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Ultrasensitive detection of clinical pathogens through a target-amplification-free collateral-cleavage-enhancing CRISPR-CasΦ tool
Nature Communications, Published online: 26 April 2025; doi:10.1038/s41467-025-59219-x
Rapid diagnosis of bloodstream infections is vital for timely effective treatment. Here, Mao and Wan et al developed a method using a dual stem-loop DNA signal amplifier, to achieve ultrasensitive, rapid, amplification-free detection of pathogens from human serum.in Nature Communications on 2025-04-26 00:00:00 UTC.
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Junctional force patterning drives both positional order and planar polarity in the auditory epithelia
Nature Communications, Published online: 26 April 2025; doi:10.1038/s41467-025-58557-0
Sound is sensed in the cochlea through a precisely organised epithelium. Prakash and colleagues show cellular organisation results from differences in junction contractility, finding mechanics is sufficient to organise a hair cell mosaic that is planar polarised.in Nature Communications on 2025-04-26 00:00:00 UTC.
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Interactive symbolic regression with co-design mechanism through offline reinforcement learning
Nature Communications, Published online: 26 April 2025; doi:10.1038/s41467-025-59288-y
Symbolic Regression is a method for uncovering mathematical and physical relationships from data. Here, the authors propose Sym-Q, an interactive reinforcement learning-based framework with a co-design mechanism that enables efficient and guided equation discovery.in Nature Communications on 2025-04-26 00:00:00 UTC.
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Quantifying the global climate feedback from energy-based adaptation
Nature Communications, Published online: 26 April 2025; doi:10.1038/s41467-025-59201-7
Forecasts of the feedback between adaptive energy use and climate change show energy-based adaptation will lower global mean surface temperature in 2099 by 0.12 °C, reducing required Paris Agreement mitigation for 85 percent of committed countries.in Nature Communications on 2025-04-26 00:00:00 UTC.
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Associations Between Factors Affecting Itching and Quality of Life in Thai Patients with Psoriasis: A Cross-Sectional Study [version 2; peer review: 2 approved with reservations]
Introduction Psoriasis is a chronic skin disease affecting quality of life and causing pruritus. The factors influencing itch and its impact on the quality of life in Thai psoriasis patients are unknown. We aimed to identify these factors and their effect on quality of life. Methods In this questionnaire-based cross-sectional study, we included patients with psoriasis who received treatment at Chulabhorn Hospital in Thailand from January 2019 to July 2021. Interviewer is the non-dermatologist practician. The patient’s information was collected, including demographic data, Itch Numeric Rating Scale (Itch NRS) score, factors affecting itch, and score on the Thai version of the Dermatology Life Quality Index (DLQI). We performed descriptive statistics and logistic regression analysis. Results Of 100 participants, most (99%) experienced itching, with a moderate degree of pruritus (mean Itch NRS score 6.5 ± 2.6) and a moderate effect on quality of life (mean DLQI score 9.4 ± 6.2). Factors associated with itch aggravation were dry skin (p-value = 0.003) and heat and humidity (p-value = 0.042). The results of binary logistic regression revealed that factors associated with moderate-to-extremely large DLQI scores were itch intensity (no-to-mild vs. moderate-to-severe itch: odds ratio [OR] = 13.33; 95% confidence interval [CI] = 2.72–65.32, p < 0.001; and adjusted odds ratio [AOR] = 31.17; 95% CI = 4.55–213.36; p < 0.001. Conclusions Our findings revealed that the quality of life among patients with psoriasis is their greatest concern. Eliminating the itch intensity that affects their quality of life is crucial but remains challenging in Thailand.in F1000Research on 2025-04-25 15:36:10 UTC.
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Correction: Mathematical modeling suggests heterogeneous replication of Mycobacterium tuberculosis in rabbits
by Vitaly V. Ganusov, Afsal Kolloli, Selvakumar Subbian
in PLoS Computational Biology on 2025-04-25 14:00:00 UTC.
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Scalable eQTL mapping using single-nucleus RNA-sequencing of recombined gametes from a small number of individuals
by Matthew T. Parker, Samija Amar, José A. Campoy, Kristin Krause, Sergio Tusso, Magdalena Marek, Bruno Huettel, Korbinian Schneeberger
Phenotypic differences between individuals of a species are often caused by differences in gene expression, which are in turn caused by genetic variation. Expression quantitative trait locus (eQTL) analysis is a methodology by which we can identify such causal variants. Scaling eQTL analysis is costly due to the expense of generating mapping populations, and the collection of matched transcriptomic and genomic information. We developed a rapid eQTL analysis approach using single-cell/nucleus RNA sequencing of gametes from a small number of heterozygous individuals. Patterns of inherited polymorphisms are used to infer the recombinant genomes of thousands of individual gametes and identify how different haplotypes correlate with variation in gene expression. Applied to Arabidopsis pollen nuclei, our approach uncovers both cis- and trans-eQTLs, ultimately mapping variation in a master regulator of sperm cell development that affects the expression of hundreds of genes. This establishes snRNA-sequencing as a powerful, cost-effective method for the mapping of meiotic recombination, addressing the scalability challenges of eQTL analysis and enabling eQTL mapping in specific cell-types.in PLoS Biology on 2025-04-25 14:00:00 UTC.
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Detecting New Lesions Using a Large Language Model: Applications in Real‐World Multiple Sclerosis Datasets
Objective
Neuroimaging is routinely utilized to identify new inflammatory activity in multiple sclerosis (MS). A large language model to classify narrative magnetic resonance imaging reports in the electronic health record (EHR) as discrete data could provide significant benefits for MS research. The objectives of the current study were to develop such a prompt and to illustrate its research applications through a common clinical scenario: monitoring response to B-cell depleting therapy (BCDT).
Methods
An institutional ecosystem that securely connects healthcare data with ChatGPT4 was applied to clinical MS magnetic resonance imaging reports in a single institutional EHR (2000–2022). A prompt (msLesionprompt) was developed and iteratively refined to classify the presence or absence of new T2-weighted lesions (newT2w) and contrast-enhancing lesions (CEL). The multistep validation included evaluating efficiency (time and cost), comparison with manually annotated reports using standard confusion matrix, and application to identifying predictors of newT2w/CEL after BCDT start.
Results
Accuracy of msLesionprompt was high for detection of newT2w (97%) and CEL (96.8%). All 14,888 available reports were categorized in 4.13 hours ($28); 79% showed no newT2w or CEL. Data extracted showed expected suppression of new activity by BCDT (>97% monitoring magnetic resonance images after an initial “rebaseline” scan). Neighborhood poverty (Area Deprivation Index) was identified as a predictor of inflammatory activity (newT2w: OR 1.69, 95% CI 1.10–2.59, p = 0.017; CEL: OR 1.54, 95% CI 1.01–2.34, p = 0.046).
Interpretation
Extracting discrete information from narrative imaging reports using an large language model is feasible and efficient. This approach could augment many real-world analyses of MS disease evolution and treatment response. ANN NEUROL 2025
in Annals of Neurology on 2025-04-25 13:03:08 UTC.
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Distinct adipose progenitor cells emerging with age drive active adipogenesis
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-25 07:00:00 UTC.
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Emergence and interstate spread of highly pathogenic avian influenza A(H5N1) in dairy cattle in the United States
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-25 07:00:00 UTC.
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Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-25 07:00:00 UTC.
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Base-modified nucleotides mediate immune signaling in bacteria
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-25 07:00:00 UTC.
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Structural mechanism of LINE-1 target-primed reverse transcription
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-25 07:00:00 UTC.
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A well-connected Earth: The science and conservation of organismal movement
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-25 07:00:00 UTC.
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Obliquity disruption and Antarctic ice sheet dynamics over a 2.4-Myr astronomical grand cycle
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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A dynamical geography of observed trends in the global ocean
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Brain feature maps reveal progressive animal-feature representations in the ventral stream
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Terrane accretion explains thin and hot ocean-continent back-arcs
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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The P2X7R/NLRP3 inflammasome axis suppresses enthesis regeneration through inflammatory and metabolic macrophage-stem cell cross-talk
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Nanosecond structural evolution in shocked coesite
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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BRD9 functions as a methylarginine reader to regulate AKT-EZH2 signaling
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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A dark-state–dominated photochemical upconversion afterglow via triplet energy transfer relay
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Adipose-derived leptin and complement factor D mediate osteoarthritis severity and pain
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Leidenfrost propulsion on symmetric textured surfaces via spontaneous symmetry breaking
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Stabilization toward air and structure determination of pyrophoric ZnR2 compounds via supramolecular encapsulation
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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A wearable tool for real-time dose monitoring during cancer radiation therapies
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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The seasonal temperature conundrum for the Holocene
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Synchronized temporal-spatial analysis via microscopy and phosphoproteomics (STAMP) of quiescence
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Efficient on-chip platform for coherent light-matter coupling using bound states in the continuum
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Directional sorting of exciton emissions from twisted WS2/WSe2 hetero-bilayers using self-coupled photonic crystal resonances
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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A dissipation-induced superradiant transition in a strontium cavity-QED system
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Dynamic protonation of ligand sites in molecular catalysts enhances electrochemical CO2 reduction
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Growth rate controls the sensitivity of gene regulatory circuits
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Chemical synthesis elucidates the absolute configuration and key antigenic epitope of Vibrio cholerae serotype O100 O-antigen
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Deconvoluting TCR-dependent and -independent activation is vital for reliable Ag-specific CD4+ T cell characterization by AIM assay
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Recombination of agricultural residues into moldable composites
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Protecting centrosomes from fracturing enables efficient cell navigation
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Nanoseed-based physically unclonable function for on-demand encryption
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Prolonged airway explant culture enables study of health, disease, and viral pathogenesis
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Erratum for the Research Article: “Regulation of tumor immune suppression and cancer cell survival by CXCL1/2 elevation in glioblastoma multiforme” by J. Hu et al.
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Erratum for the Research Article: “Multivalent supramolecular fluorescent probes for accurate disease imaging” by Q. Wu et al.
Science Advances, Volume 11, Issue 17, April 2025.
in Science Advances on 2025-04-25 07:00:00 UTC.
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Heterozygous Kmt2d loss diminishes enhancers to render medulloblastoma cells vulnerable to combinatory inhibition of LSD1 and OXPHOS
Dhar et al. show that heterozygous loss of the frequently mutated epigenetic modifier KMT2D downregulates NCOR2 expression to promote medulloblastoma (MB) genesis and that KMT2D-deficient MB can be impeded by combinatory pharmacological inhibition of the enhancer-decommissioning lysine demethylase LSD1 and OXPHOS.in Cell Reports: Current Issue on 2025-04-25 00:00:00 UTC.
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Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity
Weissenrieder et al. show that mitochondrial Ca2+ uniporter (MCU) deletion reduces growth and metastasis of murine KPCY cells by reducing cell-autologous induction of epithelial-to-mesenchymal transition (EMT). Induction of EMT with Snail expression or TGF-β treatment rescues growth and metastatic deficits. These findings have implications for therapeutic development in PDAC.in Cell Reports: Current Issue on 2025-04-25 00:00:00 UTC.
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Peroxisomes are critical for a unique metabolic demand and survival of alveolar macrophages
The role of peroxisomes in tissue-resident macrophages remains unclear. Matsushita et al. reveal that peroxisomes are essential for alveolar macrophage (AM) development by preventing lipotoxicity and maintaining mitochondrial fitness. Our findings highlight a metabolic dependency of peroxisomes on homeostatic AM survival and bioenergetics.in Cell Reports: Current Issue on 2025-04-25 00:00:00 UTC.
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Functional-based parcellation of the mouse prefrontal cortex for network perturbation analysis
Savvateev et al. release a database containing rsfMRI recordings of 100 C57BL/6J mice under light anesthesia and, with machine learning techniques, performs functional-connectivity-based clustering of the PFC area. Identified clusters are linked to isolated functional networks and only partially overlap with the commonly used anatomical demarcation.in Cell Reports: Current Issue on 2025-04-25 00:00:00 UTC.
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‘Tatooine’-like planet orbits two stars ― but at a weird angle
Nature, Published online: 25 April 2025; doi:10.1038/d41586-025-01272-z
Like the Star Wars planet, a distant world follows a path around two stars, both of them small, cool bodies called brown dwarfs.in Nature on 2025-04-25 00:00:00 UTC.
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Audio long read: Do smartphones and social media really harm teens’ mental health?
Nature, Published online: 25 April 2025; doi:10.1038/d41586-025-01310-w
While researchers agree that adolescents are struggling with mental health, there is fierce debate about how much technology is to blame.in Nature on 2025-04-25 00:00:00 UTC.
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This is not the new colour that scientists have created
Nature, Published online: 25 April 2025; doi:10.1038/d41586-025-01319-1
Firing tiny doses of laser light into people’s eyes allowed them to perceive a never-seen-before hue.in Nature on 2025-04-25 00:00:00 UTC.
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My ‘woke DEI’ grant has been flagged for scrutiny. Where do I go from here?
Nature, Published online: 25 April 2025; doi:10.1038/d41586-025-01218-5
My work in making artificial intelligence fair has been noticed by US officials intent on ending ‘class warfare propaganda’.in Nature on 2025-04-25 00:00:00 UTC.
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Hundreds more NSF grants terminated after agency director resigns
Nature, Published online: 25 April 2025; doi:10.1038/d41586-025-01312-8
Sethuraman Panchanathan abruptly leaves helm of US funding agency after Elon Musk’s DOGE arrives.in Nature on 2025-04-25 00:00:00 UTC.
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Huge reproducibility project fails to validate dozens of biomedical studies
Nature, Published online: 25 April 2025; doi:10.1038/d41586-025-01266-x
Unique reproducibility effort in Brazil focuses on common methods rather than a single field ― and prompts call for reform.in Nature on 2025-04-25 00:00:00 UTC.
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Publisher Correction: Unconventional (anti)ferroelectricity in van der Waals group-IV monochalcogenides
Nature Communications, Published online: 25 April 2025; doi:10.1038/s41467-025-58943-8
Publisher Correction: Unconventional (anti)ferroelectricity in van der Waals group-IV monochalcogenidesin Nature Communications on 2025-04-25 00:00:00 UTC.
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Chern networks: reconciling fundamental physics and device engineering
Nature Communications, Published online: 25 April 2025; doi:10.1038/s41467-025-59162-x
A rift has occurred within the scientific community between two formerly close-knit fields: condensed matter physics and electronic device engineering. What started as a union to understand the fundamental optical and electrical properties of semiconductors has been split by divergent interests. While the partnership has produced revolutionary changes in the way that information is processed and consumed by an increasingly interconnected society, now the two disciplines rarely speak to one another. As the years have passed, condensed matter physics has become enamored with delicate electronic effects in increasingly complex materials and geometries to the detriment of realistic applications. Meanwhile, device engineering has remained steadfastly focused on room-temperature performance and overall efficiency, prizing incremental improvement over potential disruptive advances using alternative materials and physics. Recent advances in topological electronic systems—in particular those exploiting Chern insulators—while elegant, prompt a necessary reexamination of the device engineering needs and the associated metrics with the goal of establishing a commonality within the blooming field of topological electronics. The purpose of this Comment is to initiate such a reexamination in the hopes that, with a better understanding of future device needs, perhaps the two areas may reunite to usher in the next electronic revolution via the use of topological phenomena.in Nature Communications on 2025-04-25 00:00:00 UTC.
