. However, the active demethylation process during this crucial period remains largely unexplored. In this study, we use single-cell chemical-labeling-enabled C-to-T conversion sequencing (CLEVER-seq) to quantify the DNA 5-formylcytosine (5fC) levels of human preimplantation embryos. We find that 5-formylcytosine phosphate guanine (5fCpG) exhibits genomic element-specific distribution features and is enriched in L1 and endogenous retrovirus-K (ERVK), the subfamilies of repeat elements long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs), respectively. Unlike in mice, paired pronuclei in the same zygote present variable difference of 5fCpG levels, although the male pronuclei experience stronger global demethylation. The nucleosome-occupied regions show a higher 5fCpG level compared with nucleosome-depleted ones, suggesting the role of 5fC in organizing nucleosome position. Collectively, our work offers a valuable resource for ten-eleven translocation protein family (TET)-dependent active demethylation-related study during human early embryonic development.

    in PLoS Biology on July 30, 2020 09:00 PM.

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    In situ characterisation and manipulation of biological systems with Chi.Bio

    by Harrison Steel, Robert Habgood, Ciarán Kelly, Antonis Papachristodoulou

    The precision and repeatability of in vivo biological studies is predicated upon methods for isolating a targeted subsystem from external sources of noise and variability. However, in many experimental frameworks, this is made challenging by nonstatic environments during host cell growth, as well as variability introduced by manual sampling and measurement protocols. To address these challenges, we developed Chi.Bio, a parallelised open-source platform that represents a new experimental paradigm in which all measurement and control actions can be applied to a bulk culture in situ. In addition to continuous-culturing capabilities, it incorporates tunable light outputs, spectrometry, and advanced automation features. We demonstrate its application to studies of cell growth and biofilm formation, automated in silico control of optogenetic systems, and readout of multiple orthogonal fluorescent proteins in situ. By integrating precise measurement and actuation hardware into a single low-cost platform, Chi.Bio facilitates novel experimental methods for synthetic, systems, and evolutionary biology and broadens access to cutting-edge research capabilities.

    in PLoS Biology on July 30, 2020 09:00 PM.

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    Should a viral genome stay in the host cell or leave? A quantitative dynamics study of how hepatitis C virus deals with this dilemma

    by Shoya Iwanami, Kosaku Kitagawa, Hirofumi Ohashi, Yusuke Asai, Kaho Shionoya, Wakana Saso, Kazane Nishioka, Hisashi Inaba, Shinji Nakaoka, Takaji Wakita, Odo Diekmann, Shingo Iwami, Koichi Watashi

    Virus proliferation involves gene replication inside infected cells and transmission to new target cells. Once positive-strand RNA virus has infected a cell, the viral genome serves as a template for copying (“stay-strategy”) or is packaged into a progeny virion that will be released extracellularly (“leave-strategy”). The balance between genome replication and virion release determines virus production and transmission efficacy. The ensuing trade-off has not yet been well characterized. In this study, we use hepatitis C virus (HCV) as a model system to study the balance of the two strategies. Combining viral infection cell culture assays with mathematical modeling, we characterize the dynamics of two different HCV strains (JFH-1, a clinical isolate, and Jc1-n, a laboratory strain), which have different viral release characteristics. We found that 0.63% and 1.70% of JFH-1 and Jc1-n intracellular viral RNAs, respectively, are used for producing and releasing progeny virions. Analysis of the Malthusian parameter of the HCV genome (i.e., initial proliferation rate) and the number of de novo infections (i.e., initial transmissibility) suggests that the leave-strategy provides a higher level of initial transmission for Jc1-n, whereas, in contrast, the stay-strategy provides a higher initial proliferation rate for JFH-1. Thus, theoretical-experimental analysis of viral dynamics enables us to better understand the proliferation strategies of viruses, which contributes to the efficient control of virus transmission. Ours is the first study to analyze the stay-leave trade-off during the viral life cycle and the significance of the replication-release switching mechanism for viral proliferation.

    in PLoS Biology on July 30, 2020 09:00 PM.

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    Neuronal and synaptic morphological alterations in the hippocampus of cannabinoid receptor type 1 knockout mice

    Neuronal and synaptic morphological alterations in the hippocampus of cannabinoid receptor type 1 knockout mice

    CB1R knockout mice showed decreased neuronal dendritic arborization and changes in synaptic structure, as such as lower thickness of postsynaptic density and a reduction in synaptophysin levels in hippocampus.


    Abstract

    Cannabinoid receptor type 1 (CB1R) modulates synaptic activity and is widely distributed in brain areas such as the hippocampus, cerebellum, cerebral cortex, and striatum, among others. CB1R is involved in processes such as memory, learning, motor coordination, and mood. Genetic deletion of CB1R causes behavioral alterations. In this work, we evaluated neuronal morphology and synaptic structure in the hippocampus of adult male CB1R knockout mice (CB1R−/−). Morphological changes in the CB1R−/− hippocampus evidenced a decrease in the expression of cytoskeletal proteins neurofilaments 160 KDa, neurofilaments 200 KDa, and microtubule‐associated protein 2. CA1 neurons showed decreased arborization and changes in synaptic structure such as lower thickness of postsynaptic density and a reduction in synaptophysin levels. Results obtained in the present work provide evidence of the participation of CB1R in the establishment of neuronal structure and networks that could have an important role in neuronal plasticity. In addition, these changes observed in CB1R−/− could be correlated with behavioral alterations reported.

    in Journal of Neuroscience Research on July 30, 2020 12:21 PM.

