Biology subjects

Wang, M.

Publications and source records attributed to Wang, M..

At least 271 records · Page 15Linked to original sources

bioRxiv2025

MS/MS Mass Spectrometry Filtering Tree for Bile Acid Isomer Annotation.

Bile acids are essential steroids regulating immunity, nutrient absorption, insulin, appetite, and body temperature. Their structural diversity is vast, but due to spectral similarities, MS/MS spectral matching often fails to resolve isomers. This study introduces a proof-of-concept workflow using a mass spectrometry query language filtering tree that distinguishes isomeric bile acids in untargeted LC-MS/MS data. Its application revealed a deoxycholyl-2-aminophenol amidate linked to whole grain consumption.

bioinformatics↗

bioRxiv2025

Automated Discovery of Therapeutic Biomaterial for Renally Impaired Hyperuricemia Patients by Natural Language Processing and Machine Learning

The exponential growth of scientific publications presents opportunities for researchers to identify valuable knowledge, especially in the highly interdisciplinary field --- biomaterials, where exploiting possible connections between unmet clinical needs and materials properties from literatures is crucial. However, with traditional literature reading, it is extremely challenging to marry unmet clinical needs with existing materials reported for different applications or other purposes. Here, to provide a not-renally cleared therapeutics for renally impaired hyperuricemia patients, we designed a multi-tiered framework MatWISE that fuses state-of-the-art natural language processing, semantic relationship mapping, and machine learning to automate the complex process of material discovery from a sea of scientific literatures published until December of 2022, and successfully identified and optimized {delta}-MnO2 into an orally administered, nonabsorbable uric acid (UA) lowering biomaterial. {delta}-MnO2 had superior serum and urine UA-lowering effect in three hyperuricemia mouse models, by comparing with a standard of care drug. {delta}-MnO2 is highly promising to serve as a safe and effective UA-lowering drug for renally impaired hyperuricemia patients. We demonstrated a new research paradigm for biomaterials that combining state-of-the-art machine learning techniques and a handful of experiments to discover a translationally relevant material from the massive existing research, for an unmet clinical need.

biochemistry↗

bioRxiv2025

Inhibition of Posterior Thalamic Nuclei Attenuates CGRP-induced Migraine-like Behavior in Mice

ObjectiveTo determine whether induction of migraine-like symptoms in mice by calcitonin gene-related peptide (CGRP) requires activation of the posterior thalamic nuclei (PoT) in the brain.BackgroundPrevious research found that both optical activation of the PoT and injection of CGRP into the PoT are sufficient to induce light aversive behavior in mice. The PoT is well known as a sensory integration center of light and pain signals in the brain. However, whether this region is required for touch hypersensitivity and light aversion following peripheral administration of CGRP was not known.MethodsThe PoT was injected in two strains of mice, inbred C57BL/6J and outbred CD-1, with viral vectors expressing inhibitory chemogenetic Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). The inhibitory DREADDs were activated by systemic intraperitoneal (ip) injection of two designer drugs, clozapine N-oxide (CNO) and DREADD agonist compound 21 (C21). We used ip injection of CGRP to induce migraine-like phenotypes and tested whether we could rescue these phenotypes by bilateral chemogenetic inhibition of the PoT. The light/dark assay was used to measure light aversive behavior (a surrogate for photophobia) and the plantar von Frey assay to measure hindpaw touch sensitivity (a surrogate for extracephalic allodynia).ResultsWe successfully induced light aversive and hindpaw touch hypersensitivity phenotypes in mice using ip injections of CGRP. Activation of the inhibitory DREADDs in the PoT using ip CNO (5 mg/kg) was sufficient to partially rescue the touch hypersensitivity phenotype, but with off target effects in the control mice. Lowering the CNO dose to 1 mg/kg alleviated off target effects but was insufficient to rescue the touch hypersensitivity phenotype. On the other hand, C21 (1 mg/kg) fully rescued the touch hypersensitivity phenotype without any off target effects. Treatment with C21 also partially rescued the light aversion phenotype. These results were consistent across both C57BL/6J and CD-1 mouse strains.ConclusionInhibition of the PoT fully rescues CGRP-induced touch hypersensitivity and partially rescues light aversion in mice, indicating that the PoT is necessary for touch hypersensitivity and partially necessary for light aversive behaviors. These data suggest the PoT is part of a central network that receives peripheral CGRP-induced signals and thus could be harnessed for future targeted therapeutics for migraine.Plain language summaryThe posterior thalamus is a central brain region that contributes to migraine pathophysiology when stimulated. In this study, we asked if inhibition of this brain region could alleviate migraine-like phenotypes in mice. We found that inhibition of the posterior thalamus fully rescues touch hypersensitivity and partially rescues light aversive behavior, suggesting that the posterior thalamus is necessary for migraine pathophysiology and could offer a potential therapeutic target for migraine.