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Microbial dormancy as an ecological and biogeochemical regulator on Earth
Nature Communications, Published online: 25 April 2025; doi:10.1038/s41467-025-59167-6
Dormancy enables microbes to withstand periods of environmental harshness. It occurs throughout diverse ecosystems and spans vast timescales, and could play an important role in shaping the co-evolution of Earth’s biosphere and geosphere.in Nature Communications on 2025-04-25 00:00:00 UTC.
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Single influenza A viruses induce nanoscale cellular reprogramming at the virus-cell interface
Nature Communications, Published online: 25 April 2025; doi:10.1038/s41467-025-58935-8
There are technical barriers to studying early virus-cell interactions with high temporal resolution. Here, using super-resolution microscopy and immobilized influenza A virions enabling live imaging the authors show nanoscale receptor accumulation, endocytosis induction, and actin remodeling.in Nature Communications on 2025-04-25 00:00:00 UTC.
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Author Correction: High-resolution fundus images for ophthalmomics and early cardiovascular disease prediction
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-05009-5
Author Correction: High-resolution fundus images for ophthalmomics and early cardiovascular disease predictionin Nature scientific data on 2025-04-25 00:00:00 UTC.
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Author Correction: An electronic toll collection gateway BLE RSSI dataset for localization of smartphones in vehicular scenarios
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-05006-8
Author Correction: An electronic toll collection gateway BLE RSSI dataset for localization of smartphones in vehicular scenariosin Nature scientific data on 2025-04-25 00:00:00 UTC.
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HCDT 2.0: A Highly Confident Drug-Target Database for Experimentally Validated Genes, RNAs, and Pathways
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-04981-2
HCDT 2.0: A Highly Confident Drug-Target Database for Experimentally Validated Genes, RNAs, and Pathwaysin Nature scientific data on 2025-04-25 00:00:00 UTC.
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Footprints of past mining in Alaska (USA) derived from high-resolution satellite imagery
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-05039-z
Footprints of past mining in Alaska (USA) derived from high-resolution satellite imageryin Nature scientific data on 2025-04-25 00:00:00 UTC.
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Long non-coding RNA and mRNA expression profiling of porcine satellite cells using strand-specific RNA-seq
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-05041-5
Long non-coding RNA and mRNA expression profiling of porcine satellite cells using strand-specific RNA-seqin Nature scientific data on 2025-04-25 00:00:00 UTC.
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Airborne imaging spectroscopy surveys of Arctic and boreal Alaska and northwestern Canada 2017–2023
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-04898-w
Airborne imaging spectroscopy surveys of Arctic and boreal Alaska and northwestern Canada 2017–2023in Nature scientific data on 2025-04-25 00:00:00 UTC.
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The telomere-to-telomere genome assembly of the wild mulberry, Morus mongolica
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-05040-6
The telomere-to-telomere genome assembly of the wild mulberry, Morus mongolicain Nature scientific data on 2025-04-25 00:00:00 UTC.
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TMNRED, A Chinese Language EEG Dataset for Fuzzy Semantic Target Identification in Natural Reading Environments
Scientific Data, Published online: 25 April 2025; doi:10.1038/s41597-025-05036-2
TMNRED, A Chinese Language EEG Dataset for Fuzzy Semantic Target Identification in Natural Reading Environmentsin Nature scientific data on 2025-04-25 00:00:00 UTC.
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Soil-mimicking microfluidic devices reveal restricted flagellar motility of Bradyrhizobium diazoefficiens under microconfinement
Communications Biology, Published online: 25 April 2025; doi:10.1038/s42003-025-07811-8
Soil-mimicking microfluidic devices were developed to visualise and characterise the swimming behavior of soil bacteria B. diazoefficiens. Molity parameters, obtained with high statistical accuracy, enable simulations of their motion in real soils.in Nature communications biology on 2025-04-25 00:00:00 UTC.
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Transcriptomic sex differences in early human fetal brain development
Communications Biology, Published online: 25 April 2025; doi:10.1038/s42003-025-08070-3
Time-series transcriptomic analysis investigates sex differences in human fetal brain development between 7.5 and 17 weeks post conception.in Nature communications biology on 2025-04-25 00:00:00 UTC.
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Stk24 deficiency causes disrupted hippocampal neurogenesis and anxiety-like behavior in mice
Communications Biology, Published online: 25 April 2025; doi:10.1038/s42003-025-08035-6
Brain-specific Stk24 deletion in mice disrupts hippocampal development, impairs adult neurogenesis, and alters stress responses including anxiety-like behavior and HPA axis reactivity.in Nature communications biology on 2025-04-25 00:00:00 UTC.
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Barcode-free multiplex plasmid sequencing using Bayesian analysis and nanopore sequencing
Plasmid construction is central to life science research, and sequence verification is arguably its costliest step. Long-read sequencing has emerged as a competitor to Sanger sequencing, with the principal benefit that whole plasmids can be sequenced in a single run. Nevertheless, the current cost of nanopore sequencing is still prohibitive for routine sequencing during plasmid construction. We develop a computational approach termed Simple Algorithm for Very Efficient Multiplexing of Oxford Nanopore Experiments for You (SAVEMONEY) that guides researchers to mix multiple plasmids and subsequently computationally de-mixes the resultant sequences. SAVEMONEY defines optimal mixtures in a pre-survey step, and following sequencing, executes a post-analysis workflow involving sequence classification, alignment, and consensus determination. By using Bayesian analysis with prior probability of expected plasmid construction error rate, high-confidence sequences can be obtained for each plasmid in the mixture. Plasmids differing by as little as two bases can be mixed as a single sample for nanopore sequencing, and routine multiplexing of even six plasmids per 180 reads can still maintain high accuracy of consensus sequencing. SAVEMONEY should further democratize whole-plasmid sequencing by nanopore and related technologies, driving down the effective cost of whole-plasmid sequencing to lower than that of a single Sanger sequencing run.in eLife on 2025-04-25 00:00:00 UTC.
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Major nuclear locales define nuclear genome organization and function beyond A and B compartments
Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here, we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Although gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.in eLife on 2025-04-25 00:00:00 UTC.
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Changes in local mineral homeostasis facilitate the formation of benign and malignant testicular microcalcifications
Testicular microcalcifications consist of hydroxyapatite and have been associated with an increased risk of testicular germ cell tumors (TGCTs) but are also found in benign cases such as loss-of-function variants in the phosphate transporter SLC34A2. Here, we show that fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, is expressed in testicular germ cell neoplasia in situ (GCNIS), embryonal carcinoma (EC), and human embryonic stem cells. FGF23 is not glycosylated in TGCTs and therefore cleaved into a C-terminal fragment which competitively antagonizes full-length FGF23. Here, Fgf23 knockout mice presented with marked calcifications in the epididymis, spermatogenic arrest, and focally germ cells expressing the osteoblast marker Osteocalcin (gene name: Bglap, protein name). Moreover, the frequent testicular microcalcifications in mice with no functional androgen receptor and lack of circulating gonadotropins are associated with lower Slc34a2 and higher Bglap/Slc34a1 (protein name: NPT2a) expression compared with wild-type mice. In accordance, human testicular specimens with microcalcifications also have lower SLC34A2 and a subpopulation of germ cells express phosphate transporter NPT2a, Osteocalcin, and RUNX2 highlighting aberrant local phosphate handling and expression of bone-specific proteins. Mineral disturbance in vitro using calcium or phosphate treatment induced deposition of calcium phosphate in a spermatogonial cell line and this effect was fully rescued by the mineralization inhibitor pyrophosphate. In conclusion, testicular microcalcifications arise secondary to local alterations in mineral homeostasis, which in combination with impaired Sertoli cell function and reduced levels of mineralization inhibitors due to high alkaline phosphatase activity in GCNIS and TGCTs facilitate osteogenic-like differentiation of testicular cells and deposition of hydroxyapatite.in eLife on 2025-04-25 00:00:00 UTC.
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Deep sequencing of yeast and mouse tRNAs and tRNA fragments using OTTR
Among the major classes of RNAs in the cell, tRNAs remain the most difficult to characterize via deep sequencing approaches, as tRNA structure and nucleotide modifications can each interfere with cDNA synthesis by commonly-used reverse transcriptases (RTs). Here, we benchmark a recently-developed RNA cloning protocol, termed Ordered Two-Template Relay (OTTR), to characterize intact tRNAs and tRNA fragments in budding yeast and in mouse tissues. We show that OTTR successfully captures both full-length tRNAs and tRNA fragments in budding yeast and in mouse reproductive tissues without any prior enzymatic treatment, and that tRNA cloning efficiency can be further enhanced via AlkB-mediated demethylation of modified nucleotides. As with other recent tRNA cloning protocols, we find that a subset of nucleotide modifications leave misincorporation signatures in OTTR datasets, enabling their detection without any additional protocol steps. Focusing on tRNA cleavage products, we compare OTTR with several standard small RNA-Seq protocols, finding that OTTR provides the most accurate picture of tRNA fragment levels by comparison to "ground truth" Northern blots. Applying this protocol to mature mouse spermatozoa, our data dramatically alter our understanding of the small RNA cargo of mature mammalian sperm, revealing a far more complex population of tRNA fragments - including both 5′ and 3′ tRNA halves derived from the majority of tRNAs – than previously appreciated. Taken together, our data confirm the superior performance of OTTR to commercial protocols in analysis of tRNA fragments, and force a reappraisal of potential epigenetic functions of the sperm small RNA payload.in eLife on 2025-04-25 00:00:00 UTC.
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Charting the nanotopography of inner hair cell synapses using MINFLUX nanoscopy
For us to hear, the cochlea encodes sounds into neural signals at synapses of inner hair cells (IHCs) and the auditory nerve with remarkable fidelity. To achieve the high rates of temporally precise synaptic transmission over long periods of time, IHCs employ sophisticated ribbon-type active zones (AZ). In order for us to understand synaptic sound encoding, we need to decipher the underpinning molecular topography of these synapse which had remained challenging due to technological limitations. Here we applied 3-dimensional minimal flux optical nanoscopy to mouse IHC synapses to chart the position of key pre- and postsynaptic proteins with single digit nanometre resolution of imaging. We demonstrate that nanoclusters of channels and interacting proteins govern the topography of AZs and postsynaptic densities (PSDs). We count synaptic proteins, their nanoclusters and determine their spatial organization feeding into computational modelling of AZ function. In conclusion, this study reveals a nanocluster-based molecular AZ and PSD topography, likely serving as functional modules in synaptic sound encoding.in bioRxiv: Neuroscience on 2025-04-25 00:00:00 UTC.
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Personalized Biomarkers of Multiscale Functional Alterations in Temporal Lobe Epilepsy
Temporal lobe epilepsy (TLE) presents with substantial inter-patient variability in clinical and neuroimaging manifestations. This multicenter study examined inter-individual differences in spatial patterns of intrinsic brain function in TLE using normative modeling at multiple spatial scales and evaluated the effectiveness of individual functional deviations for clinical diagnosis and postsurgical outcome prediction. We analyzed multimodal MRI data on 298 healthy controls, 282 TLE patients, and 45 disease controls with extratemporal epilepsy. Cortical function was profiled at local, regional, and global scales using brain signal variability, regional homogeneity, and node strength. We estimated patient-specific W-score maps to index deviations from normative metrics. Compared to healthy controls, patients with TLE showed considerable variations in patterns of functional alterations across the cortex, with the highest overlap in the ipsilateral mesiotemporal regions. Connectome-based simulation revealed the paralimbic and medial default mode regions as key disease epicenters. Functional changes were primarily underpinned by superficial white matter anomalies. Supervised pattern learning achieved classification AUCs of 0.76 for TLE versus disease controls, 0.74 for left versus right TLE, and 0.63 for seizure-free versus non-seizure-free TLE, with greater contralateral temporal functional deviations correlating with unfavorable postsurgical seizure outcome. Our findings reveal the heterogeneous impact of TLE on intrinsic cortical function. These biomarkers hold promise for clinical translation, guiding precision therapeutics and enhancing presurgical decision-making in TLE.in bioRxiv: Neuroscience on 2025-04-25 00:00:00 UTC.
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The representation of mood in primate anterior insular cortex
Understanding how the brain reflects and shapes mood requires resolving the disconnect between behavioral measures of mood that can only be made in humans (typically based on subjective reports of happiness) and detailed measures of brain activity only available in animals. To achieve this, we developed a universal mood model to predict behavioral fluctuations in human subjective happiness as individuals experienced wins and losses during a gambling task. Next, we investigated how this operationalization of mood was reflected in the brains of two monkeys engaged in the same gambling task. We found a remarkable alignment between human mood model signatures and the persistent responses of units in monkey anterior insular cortex, including a matched timescale of integration across events. In comparison, the same signatures were only weakly reflected in dorsolateral prefrontal cortex, suggesting that insular mood representations do not trivially follow from a signal (like arousal) broadcast to all higher brain areas. These results are consistent with a model in which the brain transforms experiences into mood by integrating events through a recurrently connected network of excitatory and inhibitory pools of neurons. These are among the first detailed insights into the nature of putative mood representations in the primate brain.in bioRxiv: Neuroscience on 2025-04-25 00:00:00 UTC.
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Neural trajectories reveal orchestration of cortical coding underlying natural language composition
Language is a hierarchically structured system that enables humans to communicate complex meanings. Despite recent advances, the neurocomputational mechanism underlying the composition of natural language remains unclear. Building on the neural population theory, we investigated how neural trajectories in latent spaces underpin natural language composition that integrates diverse lexical content and syntactic relations. We found that neural trajectories derived from human neocortical responses show an orchestration of distinct coding strategies during naturalistic story comprehension. Neural latent geometry is primarily associated with syntactic relations and exhibits more efficient compression relative to lexical content. We further demonstrate that these trajectories can be simulated by brain-inspired computing systems with near-critical dynamics and a preference for historical information. Overall, by positioning structure-based integration as a key computation of natural language comprehension, our findings provide a novel perspective on the mechanism underlying real-world language use and emphasize the importance of contextual information in the development of brain-inspired intelligent systems.in bioRxiv: Neuroscience on 2025-04-25 00:00:00 UTC.