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    Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry

    Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry

    Quantitative 7 Tesla MRI (susceptibility, relaxation, fractional anisotropy) found differences between ten Friedreich's ataxia patients and matched healthy controls in eight structures of brainstem and cerebellum which correlated with disease characteristics. Voxel‐based morphometry revealed white matter atrophy in partially overlapping volumes of interest (VOI) used for the VOI‐based evaluation. *Statistically significant differences between patients and controls; middle cerebellar peduncle (MCP), pontine crossing tract (PCT), corticospinal tract (CS), medial lemniscus (ML), inferior cerebellar peduncle (ICP), superior cerebellar peduncle (SCP), cerebral peduncle (CP), posterior thalamic radiation (PTR), sagittal stratum (SS), dentate nuclei (DN), red nuclei (RN), substantia nigra (SN).


    Abstract

    Friedreich's ataxia (FRDA) is a rare genetic disorder leading to degenerative processes. So far, no effective treatment has been found. Therefore, it is important to assist the development of medication with imaging biomarkers reflecting disease status and progress. Ten FRDA patients (mean age 37 ± 14 years; four female) and 10 age‐ and sex‐matched controls were included. Acquisition of magnetic resonance imaging (MRI) data for quantitative susceptibility mapping, R 1, R 2 relaxometry and diffusion imaging was performed at 7 Tesla. Results of volume of interest (VOI)‐based analyses of the quantitative data were compared with a voxel‐based morphometry (VBM) evaluation. Differences between patients and controls were assessed using the analysis of covariance (ANCOVA; p  < 0.01) with age and sex as covariates, effect size of group differences, and correlations with disease characteristics with Spearman correlation coefficient. For the VBM analysis, a statistical threshold of 0.001 for uncorrected and 0.05 for corrected p‐values was used. Statistically significant differences between FRDA patients and controls were found in five out of twelve investigated structures, and statistically significant correlations with disease characteristics were revealed. Moreover, VBM revealed significant white matter atrophy within regions of the brainstem, and the cerebellum. These regions overlapped partially with brain regions for which significant differences between healthy controls and patients were found in the VOI‐based quantitative MRI evaluation. It was shown that two independent analyses provided overlapping results. Moreover, positive results on correlations with disease characteristics were found, indicating that these quantitative MRI parameters could provide more detailed information and assist the search for effective treatments.

    in Journal of Neuroscience Research on July 30, 2020 10:55 AM.

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    Sex differences in kappa opioid receptor antinociception is influenced by the number of X chromosomes in mouse

    Sex differences in kappa opioid receptor antinociception is influenced by the number of X chromosomes in mouse

    The kappa opioid receptor (KOR) is notable for its robust sex difference, with females being less responsive to KOR agonists than males. In this study, we use two genetic mouse models (four core genotype and XY*) to isolate the sex chromosome and gonadal hormone contribution to this observed sex difference. We determine that KOR analgesia varies with the number of X chromosomes. The presence or absence of the Y chromosome or gonadal hormones had minimal influence. This study determines that genes on the X chromosome contribute to the sex difference in KOR function.


    Abstract

    Kappa opioid receptor (KOR) agonists produce robust analgesia with minimal abuse liability and are considered promising pharmacological agents to manage chronic pain and itch. The KOR system is also notable for robust differences between the sexes, with females exhibiting lower analgesic response than males. Sexually dimorphic traits can be due to either the influence of gonadal hormones during development or adulthood, or due to the complement of genes expressed on the X or Y chromosome. Previous studies examining sex differences in KOR antinociception have relied on surgical or pharmacological manipulation of the gonads to determine whether sex hormones influence KOR function. While there are conflicting reports whether gonadal hormones influence KOR function, no study has examined these effects in context with sex chromosomes. Here, we use two genetic mouse models, the four core genotypes and XY*, to isolate the chromosomal and hormonal contributions to sex differences in KOR analgesia. Mice were treated with systemic KOR agonist (U50,488H) and thermal analgesia measured in the tail withdrawal assay. We found that KOR antinociception was influenced predominantly by the number of the X chromosomes. These data suggest that the dose and/or parental imprint on X gene(s) contribute significantly to the sexually dimorphism in KOR analgesia.

    in Journal of Neuroscience Research on July 30, 2020 10:48 AM.

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    Remodelling the matrix

    Nature Reviews Neuroscience, Published online: 30 July 2020; doi:10.1038/s41583-020-0356-5

    In the hippocampus of adult mice, neuronally expressed interleukin-33 acts as a signal for microglial cell-mediated extracellular matrix remodelling, regulating synaptic plasticity and promoting memory consolidation.

    in Nature Reviews on July 30, 2020 12:00 AM.