neuroscience↗

bioRxiv2025

Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation

Structured AbstractO_ST_ABSBackgroundC_ST_ABSAPPE693Q ("Dutch") transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of A{beta} (NFA-A{beta}) and APP -carboxy terminal fragments. NFA-A{beta} correlates with synaptic loss and memory deficits more closely than does fibrillar A{beta}. MethodsWe assessed the physiological, transcriptomic, ultrastructural, histological, and metabolic changes associated with the accumulation of NFA of Dutch A{beta} in brains of APPE693Q mice. ResultsAging-related accumulation of NFA-A{beta} in APPE693Q mice was revealed by A11 immunohistochemistry and cyclic D,L--peptide-FITC microscopy. Presynaptic termini of APPE693Q mice developed physiological abnormalities in post-tetanic potentiation, synaptic fatigue, synaptic vesicle replenishment, and an aging-related reduction in mitochondrial complex I activity. Single-cell RNA sequencing showed that excitatory neurons exhibited an altered transcriptomic profile involving "protein translation" and "oxidative phosphorylation". DiscussionAccumulation of NFA-A{beta} alters neuronal metabolism but does not activate inflammation. Depletion of all forms of A{beta} may be required to eliminate A{beta} toxicity with anti-amyloid antibodies.

neuroscience↗

bioRxiv2025

PLXNB1 and other signaling drives a pathologic astrocyte state contributing to cognitive decline in Alzheimer's Disease

Alzheimers disease (AD) is marked by the coordinated emergence of disease-associated cell states across multiple cell types. Here, we first performed a meta-analysis of single-nucleus transcriptomic (snRNAseq) data from 869 brains of diverse decedents, confirming the critical role of an SLC38A2highSMTNhighCACNA1Dhighastrocyte subset, Astrocyte 10 (Ast10), in AD and aging-related cognitive decline. We then investigated the signaling drivers of Ast10s emergence in the aging brain, focusing on interactions among microglial and astrocytic subsets. Analysis of the snRNAseq data prioritized a set of ligands and receptors that are robustly predictive of Ast10 proportions across participants, and we confirm our predictions in multiple studies. Independent validation with spatial transcriptomics reveals striking colocalization of these prioritized ligands with the Ast10 signature in AD brain tissue, but not with other astrocytic states. Genetic ablation of a top receptor PLXNB1 in murine and human iPSC-derived astrocytes decreased the Ast10 signature, confirming its regulatory role. Finally, we find that Ast10 may contribute to cognitive decline through synaptic loss and is associated with cognitive decline independent of AD. Thus, Ast10 and its regulators are potential points of convergence for multiple neurodegenerative mechanisms and may be promising targets for therapeutic development to preserve cognitive function.

neuroscience↗

bioRxiv2025

A distinctive subset of microglia positioned at the paraventricular zone are dedicated to cleaning the cerebrospinal fluid

The interconnected ventricles in the central nervous system are filled with cerebrospinal fluid (CSF) which serves multifaceted roles including bring away metabolic wastes. However, whether there is an inherent "dislodging" mechanism, in addition to CSF drainage and reabsorption, at play for the removal of microparticles in the CSF is unclear. In this study, we identified a subset of microglia distributed in close proximity to the ependymal wall of ventricles. They differed from parenchymal microglia in morphology, behaviors and transcriptomes. In particular, the paraventricular microglia extended transependymal dendrites into the lumen of ventricles and were proficient in sequestering and phagocytosing intraventricular exogenous particles when present. A specific removal of the paraventricular microglia led to an acute ventriculomegaly due to an increased colloid osmotic pressure in the CSF resulting from protein accumulation. Thus, we identified the paraventricular microglia as specific guardians in monitoring and cleaning the CSF.