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Evaluating the evolution and inter-individual variability of infant functional module development from 0 to 5 yr old
AbstractThe segregation and integration of infant brain networks undergo tremendous changes due to the rapid development of brain function and organization. In this paper, we introduce a novel approach utilizing Bayesian modeling to analyze the dynamic development of functional modules in infants over time. This method retains inter-individual variability and, in comparison with conventional group averaging techniques, more effectively detects modules, taking into account the stationarity of module evolution. Furthermore, we explore gender differences in module development under awake and sleep conditions by assessing modular similarities. Our results show that female infants demonstrate more distinct modular structures between these 2 conditions, possibly implying relative quiet and restful sleep compared with male infants.in Cerebral Cortex on 2025-04-25 00:00:00 UTC.
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Dissociable neural networks for processing fearful bodily expressions at different spatial frequencies
AbstractThe human brain processes visual input across various spatial frequency (SF) ranges to extract emotional cues. Prior studies have extensively explored SF processing in facial expressions, yielding partly conflicting results. However, bodily expressions, which provide complementary emotional and survival-relevant cues, remain unexplored. We investigated the neural mechanisms underlying the processing of low (LSF), high (HSF), and broad spatial frequency (BSF) components in fearful versus neutral bodily postures. Using functional Magnetic Resonance Imaging, we examined brain activity in 20 participants viewing SF-filtered images of bodily expressions in a semi-passive task. A multivariate “searchlight” analysis based on Multi-Voxel Pattern Analysis was employed to decode the non-linear activation patterns associated with each SF band. Our findings reveal that SF processing engages distinct neural networks in response to fearful bodily expressions. BSF stimuli activated a widespread network, including the amygdala, pulvinar, frontal, and temporal cortices. These findings suggest a general threat-detection system integrating information across all SFs. HSF stimuli engaged cortical regions associated with detailed emotional evaluation and motor planning, such as the orbitofrontal cortex, anterior cingulate cortex, and premotor areas, suggesting that processing fine-grained fear cues involves computationally demanding networks related to emotional resonance and action preparation. In contrast, LSF stimuli primarily activated motor-preparatory regions linked to rapid, action-oriented responses, highlighting the brain prioritization of quick readiness to low-detail threats. Notably, the amygdala showed no SF selectivity, supporting its role as a generalized “relevance detector” in emotional processing. The present study demonstrates that the brain flexibly adapts its SF processing strategy based on the visual details available in fearful bodily expressions, underscoring the complexity and adaptability of emotional processing from bodily signals.in Cerebral Cortex on 2025-04-25 00:00:00 UTC.
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Postnatal Development of Dendritic Morphology and Action Potential Shape in Rat Substantia Nigra Dopaminergic Neurons
Substantia nigra pars compacta (SNc) dopaminergic (DA) neurons are characterized by specific morphological and electrophysiological properties. First, in ~90% of the cases, their axon arises from an axon-bearing dendrite (ABD) at highly variable distances from the soma. Second, they display a highly regular pattern of spontaneous activity (aka pacemaking) and a broad action potential (AP) that faithfully back-propagates through the entire dendritic arbor. In previous studies (
Moubarak et al., 2019 ;Moubarak et al., 2022 ), we demonstrated that the presence of a high density of sodium current in the ABD and the complexity of this dendrite played a critical role in the robustness of pacemaking and setting the half-width of the AP. In the current study, we investigated the postnatal development of both morphology and AP shape in SNc DA neurons in order to determine when and how the mature electrophysiological phenotype of these neurons was achieved. To do so, we performed electrophysiological recordings of SNc DA neurons at four postnatal ages (P3, P7, P14, P21) and fully reconstructed their dendritic and proximal axon morphology. Our results show that several morphological parameters, including the length of the ABD, display abrupt changes between P7 and P14, such that a mature morphology is reached by P14. We then showed that AP shape followed a similar timecourse. Using realistic multicompartment Hodgkin–Huxley modeling, we then demonstrated that the rapid morpho-electrical maturation of SNc DA neurons likely arises from synergistic increases in dendritic length and in somatodendritic sodium channel density.in eNeuro on 2025-04-24 16:30:20 UTC.
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The Computational Bottleneck of Basal Ganglia Output (and What to Do About it)
What the basal ganglia do is an oft-asked question; answers range from the selection of actions to the specification of movement to the estimation of time. Here, I argue that how the basal ganglia do what they do is a less-asked but equally important question. I show that the output regions of the basal ganglia create a stringent computational bottleneck, both structurally, because they have far fewer neurons than do their target regions, and dynamically, because of their tonic, inhibitory output. My proposed solution to this bottleneck is that the activity of an output neuron is setting the weight of a basis function, a function defined by that neuron’s synaptic contacts. I illustrate how this may work in practice, allowing basal ganglia output to shift cortical dynamics and control eye movements via the superior colliculus. This solution can account for troubling issues in our understanding of the basal ganglia: why we see output neurons increasing their activity during behavior, rather than only decreasing as predicted by theories based on disinhibition, and why the output of the basal ganglia seems to have so many codes squashed into such a tiny region of the brain.
in eNeuro on 2025-04-24 16:30:20 UTC.
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Heavy Metal Contamination: Sources, Health Impacts, and Sustainable Mitigation Strategies with Insights from Nigerian Case Studies [version 3; peer review: 2 approved with reservations]
Heavy metal contamination has gradually become a highly significant global issue due to its continual existence in the environment and bioaccumulation in the ecosystems, posing deleterious risks to human health. This review aims to investigate the sources, pathways, and toxicological impacts of heavy metals such as cadmium, lead, mercury, and arsenic, elucidating their health consequences and plausible mitigation strategies. Furthermore, the review explores the dual origins of heavy metal contamination; natural geological processes and anthropogenic activities such as industrial emissions, mining, and agricultural practices. These heavy metals seep into soil, water, and food chains, leading to bioaccumulation, bio-magnification and causing significant health risks, including cardiovascular diseases, neurological disorders, and reproductive toxicity. Additionally, the addition of indigenous case studies from Nigeria, such as lead poisoning in Zamfara State and contamination in the Great Kwa River of Cross Rivers State underscores the disproportionate impact of heavy metal pollution in developing nations. These case studies reveal the socio-economic and environmental dimensions of the issue, providing a contextual understanding of region-specific vulnerabilities and health outcomes. To address these problems, the review evaluates already existing mitigation strategies, including chelation therapy and phytoremediation, while proposing sustainable, cost-effective solutions for reducing exposure and mitigating impacts. It emphasizes the importance of integrative approaches involving policy, community engagement, and technological innovations to fight heavy metal contamination effectively. In conclusion, this seminar contributes to the understanding of heavy metal toxicity, giving and showcasing very much important insights into the sources and health implications of contamination. By integrating theoretical perspectives with practical solutions, this review provides a robust framework for informing policy makers and advancing sustainable environmental management practices.in F1000Research on 2025-04-24 16:20:35 UTC.
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Embracing smart wellness: Exploring perceptions of preventive healthcare technology in the digital era [version 2; peer review: 1 approved with reservations]
Background Technology is revolutionizing healthcare, making it more connected, efficient, and patient-centric. Smart healthcare tools like wearables and mobile health applications empower individuals to manage their health proactively. By leveraging these technologies, individuals can monitor chronic conditions like hypertension, diabetes, obesity, and cardiac issues, potentially preventing their detrimental consequences. This proactive approach not only enhances personal health management but also contributes to the overall well-being of society. Objective This study aims to understand individuals’ perceptions of smart technology usage and identify the antecedents influencing the adoption of smart healthcare technological applications. Methods This cross-sectional study used a structured questionnaire to collect the responses from 390 respondents in the Indian context. The data were analyzed using Partial Least Square Structural Equation Modeling. Findings and Conclusion The findings of this research show that antecedents such as self-efficacy, preventive awareness, technology promptness and innovativeness, and social influence play a significant role in the adoption of technology among individuals. Further, the study’s results will help to develop and promote technological applications to improve population health and have implications for healthcare providers, technology developers, marketers, and researchers.in F1000Research on 2025-04-24 16:11:15 UTC.
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Nat-UV DB: A Natural Products Database Underlying of Veracruz-Mexico [version 2; peer review: 3 approved]
Background Natural products databases are well-structured data sources that offer new molecular development opportunities in drug discovery, agrochemistry, food, cosmetics, and several other research disciplines or chemical industries. The crescent world’s interest in the development of these databases is related to the exploration of chemical diversity in geographical regions with rich biodiversity. Methods In this work, we introduce and discuss Nat-UV DB, the first natural products database from a coastal zone of Mexico. We discuss its construction, curation, and chemoinformatic characterization of their content, and chemical space coverage compared with other compound databases, like approved drugs, and other Mexican (BIOFACQUIM and UNIIQUIM databases) and the Latin American natural products database (LaNAPDB). Results Nat-UV DB comprises 227 compounds that contain 112 scaffolds, of which 52 are not present in previous natural product databases. The compounds present in Nat-UV DB have a similar size, flexibility, and polarity to previously reported natural products and approved drug datasets. Conclusions Nat-UV DB compounds have a higher structural and scaffold diversity than the approved drugs, but they have low structural and scaffold diversity in contrast with other natural products in the reference datasets. This database serves as a valuable addition to the global natural products landscape, bridging gaps in exploring biodiversity-rich regions.in F1000Research on 2025-04-24 16:09:12 UTC.
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Health Security inequalities in Non-EU European Countries: A Cross-National Comparative Assessment Using an Integrated MCDM-Machine Learning Approach [version 1; peer review: awaiting peer review]
Objectives In an increasingly interconnected world, the effectiveness of health security (HeS) is pivotal in shaping informed health policies and enhancing public health outcomes. This study aims to analyses HeS in 27 non-EU European countries, identifying key priorities and trends, benchmarking against African and Eastern Mediterranean regions (EMR), and ranking and clustering health security performance to inform targeted interventions. Methods Utilizing 2019, 2021, and aggregated 2017–2021 data from six Global Health Security Index indicators, this study applied an integrated Entropy-CoCoSo-K-means framework. The Entropy method was employed to identify health security (HeS) priorities and trends in Non-EU countries, enabling cross-regional comparisons with African and EMR regions to highlight priority shifts and disparities. The Entropy-CoCoSo (Combined Compromise Solution) model generated dynamic rankings, while K-means clustering categorized countries into five risk clusters (high to dangerous). This integration facilitated cross-national dynamic rankings and cluster analyses, informing targeted interventions across Non-EU countries. Results Entropy analysis reveals that detection and reporting emerged as the most critical indicator (weight: 0.388), reflecting disparities in surveillance. The risk environment remains minimally influential (0.067), highlighting consistent vulnerabilities to external threats. Compliance with norms shows a sharp rise (0.091 → 0.123), indicating emerging regulatory gaps or uneven adherence to health standards post-2019. Cross-regional comparisons highlighted a focus on detection and reporting in non-EU countries versus an emphasis on prevention in Africa and healthcare infrastructure prioritization in the EMR. Ranking and clustering revealed stark disparities: Armenia, Norway, and the UK consistently ranked “High,” In contrast, Andorra, Monaco, San Marino, and Tajikistan (Cluster 5: “Dangerous”) exhibited systemic weaknesses. Conclusion This study underscores the need for tailored policies to address non-EU Europe’s evolving HeS challenges. Harmonizing surveillance systems, scaling preventive measures, and bridging compliance gaps are critical. Regional collaboration and resource reallocation to low-performing nations are essential to mitigate disparities.in F1000Research on 2025-04-24 16:00:05 UTC.
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Delta-Aminolevulinic acid dehydratase enzyme activity and susceptibility to lead toxicity in Uganda’s urban children [version 3; peer review: 1 approved, 1 approved with reservations, 1 not approved]
Background With rapid industrialization, urbanization, and population explosion in sub-Saharan Africa including Uganda, the population has experienced increased exposure to environmental lead subsequently causing extreme (>50μg/dL) and elevated (< 50μg/dL) blood lead levels. For example, means (Blood Lead levels) of 332μg/dL, 120μg/dL, 25μg/dL,11μg/dL, and 10μg/dL in children under 18 years of age in Nigeria, DR Congo, South Africa, Sudan, and Uganda respectively are reported. Susceptibility to lead toxicity correlates with one’s nutrition status, age, and genetics. This study expounded susceptibility to lead toxicity by relating blood lead levels, delta-aminolevulinic acid dehydratase (ALAD) enzyme activity, and genetic variations of proteins that code for ALAD in urban children of Uganda aged between 6 and 60 months. Methods A total of 198 blood samples from randomly selected participants, children residing in the Katanga slum of Kampala, Uganda, were analyzed in duplicates for blood lead levels (BLL) on an atomic absorption spectrophotometer, Hemoglobin (Hb) levels, and ALAD enzyme activity were analyzed on a spectrophotometer before DNA extraction, polymerase chain reaction, and restriction fragment length digestion for ALAD polymorphism. The results are presented below. Results Geometric means of BLL (10.55μg/dL, SD = 7.4), Hb (7.85g/dL, SD = 1.3) and ALAD enzyme activity (37.15 units/L BLL, S. D = 9.7), corresponded to samples that coded for ALAD1 allele (99.5%) compared to the 0.5% that coded for ALAD2 with BLL (14.5μg/ dL, SD = 4.7), Hb (6.1 g/dL), ALAD enzyme activity (33.8 units/L, SD=1.45). There was a significant relationship with a negative linear correlation between BLL, Hb (status, and ALAD enzyme activity in the three isozymes (ALAD1-1, ALAD1-2, and ALAD2-2) in the strength of ALAD1-1 (r = 0.42, p-value = 0.02) ˂ ALAD1-2 (r = 0.62, effective size = 0.43, p-value = ˂ 0.001) ˂ ALAD2-2 (r = 0.67, effective size = 0.86, p-value = ˂ 0.001).in F1000Research on 2025-04-24 15:56:31 UTC.
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Case Report: A new modification of Loma Linda pouch technique [version 2; peer review: 1 approved with reservations]
Dental implants provide a reliable treatment option for completely or partially edentulous patients. In case of a membrane perforation, the gap can be closed using a piece of resorbable collagen membrane or by suturing the Schneiderian membrane using a resorbable suture. The present study shows a new development in this technique, which involves modifying the design of the absorbable membrane and using pins to fix the membrane. This study concluded that the novel design of the collagen membrane and its fixation with the pins led to greater stability of the bone graft and led to subsequent bone gain that enables dental implantation. Still, this technique requires a histological study to determine the nature of the bone formed.in F1000Research on 2025-04-24 15:52:24 UTC.
