Biology subjects

Zhou, W.

Publications and source records attributed to Zhou, W..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Regeneration of Sensory Hair Cells and Restoration of Vestibular Function by Notch Inhibition

Sensory hair cell loss in the vestibular organs of the inner ear causes balance disorders which are essentially irreversible due to the lack of hair cell regeneration. Here, we administered a {gamma}-secretase inhibitor to an adult mouse model of vestibular hair cell loss. The treatment regenerated type I and type II hair cells and restored canal and otolith afferent innervation, resulting in a complete recovery of rotational and translational vestibulo-ocular reflexes across all frequencies. Genetic deletion of Notch1 in supporting cells identified Notch1 as the target of the drug. The results demonstrate that a single injection of a {gamma}-secretase inhibitor is a viable therapy for functional restoration of the vestibular system in patients with balance disorders.

neuroscience↗

bioRxiv2024

Rewilding alters mouse epigenetic aging

The aging of mammalian epigenomes fundamentally alters cellular functions, and such changes are the focus of many healthspan and lifespan studies. However, studies of this process typically use mouse models living under standardized laboratory conditions and neglect the impact of variation in social, physical, microbial, and other aspects of the living environment on age-related changes. We examined differences in age-associated methylation changes between traditionally lab-reared and "rewilded" C57BL6/J mice, which lived in an outdoor field environment with enhanced ecological realism. Systematic analysis of age-associated methylation dynamics in the liver indicates a genomic region-conditioned, faster epigenetic aging rate in mice living in the field than those living in the lab, implicating perturbed 3D genome conformation and liver function. Altered epigenetic aging rates were more pronounced in sites that gain methylation with age, including sites enriched for transcription factor binding related to DNA repair. These observations underscore the overlooked role of the social and physical environment in epigenetic aging with implications for both basic and applied aging research.

genomics↗

bioRxiv2024

Contrasting patterns of specificity and transfer in human odor discrimination learning

Practice enhances olfactory performance. However, laboratory studies to date suggest that olfactory learning is largely restricted to the trained odors, posing a significant challenge for training-based rehabilitation therapies for olfactory loss. In this study, we introduce various types of odors to olfactory discrimination training, conducted unilaterally. We demonstrate contrasting patterns of specificity and transfer of learning, independent of adaptation and task difficulty. Individuals trained with odor mixtures of different ratios show long-term perceptual gains that completely transfer to the untrained nostril and effectively generalize to untrained mixtures dissimilar in structure and odor quality from the trained ones. Conversely, those trained with odor enantiomers show no transfer of learning across nostrils or to unrelated enantiomers, replicating our earlier findings (Feng & Zhou, 2019). Our observations indicate that concentration ratio and chirality represent distinct olfactory attributes. Furthermore, discrimination learning occurs at different stages of olfactory processing, depending on which attribute is task-relevant. These findings open up new avenues to enhance the effectiveness of olfactory training.

neuroscience↗

bioRxiv2024

A robust evaluation of TDP-43, poly GP, cellular pathology, and behavior in a AAV-C9ORF72 (G4C2)66 mouse model

The G4C2 hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2 hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66 mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.

neuroscience↗

bioRxiv2024

A systematic evaluation of highly variable gene selection methods for single-cell RNA-sequencing

BackgroundSelecting highly variable features is a crucial step in most analysis pipelines of single-cell RNA-sequencing (scRNA-seq) data. Despite numerous methods proposed in recent years, a systematic understanding of the best solution is still lacking. ResultsHere, we systematically evaluate 47 highly variable gene (HVG) selection methods, consisting of 21 baseline methods developed based on different data transformations and mean-variance adjustment techniques and 26 hybrid methods developed based on mixtures of baseline methods. Across 19 diverse benchmark datasets, 18 objective evaluation criteria per method, and 5,358 analysis settings, we observe that no single baseline method consistently outperforms the others across all datasets and criteria. However, hybrid methods as a group robustly outperform individual baseline methods. Based on these findings, a new HVG selection approach, mixture HVG selection (mixHVG), that incorporates top-ranked features from multiple baseline methods is proposed as a better solution to HVG selection. An open source R package mixhvg is developed to enable convenient use of mixHVG and its integration into users data analysis pipelines. ConclusionOur benchmark study not only provides a systematic comparison of existing methods, leading to a better HVG selection solution, but also creates a pipeline and resource consisting of diverse benchmark data and criteria for evaluating new methods in the future.