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    Investigating the Reliability of Population Receptive Field Size Estimates Using fMRI

    In functional MRI (fMRI), population receptive field (pRF) models allow a quantitative description of the response as a function of the features of the stimuli that are relevant for each voxel. The most popular pRF model used in fMRI assumes a Gaussian shape in the features space (e.g., the visual field) reducing the description of the voxel’s pRF to the Gaussian mean (the pRF preferred feature) and standard deviation (the pRF size). The estimation of the pRF mean has been proven to be highly reliable. However, the estimate of the pRF size has been shown not to be consistent within and between subjects. While this issue has been noted experimentally, here we use an optimization theory perspective to describe how the inconsistency in estimating the pRF size is linked to an inherent property of the Gaussian pRF model. When fitting such models, the goodness of fit is less sensitive to variations in the pRF size than to variations in the pRF mean. We also show how the same issue can be considered from a bias-variance perspective. We compare different estimation procedures in terms of the reliability of their estimates using simulated and real fMRI data in the visual (using the Human Connectome Project database) and auditory domain. We show that, the reliability of the estimate of the pRF size can be improved considering a linear combination of those pRF models with similar goodness of fit or a permutation based approach. This increase in reliability of the pRF size estimate does not affect the reliability of the estimate of the pRF mean and the prediction accuracy.

    in Frontiers in Neuroscience: Brain Imaging Methods on July 30, 2020 12:00 AM.

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    In vivo PET Imaging of Gliogenesis After Cerebral Ischemia in Rats

    In vivo positron emission tomography of neuroinflammation has mainly focused on the evaluation of glial cell activation using radiolabeled ligands. However, the non-invasive imaging of neuroinflammatory cell proliferation has been scarcely evaluated so far. In vivo and ex vivo assessment of gliogenesis after transient middle cerebral artery occlusion (MCAO) in rats was carried out using PET imaging with the marker of cell proliferation 3′-Deoxy-3′-[18F] fluorothymidine ([18F]FLT), magnetic resonance imaging (MRI) and fluorescence immunohistochemistry. MRI-T2W studies showed the presence of the brain infarction at 24 h after MCAO affecting cerebral cortex and striatum. In vivo PET imaging showed a significant increase in [18F]FLT uptake in the ischemic territory at day 7 followed by a progressive decline from day 14 to day 28 after ischemia onset. In addition, immunohistochemistry studies using Ki67, CD11b, and GFAP to evaluate proliferation of microglia and astrocytes confirmed the PET findings showing the increase of glial proliferation at day 7 after ischemia followed by decrease later on. Hence, these results show that [18F]FLT provides accurate quantitative information on the time course of glial proliferation in experimental stroke. Finally, this novel brain imaging method might guide on the imaging evaluation of the role of gliogenesis after stroke.

    in Frontiers in Neuroscience: Brain Imaging Methods on July 30, 2020 12:00 AM.

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    Assessment of Long-Term Effects of Sports-Related Concussions: Biological Mechanisms and Exosomal Biomarkers

    Concussion or mild traumatic brain injury (mTBI) in athletes can cause persistent symptoms, known as post-concussion syndrome (PCS), and repeated injuries may increase the long-term risk for an athlete to develop neurodegenerative diseases such as chronic traumatic encephalopathy (CTE), and Alzheimer’s disease (AD). The Center for Disease Control estimates that up to 3.8 million sport-related mTBI are reported each year in the United States. Despite the magnitude of the phenomenon, there is a current lack of comprehensive prognostic indicators and research has shown that available monitoring tools are moderately sensitive to short-term concussion effects but less sensitive to long-term consequences. The overall aim of this review is to discuss novel, quantitative, and objective measurements that can predict long-term outcomes following repeated sports-related mTBIs. The specific objectives were (1) to provide an overview of the current clinical and biomechanical tools available to health practitioners to ensure recovery after mTBIs, (2) to synthesize potential biological mechanisms in animal models underlying the long-term adverse consequences of mTBIs, (3) to discuss the possible link between repeated mTBI and neurodegenerative diseases, and (4) to discuss the current knowledge about fluid biomarkers for mTBIs with a focus on novel exosomal biomarkers. The conclusions from this review are that current post-concussion clinical tests are not sufficiently sensitive to injury and do not accurately quantify post-concussion alterations associated with repeated mTBIs. In the current review, it is proposed that current practices should be amended to include a repeated symptom inventory, a cognitive assessment of executive function and impulse control, an instrumented assessment of balance, vestibulo-ocular assessments, and an improved panel of blood or exosome biomarkers.

    in Frontiers in Neuroscience: Neurodegeneration on July 30, 2020 12:00 AM.

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    Acquisition Duration in Resting-State Arterial Spin Labeling. How Long Is Enough?

    Resting-state Arterial Spin Labeling (rs-ASL) is a rather confidential method compared to resting-state BOLD. As ASL allows to quantify the cerebral blood flow, unlike BOLD, rs-ASL can lead to significant clinical subject-scaled applications. Despite directly impacting clinical practicability and functional networks estimation, there is no standard for rs-ASL regarding the acquisition duration. Our work here focuses on assessing the feasibility of ASL as an rs-fMRI method and on studying the effect of the acquisition duration on the estimation of functional networks. To this end, we acquired a long 24 min 30 s rs-ASL sequence and investigated how estimations of six typical functional brain networks evolved with respect to the acquisition duration. Our results show that, after a certain acquisition duration, the estimations of all functional networks reach their best and are stabilized. Since, for clinical application, the acquisition duration should be the shortest possible, we suggest an acquisition duration of 14 min, i.e., 240 volumes with our sequence parameters, as it covers the functional networks estimation stabilization.

    in Frontiers in Neuroscience: Brain Imaging Methods on July 30, 2020 12:00 AM.