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Investigating the effects of Orthosiphon stamineus on blood glucose regulation via pancreatic endocrine and exocrine functions in Type 3c Diabetes Mellitus Wistar Bonn/Kobori (WBN/Kob) pancreatitis rat model. [version 1; peer review: awaiting peer review]
Background Type 3c diabetes mellitus (T3cDM) is a subtype that develops following pancreatic diseases, such as pancreatitis, impairing both exocrine and endocrine functions. Its management is challenging owing to exocrine enzyme deficiencies. Although plants have long been used for diabetes treatment, research on their role in T3cDM, particularly in exocrine enzymes, remains limited. The exact mechanisms by which enzymes and hormones interact remain unclear. Thus, this study aims to explore the role of Orthosiphon stamineus (OS) in glucose regulation by exploring both pancreatic endocrine and exocrine functions in the T3cDM Wistar Bonn/Kobori (WBN/Kob) pancreatitis rat model. Methods This protocol describes a planned, single-blind, randomized, controlled study conducted on animals to determine the efficacy of OS in regulating exocrine and endocrine pancreatic functions in a pancreatitis-induced WBN/Kob rat model. The groups will consist of control and different treatment groups. The duration of treatment is one month. A glucose tolerance test will be conducted orally before and after OS treatment. Blood glucose and insulin levels will be collected at different time points. Exocrine enzymes (amylase, lipase, and trypsinogen) and endocrine hormones (insulin, glucagon, ghrelin, pancreatic polypeptide, and somatostatin) will be measured in the serum. Hemoglobin A1c and lipid-soluble vitamins will also be evaluated. Results This pre-clinical study aims to explore pancreatic endocrine hormones and exocrine functions in response to OS treatment in rats with T3cDM pancreatitis. Body weight, diarrhea, and any adverse effects will be assessed as the secondary outcomes. Statistical analysis will be conducted to determine the significance of differences between the two groups. Conclusion This study protocol examines the efficacy of OS in addressing both exocrine and endocrine pancreatic dysfunction, ultimately aiding in blood glucose regulation. The findings of this study may help improve the health strategies of T3cDM patients and enhance patient outcomes.in F1000Research on 2025-04-24 15:50:43 UTC.
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Complexity reduction by symmetry: Uncovering the minimal regulatory network for logical computation in bacteria
by Luis A. Álvarez-García, Wolfram Liebermeister, Ian Leifer, Hernán A. Makse
Symmetry principles play an important role in geometry, and physics, allowing for the reduction of complicated systems to simpler, more comprehensible models that preserve the system’s features of interest. Biological systems are often highly complex and may consist of a large number of interacting parts. Using symmetry fibrations, the relevant symmetries for biological “message-passing” networks, we introduce a scheme, called Complexity Reduction by Symmetry or CoReSym, to reduce the gene regulatory networks of Escherichia coli and Bacillus subtilis bacteria to core networks in a way that preserves the dynamics and uncovers the computational capabilities of the network. Gene nodes in the original network that share isomorphic input trees are collapsed by the fibration into equivalence classes called fibers, whereby nodes that receive signals with the same “history” belong to one fiber and synchronize. Then we reduce the networks to its minimal computational core via k-core decomposition. This computational core consists of a few strongly connected components or “signal vortices,” in which signals can cycle through. While between them, these “signal vortices” transmit signals in a feedforward manner. These connected components perform signal processing and decision making in the bacterial cell by employing a series of genetic toggle-switch circuits that store memory, plus oscillator circuits. These circuits act as the central computation device of the network, whose output signals then spread to the rest of the network. Our reduction method opens the door to narrow the vast complexity of biological systems to their minimal parts in a systematic way by using fundamental theoretical principles of symmetry.in PLoS Computational Biology on 2025-04-24 14:00:00 UTC.
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Balancing complexity, performance and plausibility to meta learn plasticity rules in recurrent spiking networks
by Basile Confavreux, Everton J. Agnes, Friedemann Zenke, Henning Sprekeler, Tim P. Vogels
Synaptic plasticity is a key player in the brain’s life-long learning abilities. However, due to experimental limitations, the mechanistic link between synaptic plasticity rules and the network-level computations they enable remain opaque. Here we use evolutionary strategies (ES) to meta learn local co-active plasticity rules in large recurrent spiking networks with excitatory (E) and inhibitory (I) neurons, using parameterizations of increasing complexity. We discover rules that robustly stabilize network dynamics for all four synapse types acting in isolation (E-to-E, E-to-I, I-to-E and I-to-I). More complex functions such as familiarity detection can also be included in the search constraints. However, our meta learning strategy begins to fail for co-active rules of increasing complexity, as it is challenging to devise loss functions that effectively constrain network dynamics to plausible solutions a priori. Moreover, in line with previous work, we can find multiple degenerate solutions with identical network behaviour. As a local optimization strategy, ES provides one solution at a time and makes exploration of this degeneracy cumbersome. Regardless, we can glean the interdependecies of various plasticity parameters by considering the covariance matrix learned alongside the optimal rule with ES. Our work provides a proof of principle for the success of machine-learning-guided discovery of plasticity rules in large spiking networks, and points at the necessity of more elaborate search strategies going forward.in PLoS Computational Biology on 2025-04-24 14:00:00 UTC.
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Efficient discovery of frequently co-occurring mutations in a sequence database with matrix factorization
by Michael Robert Kolar, Debasis Mitra, Valerie Kobzarenko
We have developed a robust method for efficiently tracking multiple co-occurring mutations in a sequence database. Evolution often hinges on the interaction of several mutations to produce significant phenotypic changes that lead to the proliferation of a variant. However, identifying numerous simultaneous mutations across a vast database of sequences poses a significant computational challenge. Our approach leverages a matrix factorization technique to automatically and efficiently pinpoint subsets of positions where co-mutations occur, appearing in a substantial number of sequences within the database. We validated our method using SARS-CoV-2 receptor-binding domains, comprising approximately seven hundred thousand sequences of the Spike protein, demonstrating superior performance compared to a reasonably exhaustive brute-force method. Furthermore, we explore the biological significance of the identified co-mutational positions (CMPs) and their potential impact on the virus’s evolution and functionality, identifying key mutations in Delta and Omicron variants. This analysis underscores the significant role of identified CMPs in understanding the evolutionary trajectory. By tracking the “birth" and “death" of CMPs, we can elucidate the persistence and impact of specific groups of mutations across different viral strains, providing valuable insights into the virus’ adaptability and thus, possibly aiding vaccine design strategies.in PLoS Computational Biology on 2025-04-24 14:00:00 UTC.
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Total cerebral blood volume changes drive macroscopic cerebrospinal fluid flux in humans
by Juliana Zimmermann, Clara Boudriot, Christiane Eipert, Gabriel Hoffmann, Rachel Nuttall, Viktor Neumaier, Moritz Bonhoeffer, Sebastian Schneider, Lena Schmitzer, Jan Kufer, Stephan Kaczmarz, Dennis M Hedderich, Andreas Ranft, Daniel Golkowski, Josef Priller, Claus Zimmer, Rüdiger Ilg, Gerhard Schneider, Christine Preibisch, Christian Sorg, Benedikt Zott
In the mammalian brain, the directed motion of cerebrospinal fluid (CSF-flux) is instrumental in the distribution and removal of solutes. Changes in total cerebral blood volume (CBV) have been hypothesized to drive CSF-flux. We tested this hypothesis in two multimodal brain imaging experiments in healthy humans, in which we drove large changes in total CBV by neuronal burst-suppression under anesthesia or by transient global vasodilation in a hypercapnic challenge. We indirectly monitored CBV changes with a high temporal resolution based on associated changes in total brain volume by functional MRI (fMRI) and measured cerebral blood flow by arterial spin-labeling. Relating CBV-sensitive signals to fMRI-derived measures of macroscopic CSF flow across the basal cisternae, we demonstrate that increasing total CBV extrudes CSF from the skull and decreasing CBV allows its influx. Moreover, CSF largely stagnates when CBV is stable. Together, our results establish the direct coupling between total CBV changes and CSF-flux.in PLoS Biology on 2025-04-24 14:00:00 UTC.
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Normal locomotion in zebrafish lacking the sodium channel NaV1.4 suggests that the need for muscle action potentials is not universal
by Chifumi Akiyama, Souhei Sakata, Fumihito Ono
Extensive studies over decades have firmly established the concept that action potentials (APs) in muscles are indispensable for muscle contraction. To re-examine the significance of APs, we generated zebrafish lacking APs by editing the scn4aa and scn4ab genes, which together encode NaV1.4 (NaVDKO), using the CRISPR-Cas9 system. Surprisingly, the escape response of NaVDKOs to tactile stimuli, both in the embryonic and adult stages, was indistinguishable from that of wild-type (WT) fish. Ca2+ imaging using the calcium indicator protein GCaMP revealed that myofibers isolated from WT fish could be excited by the application of acetylcholine (ACh), even in the presence of tetrodotoxin (TTX) indicating that NaVs are dispensable for skeletal muscle contraction in zebrafish. Mathematical simulations showed that the end-plate potential was able to elicit a change in membrane potential large enough to activate the dihydropyridine receptors of the entire muscle fiber owing to the small fiber size and the disseminated distribution of neuromuscular synapses in both adults and embryos. Our data demonstrate that NaVs are not essential for muscle contraction in zebrafish and that the physiological significance of NaV1.4 in muscle is not uniform across vertebrates.in PLoS Biology on 2025-04-24 14:00:00 UTC.
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Evaluating Mycelium as an insulation material: A comparative study on thermal performance, comfort, and energy efficiency [version 1; peer review: awaiting peer review]
Background Since the building sector contributes significantly to carbon emissions, using sustainable materials is more crucial than ever. Mycelium is investigated in this study as a natural substitute for conventional insulation materials like rock wool and XPS. Its thermal performance has been evaluated in a residential building in New Cairo, Egypt, using Design-Builder simulations, paying particular attention to U-values, discomfort hours, PPD-PMV, and energy consumption. The results demonstrate that mycelium is environmentally safe, biodegradable, and provides insulation that is comparable to XPS. This demonstrates its promise as a sustainable option for building in the future. Methods This research uses Design-Builder software version 7.3.0.046 integrated with Energy-Plus to simulate the thermal conductivity of mycelium compared to two of the most frequently utilized traditional materials for insulation in Egypt, in Janna Compound, New Cairo. The analysis examines energy consumption, thermal comfort, Predicted Mean Vote (PMV), and Predicted Percentage of Dissatisfaction (PPD%). The study provides a comparative evaluation of mycelium insulation compared to traditional materials like XPS and Rockwool. Results According to the simulation results, mycelium insulation performs comparably to XPS regarding U-values, discomfort hours, PPD-PMV, and energy consumption. Specifically, mycelium achieved a 0.323 U-value, reduced discomfort hours percentage to 16.9%, and achieved a ratio of energy reduction of 15.8% compared to the base case. These results demonstrate how mycelium has the potential to compete with traditional insulation materials while offering significant sustainability advantages, such as biodegradability and a lower carbon footprint. Conclusion In Janna Compound, New Cairo, the research shows how mycelium insulation can improve thermal comfort and save energy usage. It performs similarly to XPS but has more positive environmental effects. These results support the integration of mycelium into Egypt’s sustainable housing practices, providing key insights for architects, developers, and policymakers focused on energy-efficient and sustainable urban development.in F1000Research on 2025-04-24 09:59:26 UTC.
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Internal and external risk factors analysis on pilot precondition in Indonesia [version 1; peer review: awaiting peer review]
Background Pilot errors accounted for 80% of accidents and 50% of serious incidents. The Human Factor Analysis and Classification System (HFACS) allows the identification of pilot preconditions as an imminent layer of error. This study aimed to analyze the correlation between internal and external risk factors and pilot preconditions in Indonesia. Methods A cross-sectional study design with purposive sampling, directed to male pilots who had flight duty in the past seven days, underwent medical examination at the Aviation Medical Center, Jakarta, August 12–16, 2024. The data were collected through a self-report questionnaire, Trail Making Test A and B, laboratory tests (plasma lipid, fasting blood glucose), and physical measurements (height, weight, waist circumference, and blood pressure). The independent variables included internal (Age, Burnout, Metabolic Syndrome parameters) and external (Flight Time, Duty Time, Unscheduled Flight Duty, Number of Sectors, Sleep Duration). The dependent variables were pilot preconditions based on the HFACS. Results A total of 122 participants participated in this study. Among them, 28.7% had an unscheduled flight duty in the last 30 d. Significant correlations were found between Adverse Mental State and HDL-cholesterol (95%CI=1.52 – 5.80), Adverse Physiological State and Burnout [personal (95%CI=0.005–0,04), work-related (95%CI=0.009–0.042)], Physical Mental Limitation and Fasting Blood Glucose (95%CI =(-0.479)–(-0.071)), and Number of Sectors (95%CI=0.022–3.001). For Personal Readiness (PR), a significant correlation was found between PR-psychological demand and Flight-Time One Year (95%CI=(0.000 – 0.001), Sleep Duration (95%CI =(-0.137)–(-0.013)), Waist Circumference (95%CI =(-0.014)–(-0.002)), PR-Social Support and Sleep Duration (95%IK=0.018–0.207), and Client-Related Burnout (95%IK =(-0.011)–(-0.002)). Conclusions The internal factors that correlated with pilot preconditions in Indonesia were waist circumference, high-density lipoprotein cholesterol, fasting blood glucose, personal burnout, work, and client-related burnout. External factors that correlated with pilot preconditions were the number of sectors, Flight-Time One Year and Sleep duration. These findings emphasize the need to address both physical and mental health aspects of pilots to enhance aviation safety.in F1000Research on 2025-04-24 09:43:21 UTC.
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Case Report: Management of Terminal Myelocystocele in a Neonate: A Case Report and Review of Clinical Considerations [version 1; peer review: awaiting peer review]
Terminal myelocystocele (TMC) is a rare, skin-covered congenital spinal anomaly characterized by turbulent cerebrospinal fluid (CSF) drainage, an elongated caudal spinal cord, terminal cystic dilation, and an intact dura mater. TMC is frequently associated with other congenital abnormalities affecting the anorectal, genitourinary, and vertebral systems, which necessitates careful clinical and radiological differentiation from other skin-covered spinal dysraphisms. We report a case of a two-week-old male neonate, born to a 19-year old primigravida mother, who presented with a large swelling in the lower back. Prenatal anatomical ultrasound at 20 weeks’ gestation had revealed sacrococcygeal anomalies. Postnatal spinal MRI demonstrated a well-defined, multi-lobulated sacrococcygeal cystic lesion with internal septations originating from an anterior sacral defect. Based on the imaging findings, differential diagnoses included a pure cystic sacrococcygeal teratoma and TMC. Surgical excision of the lesion was undertaken through two inverted V-shaped incisions along the caudal region. Following 8-months outpatient follow up, the infant did not demonstrate any neurological impairments. The potential for cyst expansion in TMC represents a significant clinical consideration, as it may indicate rapid neurological decline. Caregivers should be informed of this risk and advised to seek immediate medical attention if cyst enlargement is observed.in F1000Research on 2025-04-24 09:32:37 UTC.