immunology↗

bioRxiv2025

Triploidy is prominent in the duckweed Lemna minor complex

Duckweeds (Lemnaceae Martinov) are aquatic monocotyledonous flowering plants comprising five genera and 35 recognized species, known for being the smallest and fastest-growing flowering plants on Earth. Many species are morphologically indistinguishable due to their highly reduced structures, yet molecular evidence suggests that visually similar clones may represent distinct species or hybrids. For example, clonal accessions of the globally distributed Lemna minor in the Landolt Duckweed Collection exhibit genome size variations of several hundred megabases (Mb), raising questions about their taxonomic classification and evolutionary origins. We analyzed 58 presumed L. minor clones to resolve these relationships using a comprehensive suite of methods, including whole-genome sequencing (WGS), flow-cytometric genome size measurements, molecular markers, chromosome counting, and genomic in situ hybridization (GISH). Our findings reveal extensive genome plasticity within the "Lemna minor complex," identifying diploid and triploid L. minor clones, as well as di-haploid and triploid interspecific hybrids called L. x japonica (L. minor x L. turionifera), L. x mediterranea (L. minor x L. gibba), and a novel African-clade distinct from known L. minor lineages. Triploidy was prevalent, occurring in 29% of the clones, and was associated with enhanced growth under optimal conditions but reduced performance under high light and temperature. These findings highlight the widespread role of triploidy, cryptic species, and hybridization in the L. minor complex, emphasizing the importance of multiple approaches for accurately classifying duckweed species and understanding their evolutionary trajectories.

plant biology↗

bioRxiv2025

China Autism Brain Imaging Consortium: Charting Brain Growth in Chinese Children with Autism

Autism Spectrum Disorder (ASD) is a lifelong neurodevelopmental condition characterized by atypical brain growth. While advances in neuroimaging and openly sharing large-sample datasets such as the Autism Brain Imaging Data Exchange (ABIDE) have improved understanding of ASD, most studies focus on adolescents and adults, with early brain development-critical for diagnosis and intervention-remaining underexplored. Existing research predominantly involves Western samples, offering limited insight and generalizability into non-Caucasian populations. We introduce the China Autism Brain Imaging Consortium (CABIC) (https://php.bdnilab.com/resources/), a grassroots effort by researchers across the country to aggregate previously collected multi-site structural MRI datasets and phenotypic information from 1,451 autistic children and 1,119 typically developing children, covering an age range from early childhood to school age (1.0 - 12.92 years). Here, we present this resource and depict brain growth charts to push forward a more comprehensive understanding of the brain development in Chinese autism children. We constructed brain growth charts that reveal a developmental shift in autistic children, transitioning from early overgrowth to delayed maturation. Regional analyses identified distinct atypical trajectories across specific brain regions. Individual deviation scores quantified inter-subject variability, characterizing the heterogeneity of brain development in ASD. Comparative analyses between CABIC and ABIDE highlighted differences potentially attributable to ethnicity and culture, advancing our understanding of cross-population neurodevelopmental diversity. CABIC MRI datasets will be shared publicly to foster investigation of the potential neural mechanisms underlying ASD in non-Western populations and support efforts toward precision medicine for autistic individuals across diverse backgrounds.

neuroscience↗

bioRxiv2025

Spatial distribution of the proteome in human body and cancers

A comprehensive spatial distribution of the proteome in human body and cancers is fundamental for understanding human biology and diseases including cancers. Here, we present an anatomically resolved human proteome derived from 1781 benign and malignant samples from 58 major tissue types encompassing 251 specific tissues and 25 carcinomas. Based on a spectral library covering over 75% of the human protein-coding genes with 208 understudied and 82 missing proteins characterized, we quantified over 13,000 proteins in these samples using data-independent acquisition proteomics. This data resource presents the so far most comprehensive quantitative proteomic landscape of human tissues and common carcinomas. It allows systematic evaluation of tissue-specific drug responses, identification of drug candidates that may be repurposed as antineoplastics, and discovery of novel targets for anticancer therapy. This resource, available as an online knowledgebase, refines our knowledge of spatial distribution of the human proteome and tumor-specific protein modulation.

