Biology subjects

Huang, Y.-Y.

Publications and source records attributed to Huang, Y.-Y..

10 recordsLinked to original sources

bioRxiv2026

Learning stabilizes temporal activity but not neuronal selectivity in prefrontal cortex

Intelligent behavior requires neural representations to change with new demands while preserving learned structure. The prefrontal cortex is central to this ability, but the mechanisms are unclear. Here, we tracked medial prefrontal neurons for months as mice learned an association task with successive rule switches. Learning progressively stabilized when individual neurons were active during a trial, but not what task variables they responded to. Neurons repeatedly gained, lost, or changed selectivity even after their activity profile had stabilized. We developed Sparse Tensor Component Analysis to show that, rather than reflecting random drift, dynamic single-neuron selectivity arose through rule-dependent recombination of a fixed set of task representations. Thus, learning established a stable temporal scaffold in the prefrontal cortex within which neurons participated flexibly in different representations.

neuroscience↗

bioRxiv2026

Synaptopodin enables directional mechanoadaptation of integrin-based adhesions

The attachment of cells to their substrate through adhesion complexes is fundamental to tissue architecture and function. These adhesions are inherently optimized to resist shear forces parallel to the substrate, yet certain specialized cells must also withstand substantial perpendicular forces. How cells adapt their adhesion machinery to resist forces in different directions has remained unclear. In the kidney, podocytes experience perpendicular forces from pressurized filtrate flow while maintaining attachment to the glomerular basement membrane through integrin-based adhesions. Here we show that synaptopodin converts adhesions from shear-resistant to perpendicular force-resistant structures through coordinated reorganization of the actin cytoskeleton and adhesion complexes. Using an inertial force application system, we demonstrate that synaptopodin triggers force-dependent redistribution of {beta}1-integrin to the cell periphery specifically in response to perpendicular loading, while synaptopodin-deficient cells lack this directional adaptation and detach. This mechanism operates in multiple cell types and is physiologically essential: synaptopodin-null mice subjected to elevated glomerular pressure develop significant proteinuria and podocyte foot process effacement. These findings reveal a molecular basis for directional mechanoadaptation, whereby a single protein enables cells to reconfigure their adhesion architecture in response to the direction of applied force.

biophysics↗

bioRxiv2026

Orthogonal Force Balance Between Contractility and Shear Stress Governs Podocyte Dynamics

Maintenance of tissue barriers under mechanical stress represents a fundamental biological challenge across organ systems. In the kidney, podocyte cells withstand highly variable hemodynamic forces while preserving a tensioned, nanostructured filtration barrier. Dysregulation of this barrier leads to significant pathology, but the mechanical principles underlying homeostasis of cells against flow of filtrates have not yet been identified. Here, we uncover a counterintuitive mechanical homeostasis mechanism whereby podocyte attachment depends on a dynamic balance between external fluid shear stress and internal cellular contractility. Integrated biomechanical modeling and experiment reveal a previously unrecognized mechanosensing circuit that optimizes integrin distribution at foot process peripheries. Our mathematical framework for cell-matrix adhesion stability reveals, surprisingly, that reducing blood pressure can worsen outcomes when cell contractility is impaired, contrary to clinical belief that lowering blood pressure universally benefits cellular adhesion and kidney function. We validated this principle through mouse models with manipulated blood pressure and myosin inhibition, demonstrating that concurrent reduction of both shear stress and contractility worsens podocyte injury and proteinuria. Super-resolution microscopy confirms our predicted integrin redistribution patterns under these mechanical perturbations. These findings establish a fundamental mechanobiological principle applicable beyond nephrology, and suggest potential treatment pathways targeting non-equilibrium steady states.

cell biology↗

bioRxiv2022

Ancient DNA Reveals China as a Historical Genetic Melting Pot in Tiger Evolution

The contrast between the tigers (Panthera tigris) 2-3 My age and extant tigers coalescence approximately 110,000 years ago suggests an ancient demographic bottleneck. Here we collected over 60 extinct specimens across mainland Asia and generated whole genome sequences from a 10,600-year-old Russian Far East (RFE) specimen (RUSA21, 8{xi} coverage), 14 South China tigers (0.1-12{xi}), three Caspian tigers (4-8{xi}), plus 17 new mitogenomes. RUSA21 clustered within modern Northeast Asian phylogroups and partially derived from an extinct Late Pleistocene lineage. While some 8,000-10,000-year-old RFE mitogenomes are basal to all tigers, one 2,000-year-old specimen resembles present Amur tigers. The Caspian tiger likely dispersed from an ancestral Northeast Asian population and experienced gene flow from southern Bengal tigers. Lastly, genome-wide monophyly supported the South China tiger as a distinct subspecies, albeit with mitochondrial paraphyly, hence resolving its longstanding taxonomic controversy. The distribution of mitochondrial haplogroups corroborated by biogeographical modeling suggested Southwest China was a Late Pleistocene refugium for a relic basal lineage. As suitable habitat returned, Eastern China became a genetic melting pot to foster divergent lineages to merge into South China tigers and other subsequent northern subspecies to develop. Genomic information retrieved from ancient tigers hence sheds light on the species full evolutionary history leading to nine modern subspecies and resolves the natural history of surviving tigers.