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Application of digital health technologies to substance use reduction among students in higher education institutions: A scoping review [version 1; peer review: awaiting peer review]
Substance use among college and university students is associated with significant health issues, academic struggles, and premature death. This scoping review explores the potential of digital health interventions, including internet-based and mobile platforms, to reduce substance use. A comprehensive search across databases such as PubMed, PsycINFO, Scopus, and Google Scholar identified 11 eligible studies conducted across seven countries between 2013 and 2025. These studies focused primarily on alcohol use and included digital health tools like instant messaging, Telegram applications, text messaging, and web-based interventions. The results suggest that digital health technologies can effectively motivate college students in low- and middle-income countries (LMICs) to reduce or abstain from psychoactive substance use. However, there is a notable research gap in evaluating the effectiveness and feasibility of these tools, especially mobile text messaging, which remains one of the most widely used methods in LMICs. The review highlights the need for further research, including systematic reviews and meta-analyses, to better understand the impact of digital health interventions on substance use reduction and to develop evidence-based programs for behavior change.in F1000Research on 2025-04-24 09:20:12 UTC.
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Absolute Number of Thalamic Parafascicular and Striatal Cholinergic Neurons, and the Three‐Dimensional Spatial Array of Striatal Cholinergic Neurons, in the Sprague‐Dawley Rat
The absolute numbers of thalamic parafascicular (PFN) neurons and striatal cholinergic interneurons (CIN) were estimated in rats using unbiased stereological methods. Spatial statistical analysis of the three-dimensional distribution revealed that the large, mostly CIN were randomly positioned with no evidence of clustering.
ABSTRACT
The absolute number of neurons and their spatial distribution yields important information about brain function and species comparisons. We studied thalamic parafascicular neurons and striatal cholinergic interneurons (CINs) because the parafascicular neurons are the main excitatory input to the striatal CINs. This circuit is of increasing interest due to research showing its involvement in specific types of learning and behavioral flexibility. In the Sprague-Dawley rat, the absolute number of thalamic parafascicular neurons and striatal CINs is unknown. They were estimated in this study using modern stereological counting methods. From each of six young adult rats, complete sets of serial 40 µm glycol methacrylate sections were used to quantify neuronal numbers in the right parafascicular nucleus (PFN). From each of five young adult rats, complete sets of serial 20 µm frozen sections were immunostained and used to quantify cholinergic neuronal numbers in the right striatum. The spatial distribution, in three dimensions, of striatal CINs was also determined from exhaustive measurement of the x, y, z coordinates of each large interneuron in 40 µm glycol methacrylate sections in sampled sets of five consecutive serial sections from each of two rats. Statistical analysis of spatial distribution was conducted by comparing observed three-dimensional data with computer models of 10,000 pseudorandom distributions, using measures of nearest neighbor distance and Ripley's K-function for inhomogeneous samples. We found that the right PFN consisted, on average, of 30,073 neurons (with a coefficient of variation of 0.11). The right striatum consisted, on average, of 10,778 CINs (0.14). The statistical analysis of spatial distribution showed no evidence of clustering of striatal CINs in three dimensions in the rat striatum, consistent with previous findings in the mouse striatum. The results provide important data for the transfer of information through the PFN and striatum, species comparisons, and computer modeling.
in Journal of Comparative Neurology on 2025-04-24 07:00:00 UTC.
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Pax6 and Pax7 in the Central Nervous System of Cladistian Fishes: A Comprehensive Expression Analysis
The Pax6 and Pax7 expression patterns in cladistian fishes showed a high degree of conservation with all vertebrates studied, particularly in the forebrain and midbrain, and some exclusive features, such as the almost total absence of Pax6 in the adult pallium, with the exception of the putative pallial amygdala.
ABSTRACT
Among actinopterygian fishes, cladistians stand as the more basal extant species in the group, holding a key phylogenetic position close to the common ancestor of Osteichthyes. Despite the recent publication of studies regarding the neurochemical organization of their central nervous system (CNS), there is still a significant lack of genoarchitectonic data that may prove essential to fully understand the patterning of the brain of these fishes. The paired box genes Pax6 and Pax7 are known to determine several boundaries in the CNS and are indispensable, for instance, for the survival of neurons and the change from cell proliferation to cell differentiation. By means of immunohistofluorescence methods, we analyzed the expression patterns of the transcription factors Pax6 and Pax7 in the CNS of three representative species of cladistian fishes, with a particular focus on their evolutionary implications. Thus, conserved Pax6 immunoreactive cell groups were present in the olfactory bulb, subpallial areas, the prethalamus, the basal prosomere 3, the pretectum, the mesencephalic tegmentum, the cerebellum, the basal rhombencephalon, the spinal cord, and the retina. A number of exclusive features were identified, including the almost total absence of expression in the pallium, which was observed only in cladistians, and its absence in the hypothalamus, which is a primitive anamniote trait. Likewise, the Pax7 expression pattern was generally conserved, with traits like the absence of labeling in the telencephalon and the expression in the retromamillary hypothalamic domain, the basal prosomere 3, the pretectum, the optic tectum, and the alar part of the first rhombomere. Additionally, no Pax7 labeling was detected in the spinal cord, comprising a specific cladistian feature.
in Journal of Comparative Neurology on 2025-04-24 07:00:00 UTC.
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Infrared light stimulates the cochlea through a mechanical displacement detected and amplified by hair cells
Proceedings of the National Academy of Sciences, Volume 122, Issue 17, April 2025.
SignificanceCochlear implants (CIs) restore hearing by bypassing the nonfunctional sensory receptors responsible for hearing—hair cells—and directly stimulating their target neurons—spiral ganglion neurons—using electricity. Stimulation of the cochlea ...in PNAS on 2025-04-24 07:00:00 UTC.
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Molecular organization of central cholinergic synapses
Proceedings of the National Academy of Sciences, Volume 122, Issue 17, April 2025.
SignificanceSynaptic form and function are shaped by the array of proteins constituting the postsynaptic apparatus. Here, we use in vivo spatial proteomics in the developing and matureDrosophilabrain to dissect the intricate protein network surrounding ...in PNAS on 2025-04-24 07:00:00 UTC.
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Erratum for the Research Article “Structural basis for strychnine activation of human bitter taste receptor TAS2R46” by W. Xu et al.
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-24 07:00:00 UTC.
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Governance can’t be automated
Science, Volume 388, Issue 6745, April 2025.
in Science on 2025-04-24 07:00:00 UTC.
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Missed connections
Science, Volume 388, Issue 6745, Page 369-369, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Science of death
Science, Volume 388, Issue 6745, Page 369-369, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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The variable nature of sex
Science, Volume 388, Issue 6745, Page 368-368, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Microlensing events indicate that super-Earth exoplanets are common in Jupiter-like orbits
Science, Volume 388, Issue 6745, Page 400-404, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Observation of generalized t-J spin dynamics with tunable dipolar interactions
Science, Volume 388, Issue 6745, Page 381-386, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Bottom-up reconstruction of functional death fold signalosomes reveals a requirement for polymer stability and avidity
Science, Volume 388, Issue 6745, Page 415-422, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Conventional and organic farms with more intensive management have lower soil functionality
Science, Volume 388, Issue 6745, Page 410-415, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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RNA-mediated CRISPR-Cas13 inhibition through crRNA structural mimicry
Science, Volume 388, Issue 6745, Page 387-391, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Polyoxometalated metal-organic framework superstructure for stable water oxidation
Science, Volume 388, Issue 6745, Page 430-436, April 2025.
in Science on 2025-04-24 05:58:20 UTC.
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Hawaiian caterpillar patrols spiderwebs camouflaged in insect prey’s body parts
Science, Volume 388, Issue 6745, Page 428-430, April 2025.
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Aluminum distribution and active site locations in the structures of zeolite ZSM-5 catalysts
Science, Volume 388, Issue 6745, Page 423-428, April 2025.
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Ultrafast aqueous electric double layer dynamics
Science, Volume 388, Issue 6745, Page 405-410, April 2025.
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Gallium-catalyzed recycling of silicone waste with boron trichloride to yield key chlorosilanes
Science, Volume 388, Issue 6745, Page 392-400, April 2025.
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Healing waters
Science, Volume 388, Issue 6745, Page 438-438, April 2025.
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In Other Journals
Science, Volume 388, Issue 6745, Page 373-374, April 2025.
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Integrating exposomics into biomedicine
Science, Volume 388, Issue 6745, Page 356-358, April 2025.
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The cellular basis for middle-age spread
Science, Volume 388, Issue 6745, Page 360-360, April 2025.
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Reimagining silicone’s life cycle
Science, Volume 388, Issue 6745, Page 361-361, April 2025.
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Epo-calypse now
Science, Volume 388, Issue 6745, Page 358-359, April 2025.
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Editor’s note
Science, Volume 388, Issue 6745, Page 370-370, April 2025.
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US scientists must stand together
Science, Volume 388, Issue 6745, Page 370-371, April 2025.
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Rallying for US science
Science, Volume 388, Issue 6745, Page 371-371, April 2025.
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Science, not silence: Save US economic growth
Science, Volume 388, Issue 6745, Page 370-370, April 2025.
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Did the United States commit ‘ecocide’?
Science, Volume 388, Issue 6745, Page 353-353, April 2025.
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A 50-year shadow
Science, Volume 388, Issue 6745, Page 354-355, April 2025.
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News at a glance
Science, Volume 388, Issue 6745, Page 340-341, April 2025.
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NIH grants caught in crossfire as Harvard and Trump collide
Science, Volume 388, Issue 6745, Page 342-343, April 2025.
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Astronomers claim Chinese star catalog is world’s oldest
Science, Volume 388, Issue 6745, Page 343-344, April 2025.
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World agrees on pandemic treaty—without the U.S.
Science, Volume 388, Issue 6745, Page 344-345, April 2025.
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Last of Mendel’s seven genetic riddles solved
Science, Volume 388, Issue 6745, Page 346-346, April 2025.
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NSF kills grants to comply with war on woke
Science, Volume 388, Issue 6745, Page 347-347, April 2025.
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Trade war is ‘natural experiment’ for economists
Science, Volume 388, Issue 6745, Page 348-348, April 2025.
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The fog of war
Science, Volume 388, Issue 6745, Page 350-353, April 2025.
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Convergence and consensus
Science, Volume 388, Issue 6745, Page 339-339, April 2025.
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Partisan disparities in the use of science in policy
Science, Volume 388, Issue 6745, Page 362-367, April 2025.
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In Science Journals
Science, Volume 388, Issue 6745, Page 372-374, April 2025.
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Gait Speed Related Changes in Electrocortical Activity in Younger and Older Adults
Journal of Neurophysiology, Ahead of Print.
in Journal of Neurophysiology on 2025-04-24 03:19:46 UTC.
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The gut microbiota promotes pain in fibromyalgia
Cai et al. revealed that transplanting gut microbiota from women with fibromyalgia—a chronic widespread pain condition of unknown etiology—into mice induces pain. It also induces phenotypes commonly observed in patients, such as immune activation, metabolomic changes, and reduced skin innervation.in Neuron: In press on 2025-04-24 00:00:00 UTC.
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Myeloid-lineage-specific membrane protein LRRC25 suppresses immunity in solid tumor and is a potential cancer immunotherapy checkpoint target
Zhang et al. show that deficiency of the myeloid-lineage-specific membrane protein LRRC25 in the tumor microenvironment suppresses growth of multiple murine tumor models. This effect is mediated by reprogramming polarization of TAMs toward an anti-tumor phenotype and thereby enhancing infiltration and activation of CD8+T cells.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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High-confidence glycosomal membrane protein inventory unveils trypanosomal peroxin PEX15
Trypanosoma and Leishmania infections cause devastating neglected tropical diseases. These parasites harbor peroxisome-related organelles called glycosomes, which are essential for their survival. Krishna et al. established an inventory of glycosomal membrane proteins. They identified several proteins, including PEX15, which is essential for glycosome biogenesis and parasite survival.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice
Brains of aging mice harbor rare monocyte-derived microglia (MoMg) that are transcriptomically indistinguishable from yolk-sac-derived cells. MoMg are targets of clonal hematopoiesis (CH) and, hence, could be a liability. Indeed, Kim et al. show in a mouse model that when harboring a CH-associated DNMT3a variant, MoMg cause motoric deficits.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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Loss of neurofibromin induces inflammatory macrophage phenotypic switch and retinal neovascularization via GLUT1 activation
Zaidi et al. demonstrate that the loss of neurofibromin in macrophages enhances glucose uptake via membrane-bound GLUT1 in an Akt2-dependent manner, leading to increased glycolysis. This metabolic shift promotes a phenotypic switch from reparative to inflammatory macrophages, resulting in sustained inflammation and pathological neovascularization in retina and human NF1 tumors.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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Regulation of translation elongation and integrated stress response in heat-shocked neurons
Neurons fail to express Hsp70 protein during heat shock. Seluzicki et al. reveal that neuronal adaptation to heat shock accompanies a brake on mRNA translation, slowed elongating ribosomes, phosphorylation of eukaryotic elongation factor-2, and suppressed integrated stress response. If recovered within 1 h, translation is restored, and neurons survive.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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Piezo1 balances the osteogenic-tenogenic plasticity of periosteal progenitor cells through the YAP pathway
Wang et al. demonstrate that periosteal skeletal progenitor cells compromise the osteogenic ability and acquire lineage commitment favoring tendon cells upon deletion of the mechanosensitive ion channel Piezo1, providing a strategy for tissue regeneration using periosteal progenitor cells.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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Transcriptional landscape and chromatin accessibility reveal key regulators for liver regenerative initiation and organoid formation
Lian et al. show that the “Initiation_on” transcription factor (TF) ATF3 and “Initiation_off” TF ONECUT2 act as “switches” to initiate liver regeneration and organoid formation. Using multi-omics approaches they reveal key regeneration mechanisms, providing potential therapeutic targets for liver diseases with regenerative defects.in Cell Reports: Current Issue on 2025-04-24 00:00:00 UTC.
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Editorial Expression of Concern: Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesis
Nature, Published online: 24 April 2025; doi:10.1038/s41586-025-09026-7
Editorial Expression of Concern: Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesisin Nature on 2025-04-24 00:00:00 UTC.
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Editorial Expression of Concern: A melanocyte lineage program confers resistance to MAP kinase pathway inhibition
Nature, Published online: 24 April 2025; doi:10.1038/s41586-025-09027-6
Editorial Expression of Concern: A melanocyte lineage program confers resistance to MAP kinase pathway inhibitionin Nature on 2025-04-24 00:00:00 UTC.
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Science sleuths flag hundreds of papers that use AI without disclosing it
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01180-2
Telltale signs of chatbot use are scattered through the scholarly literature — and, in some cases, have disappeared without a trace.in Nature on 2025-04-24 00:00:00 UTC.
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How Trump’s attack on universities is putting research in peril
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01289-4
Scientists have little information as the US government freezes and cancels their funding.in Nature on 2025-04-24 00:00:00 UTC.