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    Modulation of Intermuscular Beta Coherence in Different Rhythmic Mandibular Behaviors

    Introduction

    Jaw movement during chewing and speech is facilitated by neural activation patterns for opening and closing movements of the mandible. This study investigated anatomic- and task-dependent differences in intermuscular coherence (IMC) and their association with the parameters of jaw muscle activity using surface electromyography (sEMG).

    Methods

    We recorded sEMG activation from bilateral and ipsilateral jaw-closing muscle pairs during non-nutritive and nutritive chewing, and during a syllable repetition task. IMC and cross-correlational analyses between bilateral and ipsilateral muscle pairs were performed.

    Results

    Intermuscular coherence in the beta band was statistically significant between agonist jaw-closing muscle pairs, with beta IMC weaker for rapid syllable repetition compared to chewing tasks. Cross-correlational analysis of muscle co-activation, as well as sEMG burst amplitude, was positively associated with beta IMC strength.

    Discussion

    Beta IMC was influenced heavily by task-dependent behavioral goals and physiologic demands, which was interpreted as evidence of shared neural drive among jaw-closing muscles.

    in Frontiers in Human Neuroscience on July 30, 2020 12:00 AM.

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    Brain-to-Brain Coupling in the Gamma-Band as a Marker of Shared Intentionality

    Cooperation and competition are two ways of social interaction keys to life in society. Recent EEG-based hyperscanning studies reveal that cooperative and competitive interactions induce an increase in interbrain coupling. However, whether this interbrain coupling effect is just a reflection of inter-subject motor coordination or can also signal the type of social interaction is unknown. Here, we show that behavioral coordination and social interaction type can be distinguished according to the frequency of oscillation in which the brains are coupled. We use EEG to simultaneously measure the brain activity of pairs of subjects, while they were performing a visual cue-target task in a cooperative and competitive manner. Behavioral responses were quasi-simultaneous between subject pairs for both competitive and cooperative conditions, with faster average response times for the competitive condition. Concerning brain activity, we found increased interbrain coupling in theta band (3–7 Hz) during cooperation and competition, with stronger coupling during competitive interactions. This increase of interbrain theta coupling correlated with a decrease in reaction times of the dyads. Interestingly, we also found an increase in brain-to-brain coupling in gamma band (38–42 Hz) only during cooperative interactions. Unlike the theta coupling effect, the gamma interbrain coupling did not correlate with dyads’ reaction times. Taken together, these results suggest that theta interbrain coupling could be linked to motor coordination processes common to cooperative and competitive interactions, while gamma brain-to-brain coupling emerges as an electrophysiological marker of shared intentionality during cooperative interactions.

    in Frontiers in Human Neuroscience on July 30, 2020 12:00 AM.

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    The Establishment of Pseudorandom Ecological Microexpression Recognition Test (PREMERT) and Its Relevant Resting-State Brain Activity

    The EMERT (ecological microexpression recognition test) by Zhang et al. (2017) used between-subjects Latin square block design for backgrounds; therefore, participants could not get comparable scores. The current study used within-subject pseudorandom design for backgrounds to improve EMERT to PREMERT (pseudorandom EMERT) and used eyes-closed and eyes-open resting-state functional magnetic resonance imaging to detect relevant brain activity of PREMERT for the first time. The results showed (1) two new recapitulative indexes of PREMERT were adopted, such as microexpression M and microexpression SD. Using pseudorandom design, the participants could effectively identify almost all the microexpressions, and each microexpression type had significant background effect. The PREMERT had good split-half reliability, parallel-forms reliability, criterion validity, and ecological validity. Therefore, it could stably and efficiently detect the participants’ microexpression recognition abilities. Because of its pseudorandom design, all participants did the same test; their scores could be compared with each other. (2) amplitude of low-frequency fluctuations (ALFF; 0.01–0.1 Hz) in both eyes-closed and eyes-open resting states and ALFF difference could predict microexpression M, and the ALFF difference was less predictive. The relevant resting-state brain areas of microexpression M were some frontal lobes, insula, cingulate cortex, hippocampus, amygdala, fusiform gyrus, parietal lobe, caudate nucleus, precuneus, thalamus, putamen, temporal lobe, and cerebellum. (3) ALFFs in both eyes-closed and eyes-open resting states and ALFF difference could predict microexpression SD, and the ALFF difference was more predictive. The relevant resting-state brain areas of microexpression SD were some frontal lobes, central anterior gyrus, supplementary motor area, insula, hippocampus, amygdala, cuneus, occipital lobe, fusiform gyrus, parietal lobe, caudate nucleus, pallidum, putamen, thalamus, temporal lobe, and cerebellum. (4) There were many similar relevant resting-state brain areas, such as brain areas of expression recognition, microexpressions consciousness and attention, and the change from expression backgrounds to microexpression, and some different relevant resting-state brain areas, such as precuneus, insula, and pallidum, between microexpression M and SD. The ALFF difference was more sensitive to PREMERT fluctuations.

    in Frontiers in Human Neuroscience on July 30, 2020 12:00 AM.