evolutionary biology↗

bioRxiv2022

Multi-omics integrated analysis reveals a specific phenotype of CD8+ T cell may contribute to immunothromosis via Th17 response in severe and critical COVID-19

T lymphocyte reduction and immunosenescence frequently occur in severe and critical coronavirus disease 2019 (COVID-19) patients, which may cause immunothrombosis and numerous sequelae. This study integrated analyzed multi-omics data from healthy donors, pneumonia, COVID-19 patients (mild & moderate, severe, and critical), and convalescences, including clinical, laboratory test, PBMC bulk RNA-seq, PBMC scRNA-seq and TCR-seq, BAL scRNA-seq, and lung proteome. We revealed that there are certain associations among T lymphocyte reduction, CD8+ T cell senescence, Th17 immune activation, and immunothrombosis. A specific phenotype (S. P.) CD8+ T cells were identified in severe and critical COVID-19 patients in both PBMC and BAL scRNA-seq, which showed highly TCR homology with terminal effector CD8+ T cells and senescent CD8+ T cells. Pseudotime analysis showed that the S. P. CD8+ T cells were located in the transition trajectory from mild to severe disease. Which may be activated by terminal effector CD8+ T cells or senescent CD8+ T cells, thereby promoting Th17 cell differentiation. This phenomenon was absent in healthy donors, mild and moderate COVID-19 patients, or convalescences. Our findings are an important reference for avoiding the conversion of patients with mild to severe diseases and provide insight into the future prevention and control of COVID-19 and its variants.

bioinformatics↗

bioRxiv2021

An ex vivo culture model of kidney podocyte injury reveals mechanosensitive, synaptopodin-templating, sarcomere-like structures.

Chronic kidney diseases are widespread and incurable. The biophysical mechanisms underlying them are unclear, in part because material systems for reconstituting the microenvironment of the relevant kidney cells are limited. A critical question is how kidney podocytes (glomerular epithelial cells) regenerate the foot processes of the filtration apparatus following injury. Recently identified sarcomere-like structures (SLSs) with periodically spaced myosin IIA (a contractile protein) and synaptopodin (an actin-associated protein) appear in injured podocytes in vivo. We hypothesized that SLSs template synaptopodin in the initial stages of recovery, and tested this hypothesis by developing an ex vivo culture system that models both kidney physiology and pathophysiology. SLSs were observed in vitro for the first time as podocytes migrated out of harvested kidney glomeruli onto micropatterns of physiologically relevant proteins. SLSs emerged over two days, and cells formed foot process-like extensions from these periodically spaced proteins. SLS distributions and morphology were sensitive to actomyosin inhibitors, substrate stiffness, and extracellular matrix proteins associated with pathology. These results indicate a role for mechanobiological factors in podocyte recovery from injury, and suggest SLSs as a target for therapeutic intervention.

cell biology↗

bioRxiv2021

Insights into the susceptibility of rice to a floral disease

Crop floral diseases are economically important as they reduce grain yield and quality and even introduce food toxins. Rice false smut has emerged as a serious floral disease producing mycotoxins. However, very little is known on the interaction mechanisms between rice flower and the causal fungus Ustilaginoidea virens. Here we show that a conserved anti-fungal immunity in rice flower is disarmed by U. virens via a secreted protein UvChi1. UvChi1 functioned as an essential virulence factor and directly interacted with the chitin receptor CEBiP and co-receptor CERK1 in rice to disrupt their oligomerizations and subsequent immune responses. Moreover, intraspecific-conserved UvChi1 could target OsCEBiP/OsCERK1 receptor complex in at least 98.5% of 5232 surveyed rice accessions. These results demonstrate that U. virens utilizes a crucial virulence factor to subvert chitin-triggered flower immunity in most rice varieties, providing new insights into the susceptibility of rice to false smut disease. One Sentence SummaryThe fungal pathogen Ustilaginoidea virens disarms chitin-triggered immunity in rice flower via a secreted chitinase.