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Daily briefing: Ancient Phoenicians spread their culture — but not their DNA
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01315-5
People from Mediterranean outposts of Phoenician culture shared no ancestry with ancient Middle Easterners. Plus, Mendel’s last pea-plant mysteries have finally been solved and an origami-inspired material can make ‘dancing’ robots.in Nature on 2025-04-24 00:00:00 UTC.
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Eugenics is on the rise again: human geneticists must take a stand
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01297-4
Scientists must push back against the threat of rising white nationalism and the dangerous and pseudoscientific ideas of eugenics.in Nature on 2025-04-24 00:00:00 UTC.
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Major European institutes join race to save US science data
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01309-3
As the administration of US President Donald Trump slashes budgets, crucial data sets on climate and other subjects could disappear.in Nature on 2025-04-24 00:00:00 UTC.
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Baffling chronic pain eases after doses of gut microbes
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01290-x
A small, preliminary trial and studies in mice draw links between fibromyalgia and alterations of the gut microbiome.in Nature on 2025-04-24 00:00:00 UTC.
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How Democrats and Republicans cite science: study reveals stark differences
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01311-9
Democratic-led congressional committees and left-wing think tanks reference research papers more often than their right-wing counterparts.in Nature on 2025-04-24 00:00:00 UTC.
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Parkinson’s gut-microbiota links raise treatment possibilities
Nature, Published online: 24 April 2025; doi:10.1038/d41586-025-01253-2
The relationship between pathology in the brain and alterations in the gut microbiome could lead to therapies — even if it’s not clear which changes come first.in Nature on 2025-04-24 00:00:00 UTC.
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Mechanisms of plant acclimation to multiple abiotic stresses
Communications Biology, Published online: 24 April 2025; doi:10.1038/s42003-025-08077-w
A review summarizes the current understanding of the complex molecular pathways mediating plant responses to multiple abiotic stresses, and discusses current and future challenges and unanswered questions.in Nature communications biology on 2025-04-24 00:00:00 UTC.
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Neural regulation of H3K27me3 during the induction of patterning competency in regenerating Axolotl limb cells
Communications Biology, Published online: 24 April 2025; doi:10.1038/s42003-025-08084-x
A simplified limb regeneration assay in axolotls reveals the nerve-dependent growth factors that are sufficient to induce patterning competency and uncovers their downstream epigenetic targets.in Nature communications biology on 2025-04-24 00:00:00 UTC.
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Species responses to weather anomalies depend on local adaptation and range position
Communications Biology, Published online: 24 April 2025; doi:10.1038/s42003-025-08032-9
Long-term data for 34 butterfly species evidence that population responses to climate change vary with adaptation to local conditions and niche position. Local adaptation implies negative effect of climatic anomalies independently of niche position.in Nature communications biology on 2025-04-24 00:00:00 UTC.
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The identification of functional regions of MEK1 using CRISPR tiling screens
Communications Biology, Published online: 24 April 2025; doi:10.1038/s42003-025-07966-4
Utilization of CRISPR tiling screens to identify protein functional regions for structure-based drug discovery, using MEK1 as a demonstration. Biological mechanism study of distinct MEK1 drug-resistant mutations combined with structural analysisin Nature communications biology on 2025-04-24 00:00:00 UTC.
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Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure
Communications Biology, Published online: 24 April 2025; doi:10.1038/s42003-025-08087-8
Increased cardiac fibulin-4 expression in response to TAC-induced pressure overload protects against cardiac hypertrophy in mouse hearts.in Nature communications biology on 2025-04-24 00:00:00 UTC.
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Stimulus representation in human frontal cortex supports flexible control in working memory
When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.in eLife on 2025-04-24 00:00:00 UTC.
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Pyruvate and related energetic metabolites modulate resilience against high genetic risk for glaucoma
A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.in eLife on 2025-04-24 00:00:00 UTC.
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RAS–p110α signalling in macrophages is required for effective inflammatory response and resolution of inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.in eLife on 2025-04-24 00:00:00 UTC.
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Stabilization of GTSE1 by cyclin D1–CDK4/6-mediated phosphorylation promotes cell proliferation with implications for cancer prognosis
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.in eLife on 2025-04-24 00:00:00 UTC.
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Molecular mapping and functional validation of GLP-1R cholesterol binding sites in pancreatic beta cells
G protein-coupled receptors (GPCRs) are integral membrane proteins which closely interact with their plasma membrane lipid microenvironment. Cholesterol is a lipid enriched at the plasma membrane with pivotal roles in the control of membrane fluidity and maintenance of membrane microarchitecture, directly impacting on GPCR stability, dynamics, and function. Cholesterol extraction from pancreatic beta cells has previously been shown to disrupt the internalisation, clustering, and cAMP responses of the glucagon-like peptide-1 receptor (GLP-1R), a class B1 GPCR with key roles in the control of blood glucose levels via the potentiation of insulin secretion in beta cells and weight reduction via the modulation of brain appetite control centres. Here, we unveil the detrimental effect of a high cholesterol diet on GLP-1R-dependent glucoregulation in vivo, and the improvement in GLP-1R function that a reduction in cholesterol synthesis using simvastatin exerts in pancreatic islets. We next identify and map sites of cholesterol high occupancy and residence time on active vs inactive GLP-1Rs using coarse-grained molecular dynamics (cgMD) simulations, followed by a screen of key residues selected from these sites and detailed analyses of the effects of mutating one of these, Val229, to alanine on GLP-1R-cholesterol interactions, plasma membrane behaviours, clustering, trafficking and signalling in INS-1 832/3 rat pancreatic beta cells and primary mouse islets, unveiling an improved insulin secretion profile for the V229A mutant receptor. This study (1) highlights the role of cholesterol in regulating GLP-1R responses in vivo; (2) provides a detailed map of GLP-1R - cholesterol binding sites in model membranes; (3) validates their functional relevance in beta cells; and (4) highlights their potential as locations for the rational design of novel allosteric modulators with the capacity to fine-tune GLP-1R responses.in eLife on 2025-04-24 00:00:00 UTC.
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Accelerated signal propagation speed in human neocortical dendrites
Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Axonal and dendritic recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Experimentally-based detailed biophysical models have shown that the key factor responsible for the accelerated EPSP propagation in human cortical dendrites is the large conductance load imposed at the soma by the large basal dendritic tree. Additionally, larger dendritic diameters and differences in cable and ion channel properties in humans contribute to enhanced signal propagation. Our integrative experimental and modeling study provides new insights into the scaling rules that help maintain information processing speed albeit the large and sparse neurons in the human cortex.in eLife on 2025-04-24 00:00:00 UTC.
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Monoclonal antibodies derived from B cells in subjects with cystic fibrosis reduce Pseudomonas aeruginosa burden in mice
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.in eLife on 2025-04-24 00:00:00 UTC.
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Cerebellar Purkinje cells control posture in larval zebrafish (Danio rerio)
Cerebellar dysfunction leads to postural instability. Recent work in freely moving rodents has transformed investigations of cerebellar contributions to posture. However, the combined complexity of terrestrial locomotion and the rodent cerebellum motivate new approaches to perturb cerebellar function in simpler vertebrates. Here, we adapted a validated chemogenetic tool (TRPV1/capsaicin) to describe the role of Purkinje cells — the output neurons of the cerebellar cortex — as larval zebrafish swam freely in depth. We achieved both bidirectional control (activation and ablation) of Purkinje cells while performing quantitative high-throughput assessment of posture and locomotion. Activation modified postural control in the pitch (nose-up/nose-down) axis. Similarly, ablations disrupted pitch-axis posture and fin-body coordination responsible for climbs. Postural disruption was more widespread in older larvae, offering a window into emergent roles for the developing cerebellum in the control of posture. Finally, we found that activity in Purkinje cells could individually and collectively encode tilt direction, a key feature of postural control neurons. Our findings delineate an expected role for the cerebellum in postural control and vestibular sensation in larval zebrafish, establishing the validity of TRPV1/capsaicin-mediated perturbations in a simple, genetically tractable vertebrate. Moreover, by comparing the contributions of Purkinje cell ablations to posture in time, we uncover signatures of emerging cerebellar control of posture across early development. This work takes a major step towards understanding an ancestral role of the cerebellum in regulating postural maturation.in eLife on 2025-04-24 00:00:00 UTC.
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A host enzyme reduces metabolic dysfunction-associated steatotic liver disease (MASLD) by inactivating intestinal lipopolysaccharide
The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been increasing worldwide. Since gut-derived bacterial lipopolysaccharides (LPS) can travel via the portal vein to the liver and play an important role in producing hepatic pathology, it seemed possible that (1) LPS stimulates hepatic cells to accumulate lipid, and (2) inactivating LPS can be preventive. Acyloxyacyl hydrolase (AOAH), the eukaryotic lipase that inactivates LPS and oxidized phospholipids, is produced in the intestine, liver, and other organs. We fed mice either normal chow or a high-fat diet for 28 weeks and found that Aoah-/- mice accumulated more hepatic lipid than did Aoah+/+ mice. In young mice, before increased hepatic fat accumulation was observed, Aoah-/- mouse livers increased their abundance of sterol regulatory element-binding protein 1, and the expression of its target genes that promote fatty acid synthesis. Aoah-/- mice also increased hepatic expression of Cd36 and Fabp3, which mediate fatty acid uptake, and decreased expression of fatty acid-oxidation-related genes Acot2 and Ppara. Our results provide evidence that increasing AOAH abundance in the gut, bloodstream, and/or liver may be an effective strategy for preventing or treating MASLD.in eLife on 2025-04-24 00:00:00 UTC.
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When working memory works for our goals
When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.in eLife on 2025-04-24 00:00:00 UTC.
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Hebb's Vision: The Structural Underpinnings of Hebbian Assemblies
In 1949, Donald Hebb proposed that groups of neurons that activate stereotypically form the organizational building blocks of perception, cognition, and behavior. He theorized that repeated activations induce the structural changes needed to group neurons in these assemblies. Despite Hebb's enduring influence, testing his predictions at relevant scales has been technically challenging. Here, we test the theory using a novel, large-scale dataset featuring in vivo calcium fluorescence imaging of neural activity with postmortem electron microscopy (EM) for detailed reconstruction of neurons from the same volume of mouse visual neocortex. A coregistration process matches EM-reconstructed neurons to their recorded fluorescence traces. From these traces, we extract neural assemblies from higher-order correlations in neural activity. We find multiple assemblies, many with overlapping neurons, and some neurons that do not participate in any assembly. We then show that these assemblies exhibit properties consistent with Hebb's theory, including more reliable responses to repeated natural movie inputs than size-matched random ensembles and superior decoding of visual stimuli. Using coregistration to probe structural correlates, we find that neurons that participate in assemblies are significantly more integrated into the structural network than those that do not. Contrary to Hebb's original prediction, we do not observe a marked increase in the strength of monosynaptic excitatory connections between cells participating in the same assembly. However, we find significantly stronger indirect feed-forward inhibitory connections targeting cells in other assemblies. Intuitively, the delineation of assemblies can be realized either by internal excitation or external inhibition. Our findings support the latter mechanism. These results show the utility of assemblies in perception and provide a structural underpinning. They lay the foundation for future studies looking at the utility of assemblies in cognition and behavior, as well as the mechanisms for the formation and maintenance of such assemblies.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Cortex-wide voltage imaging in a sensory cued reaching task reveals fast subnetwork dynamics
Oscillatory activities and network dynamics are fundamental to sensorimotor processing, motor control, and cognitive functions. Capturing the fast cortical dynamics underlying sensorimotor behaviors demands temporal resolution beyond conventional imaging methods. We employed pan-cortical JEDI-1P voltage imaging of layer 2/3 activity in a skilled reaching task to reveal previously inaccessible rapid networks dynamics. Our approach uncovered distinct spectral signatures including reward-related gamma oscillations in M2, global low-frequency suppression during movement execution, and 8 Hz large-amplitude oscillations in sensorimotor cortex during task disengagement. Using independent component analysis, we were able to separate multiplexed functional networks with fast temporal features shared among sensorimotor regions and slower dynamics such as a global preparatory ramp. These distributed activity patterns successfully predicted both sensorimotor parameters and trial outcomes. Our study bridges critical gaps in understanding rapid temporal organization of cortical networks during complex behaviors, revealing how fast neural dynamics coordinate to produce motor actions across distributed cortical regions.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Early synaptic changes and reduced brain connectivity in PD-like mice with depressive phenotype
Anxiety and depression are common in Parkinson's disease (PD), affecting quality of life. Aggregates of -synuclein (-Syn) are found in serotonergic (5-HT) raphe nuclei early in the disease, but their relationship to brain changes is unclear. We investigated synaptic plasticity, neuronal activity, and functional magnetic resonance imaging (fMRI)-based brain connectivity in a PD-like mouse model with depressive phenotype. AAV-induced human -Syn accumulation in raphe 5-HT neurons causes progressive synaptic pathology in interconnected brain regions. This is marked by lower MAP-2, PSD95 and higher SV2A, VAMP2, which are key to synaptic structure and function, as confirmed in human brain tissue samples. Abnormalities in Egr-1-dependent neuronal activity and region-specific differences in resting-state functional brain activity were also detected eight weeks post-AAV infusion, before neurodegeneration. This provides evidence for synaptic and fMRI markers associated with -Syn pathology in emotional brain circuits, and has translational importance for identifying PD patients at risk for depression.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Dopamine Dynamics in the Nucleus Accumbens Reflect Confidence in Detecting the Occurrence and Non-Occurrence of Visual Signals in Perceptual Decision-Making
Dopamine (DA) is critically involved in processes such as reward anticipation, attention, and decision-making. The present study examined the temporal dynamics of phasic DA transients in the nucleus accumbens core (NAcC) during a visual decisional task based on signal detection theory, using the fluorescent DA sensor dLight1.3b. During the decision-making phase, DA transients in the NAcC encoded real-time outcome expectancy, apparently reflecting the confidence of rats in their choices. Reward prediction errors (RPEs) emerged following reward delivery and omission and were amplified under conditions of increased uncertainty, produced either by degrading the visual target or introducing interfering distraction. Moreover, DA transients were elicited on both visual signal and no-signal trials. These findings demonstrate that DA fluctuations in the NAcC reflect the RPE that incorporates confidence and levels of uncertainty, emphasizing an involvement of nucleus accumbens DA in adaptive decision-making.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Tracking neural representations of attended and unattended features in multisensory working memory over time
Working memory supports goal-directed behavior by maintaining task-relevant information. However, a growing number of studies shows that even task-irrelevant features are automatically encoded and can interfere with the recall of task-relevant information. While this phenomenon is well documented in unisensory contexts, it remains unclear whether and how task-irrelevant information persists in multisensory working memory. We examine the role of cross-modal binding by tracking the dynamic neural representation of audio-visual objects under varying selective attention conditions, using an EEG-based audio-visual delayed-match-to-sample task. Participants attended to either auditory or visual features (selective attention), or to both features (conjunction) of two sequential audio-visual items and subsequently compared those task-relevant features to an audio-visual probe. Further, to investigate the influence of bottom-up factors on cross-modal binding, we manipulated spatial congruency by presenting both features from either the same (i.e., in the center) or from disparate positions. Behaviorally, task-irrelevant features interfered with performance even under selective attention, consistent with automatic cross-modal binding and encoding into working memory. This interference was even stronger with spatially disparate presentation, suggesting that bottom-up attentional dynamics strengthen cross-modal bindings and their subsequent storage. Condition-level representational similarity analysis (RSA) showed that EEG activity patterns under selective attention more closely resembled those of conjunction trials than unisensory trials, indicating that task-irrelevant features were incorporated into multisensory object-level representations. This conjunction-similarity persisted in attend-visual trials, but declined over time in attend-auditory trials, reflecting partial filtering of task-irrelevant orientations. Crucially, activity patterns never shifted fully towards an auditory-only profile, indicating that irrelevant visual features were not fully excluded. In addition, feature-level RSA corroborated that both sound frequency-specific and orientation-specific information were present in EEG activity patterns, irrespective of the attended modality. Overall, these results demonstrate the persistence of task-irrelevant information in multisensory working memory and offer critical insights into how attentional processes shape its representational architecture.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Characterization of Human Anterior Neural Organoids as a Model for Investigating Cohen Syndrome