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    Truncated Tau Induces Mitochondrial Transport Failure Through the Impairment of TRAK2 Protein and Bioenergetics Decline in Neuronal Cells

    Mitochondria are highly specialized organelles essential for the synapse, and their impairment contributes to the neurodegeneration in Alzheimer’s disease (AD). Previously, we studied the role of caspase-3–cleaved tau in mitochondrial dysfunction in AD. In neurons, the presence of this AD-relevant tau form induced mitochondrial fragmentation with a concomitant reduction in the expression of Opa1, a mitochondrial fission regulator. More importantly, we showed that caspase-cleaved tau affects mitochondrial transport, decreasing the number of moving mitochondria in the neuronal processes without affecting their velocity rate. However, the molecular mechanisms involved in these events are unknown. We studied the possible role of motor proteins (kinesin 1 and dynein) and mitochondrial protein adaptors (RhoT1/T2, syntaphilin, and TRAK2) in the mitochondrial transport failure induced by caspase-cleaved tau. We expressed green fluorescent protein (GFP), GFP-full-length, and GPF-caspase-3–cleaved tau proteins in rat hippocampal neurons and immortalized cortical neurons (CN 1.4) and analyzed the expression and localization of these proteins involved in mitochondrial transport regulation. We observed that hippocampal neurons expressing caspase-cleaved tau showed a significant accumulation of a mitochondrial population in the soma. These changes were accompanied by evident mitochondrial bioenergetic deficits, including depolarization, oxidative stress, and a significant reduction in ATP production. More critically, caspase-cleaved tau significantly decreased the expression of TRAK2 in immortalized and primary hippocampal neurons without affecting RhoT1/T2 and syntaphilin levels. Also, when we analyzed the expression of motor proteins—Kinesin 1 (KIF5) and Dynein—we did not detect changes in their expression, localization, and binding to the mitochondria. Interestingly, the expression of truncated tau significantly increases the association of TRAK2 with mitochondria compared with neuronal cells expressing full-length tau. Altogether these results indicate that caspase-cleaved tau may affect mitochondrial transport through the increase of TRAK2–mitochondria binding and reduction of ATP production available for the process of movement of these organelles. These observations are novel and represent a set of exciting findings whereby tau pathology could affect mitochondrial distribution in neurons, an event that may contribute to synaptic failure observed in AD.

    in Frontiers in Cellular Neuroscience on July 30, 2020 12:00 AM.

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    Characterization of Vimentin-Immunoreactive Astrocytes in the Human Brain

    Astrocytes are commonly identified by their expression of the intermediate filament protein glial fibrillary acidic protein (GFAP). GFAP-immunoreactive (GFAP-IR) astrocytes exhibit regional heterogeneity in density and morphology in the mouse brain as well as morphological diversity in the human cortex. However, regional variations in astrocyte distribution and morphology remain to be assessed comprehensively. This was the overarching objective of this postmortem study, which mainly exploited the immunolabeling of vimentin (VIM), an intermediate filament protein expressed by astrocytes and endothelial cells which presents the advantage of more extensively labeling cell structures. We compared the densities of vimentin-immunoreactive (VIM-IR) and GFAP-IR astrocytes in various brain regions (prefrontal and primary visual cortex, caudate nucleus, mediodorsal thalamus) from male individuals having died suddenly in the absence of neurological or psychiatric conditions. The morphometric properties of VIM-IR in these brain regions were also assessed. We found that VIM-IR astrocytes generally express the canonical astrocytic markers Aldh1L1 and GFAP but that VIM-IR astrocytes are less abundant than GFAP-IR astrocytes in all human brain regions, particularly in the thalamus, where VIM-IR cells were nearly absent. About 20% of all VIM-IR astrocytes presented a twin cell morphology, a phenomenon rarely observed for GFAP-IR astrocytes. Furthermore VIM-IR astrocytes in the striatum were often seen to extend numerous parallel processes which seemed to give rise to large VIM-IR fiber bundles projecting over long distances. Moreover, morphometric analyses revealed that VIM-IR astrocytes were more complex than their mouse counterparts in functionally homologous brain regions, as has been previously reported for GFAP-IR astrocytes. Lastly, the density of GFAP-IR astrocytes in gray and white matter were inversely correlated with vascular density, but for VIM-IR astrocytes this was only the case in gray matter, suggesting that gliovascular interactions may especially influence the regional heterogeneity of GFAP-IR astrocytes. Taken together, these findings reveal special features displayed uniquely by human VIM-IR astrocytes and illustrate that astrocytes display important region- and marker-specific differences in the healthy human brain.

    in Frontiers in Neuroanatomy on July 30, 2020 12:00 AM.