systems biology↗

bioRxiv2025

Capicua refines mossy fiber-CA3 axon targeting in the late postnatal hippocampus

Proper brain wiring relies on the precise distribution of axonal projections to specific subcellular domains of their target neurons. These spatially confined connections establish the anatomical foundation for neural circuit assembly. The mossy fiber (MF)-CA3 pathway in the hippocampus is an excellent system to study the mechanisms underlying lamina-specific connectivity. In rodents, MF projections develop postnatally and reach their mature configuration by the end of the second postnatal week. MF axons synapse on the proximal segments of the dendrites but avoid the somas of CA3 pyramidal neurons. As dentate gyrus granule neurons are continuously generated and integrated into the existing hippocampal circuit throughout the postnatal period and adulthood, the mechanisms that guide MF axons to achieve lamina-specific targeting of these later-born granule neurons remain unclear. Here, we show that deletion of the neurodevelopmental disorder-associated protein capicua (CIC) results in abnormal MF targeting in the mouse hippocampus. Notably, this defect emerges after the second postnatal week and persists into adulthood, distinguishing it from classical MF guidance defects, which typically manifest during the first postnatal week. We also demonstrate that this miswiring is due to CIC loss in dentate gyrus granule neurons rather than CA3 pyramidal neurons. Single-nucleus transcriptomics and trajectory analysis reveal a loss of a mature granule neuron subtype and dysregulation of axon guidance genes that are normally downregulated as granule neurons mature. Our findings uncover a previously unrecognized role for CIC in hippocampus development and offer insights into the regulation of lamina-specific MF connectivity in the postnatal brain.

neuroscience↗

bioRxiv2025

Transcriptomic and spatial GABAergic neuron subtypes in zona incerta mediate distinct innate behaviors

Understanding the anatomical connection and behaviors of transcriptomic neuron subtypes is critical to delineating cell type-specific functions in the brain. Here we integrated single-nucleus transcriptomic sequencing, in vivo circuit mapping, optogenetic and chemogenetic approaches to dissect the molecular identity and function of heterogeneous GABAergic neuron populations in the zona incerta (ZI) in mice, a region involved in modulating various behaviors. By microdissecting ZI for transcriptomic and spatial gene expression analyses, our results revealed two non-overlapping Ecel1- and Pde11a-expressing GABAergic neurons with dominant expression in the rostral and medial zona incerta (ZIrEcel1 and ZImPde11a), respectively. The GABAergic projection from ZIrEcel1 to periaqueductal gray mediates self-grooming, while the GABAergic projection from ZImPde11a to the oral part of pontine reticular formation promotes transition from sleep to wakefulness. Together, our results revealed the molecular markers, spatial organization and specific neuronal circuits of two discrete GABAergic projection neuron populations in segregated subregions of the ZI that mediate distinct innate behaviors, advancing our understanding of the functional organization of the brain.

neuroscience↗

bioRxiv2025

SpecImmune accurately genotypes diverse immune-related gene families using long-read data

Polymorphic immune-related genes (HLA, KIR, IG, TCR, and CYP) exhibit significant complexity due to their extensive heterozygosity and inter-loci homology, necessitating specific methods for accurate characterization. We present SpecImmune, the first comprehensive tool leveraging long-read sequencing data to resolve the full spectrum of these immune-related genes. The method adopts an iterative graph-based algorithm for haplotype reconstruction. We validated SpecImmune across 1,019 samples from the 1kGP ONT cohort, 42 PacBio CLR and 9 PacBio HiFi samples from the HGSVC project, and 47 PacBio HiFi and 37 ONT samples from the HPRC project. SpecImmune achieved an accuracy of 98% in HLA typing, which represents a 12% improvement over both SpecHLA and HLA*LA. SpecImmune is the initial method to type multiple CYP loci, as well as the foremost approach to allow precise KIR and germline IG/TCR typing using long reads. Comprehensive genotyping of these loci by SpecImmune unveils a new observation of substantial linkage disequilibrium among HLA, KIR, and CYP loci. The proteins derived from these loci exhibit strong binding affinities, which suggest the origin of the marked linkage disequilibrium. Further, SpecImmune unveils a novel finding of elevated IG/TCR heterozygosity in African populations. Additionally, SpecImmune facilitates the detection of de novo mutations and enables allele-specific drug recommendations.