Neural organoids display three-dimensional (3D) structures that resemble in vivo neural architectures. Previously, we developed a novel two-dimensional (2D) neural induction-based protocol for culturing spinal cord organoids, enabling size control and recapitulating neural tube morphogenesis. In this study, we evaluated the application of this concept to induce the anterior regions of the brain and generate human anterior neural organoids (hANOs). By inducing neuroepithelial (NE) cells in 2D and re-aggregating them led to tube-forming morphogenesis similar to that posterior spinal cord induction. The transcriptome profiles of these hANOs resembled the frontal cortex of 20 weeks post-conception (PCW) human embryos. Using this hANOs protocol, we investigated microcephaly phenotypes associated with Cohen syndrome (CS), caused by biallelic loss-of-function variants in VPS13B gene. Deleting VPS13B in human pluripotent stem cells resulted in Golgi dispersion and growth retardation onset in mutant hANOs, akin to CS patients with postnatal microcephaly. This delay is partly linked to reduced neuronal growth. Additionally, mature CS organoids showed enhanced hyper-excitability associated with an excitatory/inhibitory imbalance. In conclusion, this protocol is suitable for studying microcephaly phenotypes from human genetic mutations due to its simplicity and scalability.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Activity deprivation modulates the Shank3/Homer1/mGluR5 signaling pathway to enable synaptic upscaling
Shank3 is an autism spectrum disorder-associated postsynaptic scaffold protein that links glutamate receptors to trafficking and signaling networks within the postsynaptic density. Shank3 is required for synaptic scaling (Tatavarty et al., 2020), a form of homeostatic plasticity that bidirectionally modulates post-synaptic strength in the right direction to stabilize neuronal activity. Shank3 undergoes activity-dependent phosphorylation/dephosphorylation at S1586/S1615, and dephosphorylation at these sites is critical for enabling synaptic upscaling (Wu et al., 2022). Here, we probe the molecular machinery downstream of Shank3 dephosphorylation that allows for synaptic upscaling. We first show that a phosphomimetic mutant of Shank3 has reduced binding ability and interaction with long-form Homer1, a postsynaptic protein also crucial for scaling, and a known binding partner of Shank3. Since metabotropic glutamate receptor 5 (mGluR5) has been shown to associate with Shank3 through long-form Homer1, we manipulated mGluR5 signaling with either noncompetitive or competitive inhibitors and found that only competitive inhibition (which targets agonist-dependent signaling) impairs synaptic upscaling. Further, we found that mGluR5 activation rescues synaptic upscaling in the presence of phosphomimetic Shank3, thus is downstream of Shank3 phosphorylation. Finally, we identify necessary signaling pathways downstream of group I mGluR. Taken together, these data show that activity-dependent dephosphorylation of Shank3 remodels the Shank3/Homer1/mGluR signaling pathway to favor agonist-dependent mGluR signaling, which is necessary to enable synaptic upscaling. More broadly, because downscaling depends on agonist-independent mGluR5 signaling, these findings demonstrate that synaptic up and downscaling rely on distinct functional configurations of the same signaling elements.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Complementary cortical and striatal encoding of locomotor preparation and performance
Cortical and striatal circuits play an important role in motor planning and execution, and encode movement-related information. While neural dynamics in these areas show substantial similarities, possibly reflecting shared information content, studies directly comparing the cortical and striatal encoding of locomotor preparation and performance have been lacking. Here we contrasted the neural coding properties of mouse primary motor and medial prefrontal cortex, as well as dorsolateral and dorsomedial striatum, prior to and during bouts of self-initiated walking. All four areas contained cells active during both the preparatory and performance periods of locomotion. However, the decoding of behaviorally relevant information using population-level activity revealed significant regional variations. Specifically, dorsomedial striatum more accurately encoded the preparatory period prior to walking, while primary motor cortex more accurately encoded rhythmic limb kinematics during walking. Together, this work provides evidence for a complementary neural coding scheme for locomotor preparation and performance in cortical and striatal circuits.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Large Language Models Reveal the Neural Tracking of Linguistic Context in Attended and Unattended Multi-Talker Speech
Large language models (LLMs) have shown strong alignment with contextualized semantic encoding in the brain, offering a new avenue for studying language processing. However, natural speech often occurs in multi-talker environments, which remain underexplored. We investigated how auditory attention modulates context tracking using electrocorticography (ECoG) and stereoelectroencephalography (sEEG) from three epilepsy patients in a two-conversation "cocktail party" paradigm. LLM embeddings were used to predict brain responses to attended and unattended speech streams. Results show that LLMs reliably predict brain activity for the attended stream, and notably, contextual features from the unattended stream also contribute to prediction. Importantly, the brain appears to track shorter-range context in the unattended stream compared to the attended one. These findings reveal that the brain processes multiple speech streams in parallel, modulated by attention, and that LLMs can be valuable tools for probing neural language encoding in complex auditory settings.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Activation of complement protein C3 depicts the dynamic tissue damage of the cochlea after noise trauma.
Hearing loss is characterized by dysfunction and pathological changes of the cochlea, including the loss of sensory hair cells and connected synapses. Growing evidence has revealed that the immune system plays critical roles in shaping cochlear responses to tissue injury and the clearance of damaged cells under pathological conditions such as noise-induced hearing loss (NIHL). However, the underlying mechanisms that regulate this process remain unclear. As a crucial part of the innate immune system, the complement system is widely known to respond to tissue damage and help remove cellular debris. Such functions are yet to be fully explored in the auditory system, especially in the cochlea. Among various complement factors, the activation of complement protein C3 is an essential functional hub of the complement cascade, resulting in the phagocytosis of dead or dying cells. In this study, we sought to investigate whether C3 exists in the cochlea and what roles it might play upon noise injury. To test this, we studied C3 activation using immunohistochemistry in the cochleae of various mouse models that were noise exposed to an octave band noise (8-16 kHz) for two hours at 112 dB SPL. Mice were sacrificed at various post exposure times to examine cochlear pathology. We found damage dependent C3 activity in the organ of Corti in mice after noise exposure (NE), especially in damaged outer hair cell (OHC) area. Specifically, C3 opsonized damaged cellular structures include degenerating OHCs, OHC debris, ribbon synapses, and efferent synaptic boutons, and the temporal dynamics of the opsonization closely resemble the timing of cochlear tissue damages post exposure. Unexpectedly, C3-deficient mice exhibited similar ABR thresholds and OHC counts at baseline as wild type mice, as well as comparable ABR threshold shifts and OHC loss after NE. However, we observed significantly reduced MOC terminal bouton degeneration in C3-deficient mice upon 112 dB SPL noise injury, indicating that C3 does modulate tissue damage and clearance, at least at the MOC terminals. Our results suggest that complement C3 is dynamically activated in the cochlea upon noise injury, which may play significant roles in damage recognition and further immune recruitment during the development of NIHL.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Horizontal saccade bias results from combination of saliency anisotropies and egocentric biases
Saccadic eye movements shift the fovea between objects of interest to build a visual percept. In humans, saccades are predominantly executed along the cardinal axes, particularly in the horizontal direction. It is unknown how this horizontal saccade bias could arise mechanistically, though previous work suggests contributions from neural, image-based, and ocular motor factors. Here we used two publicly available eye movement datasets to first investigate which image features -- spatial frequency, saliency, and structural content -- relate to the horizontal saccade bias. Among the three image features, we found that orientation anisotropies in saliency content best predicted the strength of the horizontal saccade bias. Based on this result, we next implemented a saccade target selection model combining allocentric biases aligned with image orientation and egocentric biases aligned with eye or head orientation, independent of image content. As in prior work, this combination successfully replicated human saccade distributions during free viewing of upright images. When applied to tilted images, the model produced effects of image tilt and saccade size that were correlated with prior empirical findings, though with reduced amplitude, suggesting that current saliency models do not fully capture image effects. Taken together, these results suggest that saccade generation reflects both the allocentric biases present in the structure of natural scenes and the egocentric biases present in the saccade generation system itself. An open question is why the egocentric saccade bias exists, but our results suggest that it is adaptive in response to regularities in the world and our typical upright orientation.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Characterization of iGABASnFR2 for in vivo mesoscale imaging of intracortical GABA dynamics
Most genetically encoded sensors for mesoscopic cortical imaging target excitatory signals, leaving inhibitory dynamics less understood. Capturing large-scale extracellular GABA activity in vivo is essential for understanding how inhibition shapes cortical processing across brain states. To validate the genetically encoded sensor iGABASnFR2 for mesoscale in vivo imaging of extracellular GABA dynamics and to assess how inhibitory activity reorganizes with sensory input, behavioral state, and pharmacological manipulation. We used wide-field imaging in head-fixed mice expressing iGABASnFR2 via retro-orbital AAV injection. Imaging was performed under anesthesia, during quiet wakefulness, natural sleep (NREM, REM), and after administration of the GABA reuptake inhibitor Tiagabine. We analyzed sensory-evoked and spontaneous GABA signals using seed-pixel correlation and spectral analyses. iGABASnFR2 revealed delayed, modality-specific inhibitory responses to sensory stimulation that were stronger and faster in the contralateral cortex. These responses were conserved between anesthesia and quiet wakefulness. During spontaneous activity, GABAergic networks showed state-dependent reorganization: widespread bilateral synchrony was observed in NREM and wakefulness, while REM sleep showed reduced GABA levels and decoupling. Tiagabine elevated baseline GABA, prolonged sensory responses, and enhanced long-range inhibitory connectivity. iGABASnFR2 enables reliable, real-time imaging of extracellular GABA across large cortical areas. These findings demonstrate its utility for tracking state-dependent inhibitory motifs and highlight the dynamic architecture of cortical inhibition in health and disease.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Structural insights into allosteric mechanism of glycine transporter-mediated analgesia
Chronic neuropathic pain, caused by nerve damage or disease, affects 10% of the population with rising incidence. The burden is exacerbated by ineffective treatments and overreliance on opioids. Neuronal glycine transporter, GlyT2, represents a promising target to restore disrupted inhibitory glycinergic neurotransmission in neuropathic pain. However, most GlyT2 inhibitors have not progressed to clinical use because of significant side effects, partly from irreversible inhibition at analgesic doses. Here, we report cryo EM structures of human GlyT2 bound to the potent pseudo irreversible inhibitor ORG25543, a reversible analogue RPI-GLYT2-82, and in substrate-free state. Both inhibitors bind an extracellular allosteric site, locking the transporter in an outward open conformation, whereas the substrate-free GlyT2 adopts an inward-open conformation. We demonstrate that RPI GLYT2 82 has a faster off-rate, providing analgesia in mouse neuropathic pain models, with no observed mechanism-based side-effects or addiction liability. Our data provide a model for allosteric inhibition, enabling structure-based design of new non-opioid analgesics.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Dissociating stimulus encoding and task demands in ECoG responses from human visual cortex
Brain responses to sensory stimuli depend on the specific task performed by the observer. Previously, fMRI measurements in ventral temporal cortex (VTC) showed that BOLD responses to words and faces scale with the difficulty of a categorization task compared to responses observed during a fixation task (Kay and Yeatman, 2017). This scaling of BOLD responses is thought to be driven by the engagement of cognitive functions during image categorization. To understand how these cognitive task demands change dynamically over time and influence neural activity in VTC, we measured electrocorticography (ECoG) data in two human participants during the same experimental tasks. The ECoG high frequency broadband activity (>70 Hz) showed that local neuronal responses increased with image contrast (as expected for sensory encoding) and were scaled by task demands 0.2 seconds after stimulus onset. In contrast, ECoG low frequency activity in the alpha/beta range (8-28 Hz) was insensitive to image contrast and showed larger suppression with increasing task demands. These results indicate that high frequencies in VTC reflect both the encoding of sensory inputs and task demands, similar to prior BOLD response measurements, whereas low frequency oscillations represent task demands, not sensory inputs per se. In line with the interpretation that low frequency oscillations reflect pulsed inhibition, we speculate that suppression of low frequency oscillations amplifies neural activity in VTC in support of visual task demands.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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The influence of similarity, sensitivity and bias on letter identification
Previous studies have demonstrated that bias, sensitivity and similarity between letters are causes of errors in letter identification. However, these factors and their relative contribution in letter identification have not been investigated extensively. Our previous model (noisy template model) was devised to calculate the effect of bias and sensitivity in letter identification task. In the current study, we used the method of constant stimuli to measure letter acuity for Sloan letters at an eccentricity of 7 deg from fixation (temporal visual field). Similar to our previous work, we devised an tested a variety of models to estimate the joint role of bias and sensitivity, but extended our model to also incorporate the similarity between letters. Modelling results showed that bias is the major factor in determining the pattern of total, correct and incorrect responses in letter identification. Furthermore, the joint effect of similarity and bias was found to be higher than the joint effect of either bias and sensitivity or similarity and sensitivity in shaping the pattern of overall responses in letter identification. Incorporating the similarity factor to the noisy template model improved our understanding of the simultaneous contribution of the bias, sensitivity and similarity between letters in the letter identification task.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Differential memory enrichment of cytotoxic CD4 T cells in Parkinson's disease patients reactive to α-synuclein
Parkinson's disease (PD) is a complex neurodegenerative disease with a largely unknown etiology. Although the loss of dopaminergic neurons in the substantia nigra pars compacta is the pathological hallmark of PD, neuroinflammation also plays a fundamental role in PD pathology. We have previously reported that PD patients have increased frequencies of T cell reactive to peptides from -synuclein (-syn). However, not all PD participants respond to -syn. Furthermore, we have previously found that CD4 T cells from PD participants responding to -syn (PD_R) are transcriptionally distinct from PD participants not responding to -syn (PD_NR). To gain further insight into the pathology of PD_R participants, we investigated surface protein expression of 11 proteins whose genes had previously been found to be differentially expressed when comparing PD_R and healthy control participants not responding to -syn (HC_NR). We found that Cadherin EGF LAG seven-pass G-type receptor 2 (CELSR2) was expressed on a significantly higher proportion of CD4 effector memory T cells (TEM) in PD_R compared to HC_NR. Single-cell RNA sequencing analysis of cells expressing or not expressing CELSR2 revealed that PD_R participants have elevated frequencies of activated TEM subsets and an almost complete loss of cytotoxic TEM cells. Flow cytometry analyses confirmed that Granulysin+ CD4 cytotoxic TEM cells are reduced in PD_R. Taken together, these results provide further insight into the perturbation of T cell subsets in PD_R, and highlights the need for further investigation into the role of Granulysin+ CD4 cytotoxic TEM in PD pathology.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Behavioral deficits and exacerbated hemodynamics during lifespan of a mouse model of late onset Alzheimer's disease expressing humanized APOEϵ4 and Trem2*R47H
Alzheimer's Disease (AD) poses a significant global health challenge, being the most prominent cause of dementia with prevalence increasing as the population ages. While the majority of AD cases are late-onset (LOAD), current animal models predominantly represent the more aggressive, faster progressing early-onset AD (EOAD), limiting their ability in assessing early biomarkers and gaining deeper understanding of LOAD progression. This study explores a promising translatable model, the APOE4.TREM2 mouse, which combines the APOE4 allele and the Trem2 p.R47H mutation, both linked to increased AD risk in the human population. We performed behavioral phenotyping and measured hemodynamics in dorsal olfactory bulbs (dOB) during odor stimulation of the APOE4.TREM2 mouse line. Experimental evidence of olfactory dysfunction prior to clinical symptoms suggests the opportunity of utilizing smell testing and fMRI as tools for screening of AD, both for preclinical and clinical studies. Here we assess and confirm the translatability of the APOE4.TREM2 mouse LOAD model, reporting exacerbated anxiety, deficits in odor-based foraging and spatial memory, and exacerbated odor-evoked dOB intrinsic responses in an age-dependent manner.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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T cell responses towards PINK1 and α-synuclein are elevated in prodromal Parkinson's disease
A role of the immune system in Parkinson's disease (PD) progression has long been suspected due to the increased frequency of activated glial cells and infiltrating T cells into the substantia nigra. It was previously reported that PD donors have increased T cell responses towards PINK1 and -synuclein (-syn), two Lewy body-associated proteins. Further, T cell reactivity towards -syn was highest closer to disease onset, highlighting that autoreactive T cells might play a role in PD pathogenesis. However, whether T cell autoreactivity is present during prodromal PD is unknown. Here, we investigated T cell responses towards PINK1 and -syn in donors at high risk of developing PD (i.e. prodromal PD: genetic risk, hyposmia, and or REM sleep behavior disorder), in comparison to PD and healthy control donors. T cell reactivity to these two autoantigens was detected in prodromal PD at levels comparable to those detected in individuals with clinically diagnosed PD. Aligned with the increased incidence of PD in males, we found that males with PD, but not females, had elevated T cell reactivity compared to healthy controls. However, among prodromal PD donors, males and females had elevated T cell responses. These differing trends in reactivity highlights the need for further studies of the impact of biological sex on neuroinflammation and PD progression.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of Fragile X mice and identifies EPAC2 as a therapeutic target.