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    Classification and Graphical Analysis of Alzheimer’s Disease and Its Prodromal Stage Using Multimodal Features From Structural, Diffusion, and Functional Neuroimaging Data and the APOE Genotype

    Graphical, voxel, and region-based analysis has become a popular approach to studying neurodegenerative disorders such as Alzheimer’s disease (AD) and its prodromal stage [mild cognitive impairment (MCI)]. These methods have been used previously for classification or discrimination of AD in subjects in a prodromal stage called stable MCI (MCIs), which does not convert to AD but remains stable over a period of time, and converting MCI (MCIc), which converts to AD, but the results reported across similar studies are often inconsistent. Furthermore, the classification accuracy for MCIs vs. MCIc is limited. In this study, we propose combining different neuroimaging modalities (sMRI, FDG-PET, AV45-PET, DTI, and rs-fMRI) with the apolipoprotein-E genotype to form a multimodal system for the discrimination of AD, and to increase the classification accuracy. Initially, we used two well-known analyses to extract features from each neuroimage for the discrimination of AD: whole-brain parcelation analysis (or region-based analysis), and voxel-wise analysis (or voxel-based morphometry). We also investigated graphical analysis (nodal and group) for all six binary classification groups (AD vs. HC, MCIs vs. MCIc, AD vs. MCIc, AD vs. MCIs, HC vs. MCIc, and HC vs. MCIs). Data for a total of 129 subjects (33 AD, 30 MCIs, 31 MCIc, and 35 HCs) for each imaging modality were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) homepage. These data also include two APOE genotype data points for the subjects. Moreover, we used the 2-mm AICHA atlas with the NiftyReg registration toolbox to extract 384 brain regions from each PET (FDG and AV45) and sMRI image. For the rs-fMRI images, we used the DPARSF toolbox in MATLAB for the automatic extraction of data and the results for REHO, ALFF, and fALFF. We also used the pyClusterROI script for the automatic parcelation of each rs-fMRI image into 200 brain regions. For the DTI images, we used the FSL (Version 6.0) toolbox for the extraction of fractional anisotropy (FA) images to calculate a tract-based spatial statistic. Moreover, we used the PANDA toolbox to obtain 50 white-matter-region-parcellated FA images on the basis of the 2-mm JHU-ICBM-labeled template atlas. To integrate the different modalities and different complementary information into one form, and to optimize the classifier, we used the multiple kernel learning (MKL) framework. The obtained results indicated that our multimodal approach yields a significant improvement in accuracy over any single modality alone. The areas under the curve obtained by the proposed method were 97.78, 96.94, 95.56, 96.25, 96.67, and 96.59% for AD vs. HC, MCIs vs. MCIc, AD vs. MCIc, AD vs. MCIs, HC vs. MCIc, and HC vs. MCIs binary classification, respectively. Our proposed multimodal method improved the classification result for MCIs vs. MCIc groups compared with the unimodal classification results. Our study found that the (left/right) precentral region was present in all six binary classification groups (this region can be considered the most significant region). Furthermore, using nodal network topology, we found that FDG, AV45-PET, and rs-fMRI were the most important neuroimages, and showed many affected regions relative to other modalities. We also compared our results with recently published results.

    in Frontiers in Ageing Neuroscience on July 30, 2020 12:00 AM.

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    Detecting Amyloid Positivity in Elderly With Increased Risk of Cognitive Decline

    The importance of early interventions in Alzheimer’s disease (AD) emphasizes the need to accurately and efficiently identify at-risk individuals. Although many dementia prediction models have been developed, there are fewer studies focusing on detection of brain pathology. We developed a model for identification of amyloid-PET positivity using data on demographics, vascular factors, cognition, APOE genotype, and structural MRI, including regional brain volumes, cortical thickness and a visual medial temporal lobe atrophy (MTA) rating. We also analyzed the relative importance of different factors when added to the overall model. The model used baseline data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) exploratory PET sub-study. Participants were at risk for dementia, but without dementia or cognitive impairment. Their mean age was 71 years. Participants underwent a brain 3T MRI and PiB-PET imaging. PiB images were visually determined as positive or negative. Cognition was measured using a modified version of the Neuropsychological Test Battery. Body mass index (BMI) and hypertension were used as cardiovascular risk factors in the model. Demographic factors included age, gender and years of education. The model was built using the Disease State Index (DSI) machine learning algorithm. Of the 48 participants, 20 (42%) were rated as Aβ positive. Compared with the Aβ negative group, the Aβ positive group had a higher proportion of APOE ε4 carriers (53 vs. 14%), lower executive functioning, lower brain volumes, and higher visual MTA rating. AUC [95% CI] for the complete model was 0.78 [0.65–0.91]. MRI was the most effective factor, especially brain volumes and visual MTA rating but not cortical thickness. APOE was nearly as effective as MRI in improving detection of amyloid positivity. The model with the best performance (AUC 0.82 [0.71–0.93]) was achieved by combining APOE and MRI. Our findings suggest that combining demographic data, vascular risk factors, cognitive performance, APOE genotype, and brain MRI measures can help identify Aβ positivity. Detecting amyloid positivity could reduce invasive and costly assessments during the screening process in clinical trials.

    in Frontiers in Ageing Neuroscience on July 30, 2020 12:00 AM.

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    SUMOylation of Enzymes and Ion Channels in Sensory Neurons Protects against Metabolic Dysfunction, Neuropathy, and Sensory Loss in Diabetes

    Agarwal et al. show that the post-translational modification of SUMO-conjugation of proteins (SUMOylation) in pain-sensing neurons regulates sensory ion channels and metabolic enzymes governing energy production. Reduced SUMOylation in diabetes leads to metabolic arrest and accumulation of toxic metabolites, driving neuropathy and sensory loss. Enhancing SUMOylation may reverse diabetic neuropathy.

    in Neuron: In press on July 30, 2020 12:00 AM.