bioinformatics↗

bioRxiv2025

Increased maize chromosome number by engineered chromosome fission

Activation of synthetic centromeres on chromosome 4 in maize leads to its breakage and formation of trisomic fragments called neochromosomes. A limitation of neochromosomes is their low and unpredictable transmission rates due to trisomy. Here we report that selecting for dicentric recombinants through male crosses uncovers stabilized chromosome 4 fission events which split it into 4a-4b complementary chromosome pairs, where 4a carries a native centromere and 4b a synthetic one. The cells rapidly stabilized chromosome ends by de novo telomere formation and the new centromeres spread among genes without altering their expression. When both 4a and 4b chromosomes were present in a homozygous state, they segregated through meiosis indistinguishably from wild-type, and gave rise to healthy plants with normal seed set. This work leverages synthetic centromeres to engineer chromosome fission, effectively raising the diploid chromosome number of maize from 20 to 22. TEASERUsing synthetic centromeres, we divide one maize chromosome into two chromosomes, and show that both chromosomes are fully functional.

synthetic biology↗

bioRxiv2025

Mental exploration of future choices during immobility theta oscillations

Mental exploration enables flexible evaluation of potential future choices, guiding decision-making without requiring direct real-world iterations. Although the hippocampus is known to be active while imagining the future, the precise mechanisms that support mental exploration of future choices remain unclear. In the hippocampus, the theta rhythm (4-12 Hz) is prevalent during movement and supports memory coding during real-world exploration by organizing neuronal activity patterns into short virtual path segments (theta sequences) around the rats location. We observed these theta-related neural activity patterns during movement in a hippocampus-dependent working memory task and also, unexpectedly, theta oscillations and theta-related neural activity during immobility. Compared to standard theta sequences during movement, theta sequences during immobility differed in that they occurred at a shifted theta phase and preferentially represented remote locations, in particular the next choice in the working memory task. Coding for future locations was also observed during awake sharp wave ripple, but these short-lasting events occurred rarely and were biased toward frequently visited locations. Therefore, our findings suggest that recurring bouts of theta oscillations during immobility, which are also observed in primates and humans, support the cognitive demands of mental exploration in the hippocampal network and facilitate ongoing predictions of future choices.

neuroscience↗

bioRxiv2025

Matrix stiffness induces heritable changes in chromosome numbers, consistent with solid tumor heterogeneity

Solid tumors often have an abundance of collagen-I that stiffens the tissue, and they are invariably driven by mutations that include chromosome losses and gains. These observations are linked here by showing that 3D matrix stiffness induces heritable changes to a cells DNA. We use live-cell chromosome reporters (ChReporters) and hydrogels of tunable stiffness to show mitotic compression, micronuclei counts, ChReporter losses and heterogeneity all increase as functions of stiffness. Increased mistakes occur despite suppressed cell division in stiff matrix and minimal size variation between spheroids. Colonies of ChReporter-negative cells within cancer spheroids align with Luria-Delbrucks seminal theory for heritable mutations, which predicts inter-spheroid variances that exceed Poisson statistics. Suppression of the contractility motor Myosin-II also increases chromosome loss in 3D but not 2D and does not affect spheroid growth - thus clarifying Myosin-IIs putative role as a tumor suppressor. Consistent with experiments, pan-cancer analyses of clinical data associates chromosome losses and gains with collagen-I levels and genetic variation. Stiff extracellular matrix thus drives mechano-evolution of solid tumors as a Darwin-Lamarck process with heterogeneity that complicates therapy.

biophysics↗

bioRxiv2025

Genomic and Transcriptomic Characterization of Carbohydrate-Active Enzymes in the Anaerobic Fungus Neocallimastix cameroonii var. constans