plant biology↗

bioRxiv2021

Proteasome maturation factor UMP1 confers broad-spectrum disease resistance by modulating H2O2 accumulation in rice

Crops with broad-spectrum resistance (BSR) to diseases are highly desirable in agricultural production. Identification of BSR loci and dissection of the underlying mechanisms are fundamental for crop resistance breeding. Here, we describe the identification and characterization of a rice UMP1 allele, which confers race-nonspecific BSR against blast pathogen Magnaporthe oryzae. OsUMP1 encodes a proteasome maturation factor that contributes to 26S proteasome abundance and activity in rice. Modulation of OsUMP1 expression leads to proteome changes, particularly affects the amounts and activities of H2O2-degrading enzymes. Consequently, H2O2 accumulation and disease resistance are enhanced in OsUMP1-overexpressing rice but reduced in loss-of-function mutants. Elevation of OsUMP1 expression also promotes rice resistance to foliar pathogens Rhizoctonia solani and Xanthomonas oryzae pv. oryzae and a floral pathogen Ustilaginoidea virens without observable yield penalty. These results indicate a BSR pathway linking the proteasome machinery and H2O2 homeostasis, and provide a candidate gene for balancing BSR and yield traits in rice breeding. One Sentence SummaryA natural allele of rice UMP1 promotes resistance to multiple pathogens by boosting H2O2 accumulation.

plant biology↗

bioRxiv2020

FEP-based screening prompts drug repositioning against COVID-19

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global crisis. There is no therapeutic treatment specific for COVID-19. It is highly desirable to identify potential antiviral agents against SARS-CoV-2 from existing drugs available for other diseases and, thus, repurpose them for treatment of COVID-19. In general, a drug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. Here we report a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions and its use in identifying drugs targeting SARS-CoV-2 main protease (Mpro). The accurate FEP-ABFE predictions were based on the use of a new restraint energy distribution (RED) function designed to accelerate the FEP-ABFE calculations and make the practical FEP-ABFE-based virtual screening of the existing drug library possible for the first time. As a result, out of twenty-five drugs predicted, fifteen were confirmed as potent inhibitors of SARS-CoV-2 Mpro. The most potent one is dipyridamole (Ki=0.04 M) which has showed promising therapeutic effects in subsequently conducted clinical studies for treatment of patients with COVID-19. Additionally, hydroxychloroquine (Ki=0.36 M) and chloroquine (Ki=0.56 M) were also found to potently inhibit SARS-CoV-2 Mpro for the first time. We anticipate that the FEP-ABFE prediction-based virtual screening approach will be useful in many other drug repurposing or discovery efforts. Significance StatementDrug repurposing effort for treatment of a new disease, such as COVID-19, usually starts from a virtual screening of existing drugs, followed by experimental validation, but the actual hit rate is generally rather low with traditional computational methods. It has been demonstrated that a new virtual screening approach with accelerated free energy perturbation-based absolute binding free energy (FEP-ABFE) predictions can reach an unprecedently high hit rate, leading to successful identification of 16 potent inhibitors of SARS-CoV-2 main protease (Mpro) from computationally selected 25 drugs under a threshold of Ki = 4 M. The outcomes of this study are valuable for not only drug repurposing to treat COVID-19, but also demonstrating the promising potential of the FEP-ABFE prediction-based virtual screening approach.

biophysics↗

bioRxiv2017

Association of BDNF Val66Met Polymorphism and Brain BDNF levels with Major Depression and Suicide

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depressive disorder (MDD) and suicide. Both are partly caused by early life adversity (ELA) and ELA reduces both BDNF protein and gene expression. This study examines the association of BDNF Val66Met polymorphism and brain BDNF levels with depression and suicide. We hypothesized that both major depression and ELA would be associated with the Met allele and lower brain BDNF levels. Such an association would be consistent with low BDNF mediating the effect of ELA on adulthood suicide and MDD. METHODS: BDNF Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 non-suicides. Additionally, BDNF protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9; BA9), anterior cingulate cortex (ACC; BA24), caudal brainstem and rostral brainstem. The relationships between these measures and major depression, death by suicide and reported childhood adversity were examined. RESULTS: Depressed subjects had an excess of the Met allele and lower BDNF levels in ACC and caudal brainstem compared with non-depressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower BDNF levels in ACC were found in subjects who had been exposed to early life adversity and/or died by suicide compared to nonsuicide decedents and no reported childhood adversity. CONCLUSIONS: This study provides further evidence for low BDNF in major depression related to the BDNF met risk allele. Future studies should seek to determine how altered BDNF expression contributes to MDD and suicide.

neuroscience↗