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    The CRF1 receptor mediates social behavior deficits induced by opiate withdrawal

    The CRF1 receptor mediates social behavior deficits induced by opiate withdrawal

    Sociability deficits and aggressive behavior are common clinical features of opioid use disorders. Herein, genetic inactivation of the corticotropin‐releasing factor receptor 1 (CRF1) eliminated social approach deficits or hostility‐linked social approach in morphine‐withdrawn female or male mice, respectively. Thus, reduction of CRF1 receptor activity might ameliorate sociability of opiate‐dependent patients.


    Abstract

    Poor sociability and aggressive behavior are key clinical features of opioid use disorders. The corticotropin‐releasing factor (CRF) system may mediate behavioral effects of substances of abuse but its implication in substance‐induced social behavior deficits and outward‐directed hostility remains largely unknown. CRF signaling is mediated by two receptor types, termed CRF1 and CRF2. The present study aimed at understanding the role for the CRF1 receptor in social and aggressive behavior induced by withdrawal from repeated opiate administration. Thus, wild‐type (CRF1+/+), CRF1 receptor heterozygous (CRF1+/−), and null mutant (CRF1−/−) female and male mice were treated with saline or escalating doses of morphine (20‐100 mg/kg, i.p.) during six consecutive days and tested in the three‐chamber task for sociability (i.e., preference for an unfamiliar same‐sex conspecific vs. an object) 7 days after the last administration. Moreover, aggressive biting behavior toward the unfamiliar conspecific was assessed during the three‐chamber test. Opiate withdrawal disrupted sociability in CRF1+/+ and CRF1+/−, but not in CRF1−/−, female mice, without affecting aggressive biting behavior in any genotype. In contrast, opiate withdrawal did not affect sociability but increased aggressive biting behavior in male mice, independently of CRF1 receptor‐deficiency. Nevertheless, in opiate‐withdrawn CRF1+/+, but not CRF1+/− and CRF1−/−, male mice, sociability directly correlated with aggressive biting behavior, suggesting a role for the CRF1 receptor in hostility‐linked social approach. These findings demonstrate the implication of the CRF1 receptor in social behavior deficits associated with repeated opiate administration and withdrawal, revealing a new potential target for the treatment of opioid use disorders.

    in Journal of Neuroscience Research on July 29, 2020 07:17 PM.

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    The role of nucleus accumbens CREB attenuation in rescuing low voluntary running behavior in female rats

    The role of nucleus accumbens CREB attenuation in rescuing low voluntary running behavior in female rats

    cAMP response element binding protein (CREB) was evaluated for its role in physical activity motivation of wild‐type (WT) and low voluntary wheel‐running (LVR) rats. Elevated CREB activity has been associated with reward deficits and was found to be higher in the nucleus accumbens (NAc) of LVR rats. Reducing NAc activity through Gi‐DREADDs, pharmacology (C646/SR11302), and environmental enrichment increased LVR wheel‐running behavior. These findings highlight a potential molecular pathway important for the motivation to be physically active.


    Abstract

    Given the integral role of nucleus accumbens (NAc) cAMP response element binding protein (CREB) activity in motivational processes, the goal of the current study was to determine whether blunting chronic NAc CREB activity could rescue the low physical activity motivation of female, low voluntary running (LVR) rats. NAc CREB phosphorylation is elevated in these rats, a state previously attributed to deficits in reward valuation. It was recently shown that overexpression of the upstream CREB inhibitor, protein kinase inhibitor alpha (PKIα), increased LVR nightly running by ~threefold. Therefore, the current study addresses the extent to which NAc CREB attenuation influences female LVR and wild‐type (WT) wheel‐running behavior. Inducible reductions in NAc neuronal activity using Gi‐coupled hM4Di DREADDs increased running behavior in LVR, but not in WT, rats. Similarly, site‐directed pharmacological inhibition of NAc CREB activity significantly increased LVR nightly running distance and time by ~twofold, with no effect in WT rats. Finally, environmentally enriched LVR rats exhibit higher levels of running compared to socially isolated rats in what appeared to be a CREB‐related manner. Considering the positive outcomes of upstream CREB modulation and environmental enrichment on LVR behavior, we believe that blunting NAc CREB activity has the neuromolecular potential to partially reverse low physical activity motivation, as exemplified by the LVR model. The positive physical activity outcome of early life enrichment adds translatable value to human childhood enrichment and highlights its importance on motivational processes later in life.

    in Journal of Neuroscience Research on July 29, 2020 07:15 PM.

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    Plasma endothelial microvesicles and their carrying miRNA‐155 serve as biomarkers for ischemic stroke

    Plasma endothelial microvesicles and their carrying miRNA‐155 serve as biomarkers for ischemic stroke

    Our population study found that the area under ROC curve (AUC) of plasma endothelial microvesicles (EMVs) and EMVs‐miR‐155 levels in ischemic stroke (IS) was 0.778 (sensitivity 85.9% and specificity 58%) and 0.851 (sensitivity 75% and specificity 81.2%), respectively, and AUC of their combination was 0.892 (sensitivity 75% and specificity 91.3%). Our study suggests that plasma EMVs and EMVs‐miR‐155 levels are promising biomarkers for IS. The diagnostic value of EMVs‐miR‐155 is higher and their combination is the best.