Anaerobic gut fungi effectively degrade lignocellulose in the guts of large herbivores, but there remains a limited number of isolated, publicly available, and sequenced strains that impede our understanding of the role of anaerobic fungi within microbial communities. We isolated and characterized a new fungal isolate, Neocallimastix cameroonii var. constans, providing a transcriptomic and genomic understanding of its ability to degrade diverse carbohydrates. This anaerobic fungal strain was stably cultivated for multiple years in vitro among members of an initial enrichment microbial community derived from goat feces, and it demonstrated the ability to pair with other microbial members, namely archaeal methanogens to produce methane from lignocellulose. Genomic analysis revealed a higher number of predicted carbohydrate-active enzymes encoded in the N. cameroonii var. constans genome compared to most other sequenced anaerobic fungi. The carbohydrate-active enzyme profile for this isolate contained 660 glycoside hydrolases, 160 carbohydrate esterases, 194 glycosyltrasferases, and 85 polysaccharide lyases. Differential gene expression analysis showed the upregulation of thousands of genes (including predicted carbohydrate-active enzymes) when N. cameroonii var. constans was grown on lignocellulose (reed canary grass) compared to less complex substrates, such as cellulose (filter paper), cellobiose, and glucose. AlphaFold was used to predict functions of transcriptionally active yet poorly annotated genes, revealing feruloyl esterases that likely play an important role in lignocellulose degradation by anaerobic fungi. The combination of this strains genomic and transcriptomic characterization, omics-informed structural prediction, and robustness in microbial co-culture make it a well-suited platform to conduct future investigations into bioprocessing and enzyme discovery.

microbiology↗

bioRxiv2025

High-speed mapping of whole-mouse peripheral nerves at subcellular resolution

In contrast to the rapid advancements in mesoscale connectomic mapping of the mammalian brain, similar mapping the peripheral nervous system has remained challenging due to the bodys size and complexity. Here, we present a high-speed blockface volumetric imaging system with an optimized workflow of whole-body clearing, capable of imaging the entire adult mouse at micrometer resolution within 40 hours. Three-dimensional reconstruction of individual spinal fibers in Thy1-EGFP mice reveals distinct morphological features of sensory and motor projections along the ventral and dorsal rami. Immunostaining facilitates body-wide mapping of sympathetic nerves and their branches, highlighting their perivascular patterns in limb muscles, bones, and most visceral organs. Viral tracing elucidates the fine architecture of vagus nerves and individual vagal fibers, revealing unexpected projection routes to various organs. Our approach offers an effective means to achieve a holistic understanding of cellular-level interactions among different systems that underlie body physiology and disease. HighlightsO_LIImaging of whole adult mouse at uniform subcellular resolution within 40 hours C_LIO_LIReconstruction of 191 thoracic spinal neuron projections for Thy1-EGFP mice C_LIO_LIMapping of immunolabeled sympathetic projections and their perivascular patterns C_LIO_LIResolving virus-labeled architecture of vagus nerves and complex single-fiber routes C_LI

neuroscience↗

bioRxiv2025

Meta all the way down: An overview of neuroimaging meta-analyses

Meta-analyses are invaluable tools for navigating the rapidly expanding scientific literature. Given their high value, ensuring the quality of meta-analyses is paramount. We conducted a multifaceted overview, examining each step in a manual neuroimaging meta-analysis on a large scale. We used four novel datasets comprising over 14,000 papers, including fMRI meta-analyses, fMRI studies, studies included in meta-analyses, and studies associated with image data on NeuroVault. Regarding successes, two-thirds of meta-analyses stated that they followed PRISMA guidelines, and 65% included a flowchart describing their inclusion process. We point out several areas for improvement. Pre-registration was fairly rare (20%), and only half listed their exact search strategy. There could be a location bias in which papers are included, and many did not include enough studies to be robust against publication bias (68% of meta analyses have less than 30 studies included). We also offer ideas for future directions. As image based meta-analysis is the gold standard, we have indicated which topics have the most image data available. The potential redundancy of topics can be visualized in our paper, and we recommend future meta-analyses be in conversation with past ones by citing and discussing previous similar work. By addressing these findings, the neuroimaging community can collectively improve the field of neuroimaging meta-analyses.

neuroscience↗