Symptoms of Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell type specific mRNA sequencing to profile molecular alterations of cortical excitatory and inhibitory neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. Differentially expressed genes (DEG) were largely upregulated in Camk2a expressing excitatory neurons but downregulated in Pvalb-expressing inhibitory neurons, and the underlying signaling pathways were often altered in opposite directions. Among the 184 DEGs that were concordantly dysregulated across both cell types, only Rapgef4 (Epac2) was also an FMRP target, an ASD risk gene and brain enriched. EPAC2 has been implicated in synaptic maturation and plasticity. Systemic administration of an EPAC2 antagonist restored cortical circuit function in Fmr1 KO mice and ameliorated sensory behavioral phenotypes. EPAC2 is a potential target for therapy in FXS.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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The C. elegans gustatory receptor homolog LITE-1 is a chemoreceptor required for diacetyl avoidance
The nematode C. elegans does not have eyes but can respond to aversive UV and blue light stimulation and even distinguish colours. The gustatory receptor homolog LITE-1 was identified in forward genetic screens for worms that failed to respond to blue light stimulation. When LITE-1 is expressed in body-wall muscles, it causes contraction in response to blue light suggesting that LITE-1 is both necessary and sufficient for blue light response. Here we show that in addition to light avoidance, LITE-1 is also required for worms' avoidance of high concentrations of diacetyl, an odorant that is attractive at low concentrations. Like blue light, diacetyl causes muscle contraction in transgenic worms engineered to express LITE-1 in body-wall muscles. These data are consistent with a direct chemoreceptor function for LITE-1 which would make it a multimodal sensor of aversive stimuli.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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FGF21 signals through KLB-expressing glutamatergic neurons in the hindbrain to mediate the effects of dietary protein restriction
Animals adaptively respond to protein restriction by altering both behavior and metabolism. Previous work demonstrated that the metabolic hormone FGF21 acted in the brain to coordinate these adaptive responses, but the exact site of action remains unclear. Here, we identify a discrete population of glutamatergic, Klb-expressing neurons in the nucleus of the solitary tract (NTS), demonstrating that these neurons are key to mediating FGF21 action during protein restriction. Using a novel Klb-Flp mouse line combined with intersectional genetics, we demonstrate that these neurons are directly activated by FGF21. While previous work implicated the SCN, PVN, and VMH in FGF21 action, we find that these areas do not impact the response to protein restriction. Instead, selective ablation of NTS-KLB neurons prevents metabolic adaptations to protein restriction (food intake, food choice, and energy expenditure), while their chemogenetic activation is sufficient to drive these responses. These findings establish NTS-KLB neurons as a critical node for detecting protein status and coordinating whole-body metabolic responses, providing new insight into how the brain monitors and maintains protein homeostasis.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Aperiodic neural timescales in prefrontal cortex dilate with increased task abstraction
Navigating everyday environments requires that the brain perform information processing at multiple different timescales. For example, while watching a movie we use sensory information from every video frame to construct the current movie scene, which itself is continuously integrated into the narrative arc of the film. This critical function is supported by sensory inputs propagating from dynamic sensory cortices to association cortices, where neural activity remains more stable over time. The hierarchical organization of cortex is therefore reflected in a gradient of neural timescales. While this propagation of inputs up the cortical hierarchy is facilitated by both rhythmic (oscillatory) and non-rhythmic (aperiodic) neural activity, traditional measures of oscillations are often confounded by the influence of aperiodic signals. The reverse is also true: traditional measures of aperiodic neural timescales are influenced by oscillations. This makes it difficult to distinguish between oscillatory and timescale effects in cognition. Here, we analyzed electroencephalography (EEG) data from participants performing a cognitive control task that manipulated the amount of task-relevant contextual information, called task abstraction. Critically, we separated aperiodic neural timescales from the confounding influence of oscillatory power. We hypothesized that neural timescales would increase during the task, and more so in high-abstraction conditions. We found that task abstraction dilated the aperiodic neural timescale, as estimated from the autocorrelation function, over prefrontal cortical regions. Our findings suggests that neural timescales are a dynamic feature of the cerebral cortex that change to meet task demands.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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TDP-43 toxic gain of function links ALS/FTLD-TDP and Alzheimer's Disease through splicing
Loss of nuclear TDP-43 splicing activity is a common feature across neurodegenerative diseases, but its relevance to Alzheimer's disease (AD) remains unclear. Here, we show that TDP-43 pathology in AD is broadly associated with splicing abnormalities, including aberrant splicing of amyloid precursor protein (APP). We demonstrate that TDP-43 drives the formation of elongated APP isoforms, APP751 and APP770. Thus, TDP-43 dysregulation disrupts APP695/751/770 alternative splicing across ALS/FTLD-TDP and AD, providing a compelling mechanism for a 37-year-old observation of APP isoform dysregulation. We further establish a mechanistic link between TDP-43 pathology, APP splicing, and A{beta} pathology. Unexpectedly, this effect is mediated by a toxic gain of cytoplasmic TDP-43 function, rather than loss of its nuclear role. Using proximity proteomics and base editing in human iPSC-derived neurons, we show that TDP-43 pathology causes cytoplasmic co-sequestration of splicing regulators SCAF11, SRSF5, and TIAL1, which are involved in APP mis-splicing, but not in the regulation of other TDP-43 targets such as STMN2 or UNC13A. Together, our findings suggest that TDP-43-mediated splicing dysfunction upstream of APP contributes to the pathogenesis of seemingly disparate neurodegenerative diseases, uniting AD and ALS/FTLD-TDP through a shared molecular mechanism.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Temporal Synchronization Analysis: A Model-Free Method for Detecting Robust and Nonlinear Brain Activation in fMRI Data
The sluggishness of the fMRI blood oxygenation level dependent (BOLD) signal has motivated the use of block or trial-based experimental designs that rely on the assumption of linearity, typically modeled using the General Linear Model (GLM). But many non-sensory brain regions and subcortical areas do not correspond to such linearities. We introduce a model-free estimation method called Temporal Synchronization Analysis (TSA) which detects significant brain activations across trials and subjects at an individual time point. We validate it across multiple cognitive tasks (combined n=1600). In constrained task stimuli like visual checkerboard paradigms, we discovered novel nonlinearities not reported previously. In model-free task paradigms like listening to naturalistic auditory stimuli, TSA can detect unique stimuli linked quasi-temporal activations across default mode and language networks. Our user-friendly Python toolkit enables cognitive neuroscience researchers to identify stable and robust brain activation across various cognitive paradigms that are challenging to model with current methods.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Identifying Networks within an fMRI Multivariate Searchlight Analysis
There is great interest in understanding how different brain regions represent information across space and time. Information-based searchlight analyses systematically examine the information encoded within clusters of functional magnetic resonance imaging (fMRI) voxels across the brain. Significant searchlights contain information that can be used to decode conditions of interest, but significant discriminability can be achieved in a variety of ways. We have developed and report on a new analysis method that can identify sub-networks of searchlights. Notably, unlike methods that collapse trials by condition, such as Representational Similarity Analysis, our method groups searchlights based on them having similar temporal changes in information. We present this method and apply it to fMRI data collected as participants viewed words, faces, shapes, and numbers. After running a searchlight analysis with a 4-way Gaussian Naive Bayes (GNB) classifier, the accuracy vector was submitted to a multi-subject Independent Component Analysis (ICA) to group searchlights based on their decoding timeseries. The ICA identified seven components (sub-networks) of searchlights. These networks identified sets of brain areas that have been commonly associated with the processing of faces, words, shapes and numbers. For instance, two of the components drew strongly on the face-processing network, including fusiform cortex. Switching the classification scheme to faces versus non-faces reconfigured the observed network to reflected face-related systems. These results demonstrate that this method can divide searchlight maps into meaningful components.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Lipid Mediated Formation of Antiparallel Aggregates in Cerebral Amyloid Angiopathy
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder marked by amyloid-{beta} (A{beta}) deposition in blood vessel walls, leading to hemorrhage and recurring stroke. Despite significant overlap with Alzheimer's disease (AD) through shared A{beta} pathology, the specific structural characteristics of A{beta} aggregates in CAA and their variations between stages of disease severity are yet to be fully understood. Traditional approaches relying on brain-derived fibrils can potentially overlook the polymorphic heterogeneity and chemical associations within vascular amyloids. This study utilizes sub-diffraction, label-free mid-infrared photothermal (MIP) spectroscopic imaging to directly probe the chemical structure and heterogeneity of vascular amyloid aggregates within human brain tissues across different CAA stages. Our results demonstrate a clear increase in {beta}-sheet content within vascular A{beta} deposits corresponding to disease progression. Crucially, we identify a significant presence of antiparallel {beta}-sheet structures, particularly prevalent in moderate/severe CAA. The abundance of antiparallel structures correlates strongly with co-localized lipids, implicating a lipid-mediated aggregation mechanism. We substantiate the ex-vivo observations using nanoscale AFM-IR spectroscopy and demonstrate that A{beta}40 aggregated in vitro with brain-derived lipids adopts antiparallel structural distributions mirroring those found in CAA vascular lesions. This work provides critical insights into the structural distributions of A{beta} aggregates in CAA, highlighting the presence of polymorphs typically associated with transient intermediates, which may lead to alternate mechanisms for neurotoxicity.in bioRxiv: Neuroscience on 2025-04-24 00:00:00 UTC.
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Investigation of hepatitis B virus mutations associated with immune escape and drug resistance in human immunodeficiency virus-infected patients [version 3; peer review: 1 approved with reservations, 1 not approved]
Background Co-infection of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) has an impact on high HBV replication and progression to liver cancer. These may lead to cross-resistance of drugs due to natural mutations or therapeutic pressure. These require continuous monitoring of HBV variants for better diagnosis and treatment strategies. Methods Convenience sampling was used to collect fifty archival sera from Inkosi Albert Luthuli Central Hospital. Sera were subjected to HBsAg screening using ELISA, DNA extraction, PCR amplification, Sanger sequencing, genotype prediction and mutation analysis. Results Of the 50 samples, 86% (N= 43/50) were HBsAg positive; 82% (N=41/50) PCR positive with 92% (N=38/41) sequenced and only 26 sequences were subjected to molecular characterization. The HBV sequences showed similarity to genotype A (73% [N=19/26]), genotypes G (5% [N=3/26]) and genotype c (15% [N=4/26]). Prevalence of the mutations in the surface region was (47% [N=18/38]); including diagnostic failure (K122R and T143S) and immune escape mutations (P127T, G145R, S207N, Y200T, E164D, Y206H and L209V). The mutations in the RT were at (36% [N=14/38]) with drug resistance mutations (DRM) at (50% [7/14]). Mutations showed resistance to lamivudine (LMV) at (35% [5/14]), telbivudine (LdT) at (29% [4/14]), (14% [2/14]) for entecavir (ETV) and (21% [3/14]) for adefovir (ADV). One sample had a combination of L180M, M204V, S202K, and M250I mutations. Conclusions Our findings highlight the prevalence of HBV genotype A in HIV-infected patients in South Africa. The study provides evidence of mutations linked to immune evasion and drug resistance; this infers that these mutations may have clinical implications for the diagnosis and treatment of HBV in HBV/HIV co-infected individuals. Further in vitro studies must be conducted to explore the impact of the identified mutation on the surface protein expression during diagnosis; phenotype impact of the mutant virus towards the antiviral drugs.in F1000Research on 2025-04-23 16:32:27 UTC.
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in Journal of Neuroscience on 2025-04-23 16:30:27 UTC.
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