    Abstract

    Endothelial microvesicles (EMVs) could reflect the status of endothelial cells (ECs) which are involved in the pathogenesis of ischemic stroke (IS). MiR‐155 could regulate EC functions. However, their roles in IS remain unclear. This study aimed to investigate the levels of plasma EMVs and EMVs carrying miRNA‐155 (EMVs‐miR‐155) in IS patients to explore their potential roles as biomarkers. Ninety‐three IS patients and 70 controls were recruited in this study. The levels of circulating EMVs and EMVs‐miR‐155 were detected by fluorescence nanoparticle tracking analysis and quantitative real‐time PCR, respectively. The correlations between level of EMVs/EMVs‐miR‐155 and the onset time, severity, infarct volume, and subtypes of IS were analyzed. The severity and infarct volume were assessed by NIHSS and magnetic resonance imaging, respectively. Multivariate logistic regression analysis was used to investigate the risk factors of IS. The ROC curve and area under ROC curve (AUC) of EMVs and EMVs‐miR‐155 were determined. The levels of plasma EMVs and EMVs‐miR‐155 were increased significantly in acute and subacute stages of IS and remained unchanged in chronic stage, and were positively related to the infarct volume and NIHSS scores and were associated with large artery atherosclerosis and cardioembolism subtypes defined by Trial of Org 10 172 in acute stroke treatment (TOAST) classification. Multivariate logistic regression analysis demonstrated that plasma EMVs and EMVs‐miR‐155 were significant and independent risk factors of IS and their AUC were 0.778 and 0.851, respectively, and increased to 0.892 after combination. Our study suggests that plasma EMVs and EMVs‐miR‐155 are promising biomarkers for IS. The diagnostic value of EMVs‐miR‐155 is higher and their combination is the best.

    in Journal of Neuroscience Research on July 29, 2020 07:15 PM.

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    Modeling human‐specific interlaminar astrocytes in the mouse cerebral cortex

    Modeling human‐specific interlaminar astrocytes in the mouse cerebral cortex

    We engrafted RFP‐expressing astrocytes differentiated from hiPSCs into the cortex of immunodeficient mice neonatally. Nine months post engraftment, the human astrocytes in the superficial cortex developed into interlaminar astrocytes that mimicked the interlaminar astrocytes architecture of the adult human cortex. This chimeric mouse model will enable the study of human‐specific interlaminar astrocytes in vivo.


    Abstract

    Astrocytes, a highly heterogeneous population of glial cells, serve as essential regulators of brain development and homeostasis. The heterogeneity of astrocyte populations underlies the diversity in their functions. In addition to the typical mammalian astrocyte architecture, the cerebral cortex of humans exhibits a radial distribution of interlaminar astrocytes in the supragranular layers. These primate‐specific interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. However, due to the lack of accessible experimental models, their functional properties and their role in regulating neuronal circuits remain unclear. Here we modeled human interlaminar astrocytes in humanized glial chimeric mice by engrafting astrocytes differentiated from human‐induced pluripotent stem cells into the mouse cortex. This model provides a novel platform for understanding neuron‐glial interaction and its alterations in neurological diseases.

    in Journal of Comparative Neurology on July 29, 2020 06:38 PM.

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    Lithium influences whole‐organism metabolic rate in Drosophila subobscura

    Lithium influences whole‐organism metabolic rate in Drosophila subobscura

    Metabolic parameters (O2 consmption and CO2 production) are influenced by lithium in dose‐dependent fashion showing a narrow therapeutic index with a subtle balance between low and high metabolic rate. We confirmed in vivo that treatment efficiency is dependent on mitochondrial genetic background and sex.


    Abstract

    Lithium is widely used to treat bipolar disorder. However, the efficacy and vulnerability as to its side effects are known to differ. Although the specific biochemical mechanism of action is still elusive, lithium may influence mitochondrial function, and consequently, metabolism. Lithium exposure in this study was conducted on a unique set of mito‐nuclear introgression lines of Drosophila subobscura to disentangle the independent effects of mitochondrial DNA (mtDNA) against a common nuclear DNA background. The study addressed three issues: (a) whether lithium has a dose‐dependent effect on whole‐organism metabolic rate, (b) whether mtDNA haplotypes show divergent metabolic efficiency measured by metabolic rate to lithium exposure and (c) whether lithium influences the whole‐organism metabolic rate across sexes. The results confirm that lithium influenced the whole‐organism metabolic rate, showing a subtle balance between efficacy and adverse effects within a narrow dose range. In addition, lithium exposure was found to influence metabolism differently based on mtDNA haplotypes and sex. This preliminary research may have a range of biological implications for the role of mitochondrial variability in psychiatric disease and treatment by contributing to the understanding and predicting of the lithium treatment response and risk for toxic side effects.

    in Journal of Neuroscience Research on July 29, 2020 04:04 PM.

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