bioinformatics↗

bioRxiv2024

Optics-free Spatial Genomics for Mapping Mouse Brain Aging

Spatial transcriptomics has revolutionized our understanding of cellular network dynamics in aging and disease by enabling the mapping of molecular and cellular organization across various anatomical locations. Despite these advances, current methods face significant challenges in throughput and cost, limiting their utility for comprehensive studies. To address these limitations, we introduce IRISeq (Imaging Reconstruction using Indexed Sequencing), a optics-free spatial transcriptomics platform that eliminates the need for predefined capture arrays or extensive imaging, allowing for the rapid and cost-effective processing of multiple tissue sections simultaneously. Its capacity to reconstruct images based solely on sequencing local DNA interactions allows for profiling of tissues without size constraints and across varied resolutions. Applying IRISeq, we examined gene expression and cellular dynamics in thirty brain regions of both adult and aged mice, uncovering region-specific changes in gene expression associated with aging. Further cell type-centric analysis further identified age-related cell subtypes and intricate changes in cell interactions that are distinct to certain spatial niches, emphasizing the unique aspects of aging in different brain regions. The affordability and simplicity of IRISeq position it as a versatile tool for mapping region-specific gene expression and cellular interactions across various biological systems. One Sentence Summary: IRISeq, an innovative optics-free spatial transcriptomics method, uncovers aging-related changes in spatial gene expression and focal cell interactions in brain aging.

genomics↗

bioRxiv2024

Gut microbiome shifts in chronic systolic heart failure are associated with disease severity and clinical improvement

Chronic systolic heart failure (HF) is a prevalent and morbid disease with marked variability in its progression and response to therapies. The gut microbiome may play a role in pathophysiology and progression of chronic HF, but clinical studies investigating relationships between the two are lacking. We analyzed the gut microbiome in a cohort of adults with chronic systolic HF caused by non-ischemic cardiomyopathy (n=59) using multi-omics profiling and, in some cases, longitudinal sampling. We identified microbiome differences compared to healthy subjects (n=50) and associated these differences with host metabolites, inflammatory markers and physiology. We found depletion of the anti-inflammatory probiotic Bifidobacterium and the associated short chain fatty acid producing and formaldehyde detoxifying pathways in the chronic HF cohort. We also discovered HF-specific microbiome-host immunome interactions. In addition to identifying several taxa and microbial pathways broadly associated with HF disease severity, we found significant links between Bifidobacterium and clinical HF improvement over time. Gut microbiome-host multi-omic data integration revealed a close association between Bifidobacterium and circulating metabolites previously implicated in cardiovascular physiology (e.g., malonic acid), thus pointing to potential mechanisms through which Bifidobacterium may affect chronic HF physiology. Our results suggest that Bifidobacterium may serve as a biomarker for chronic HF trajectory as well as suggest potential novel therapeutic interventions strategies.

microbiology↗

bioRxiv2024

PCL-seq: enhanced high-resolution transcriptomic profiling of region of interest in fresh frozen and FFPE tissues

The spatial heterogeneity of gene expression has propelled the development of multiple spatial transcriptomics technologies. Here, we present photocleavage and ligation sequencing (PCL-seq), an method for spatial indexing using a light-controlled DNA labeling strategy on tissue section. PCL-seq uses photocleavable oligonucleotides and ligation adapters to construct transcription profiles of region of interest (ROI), selected by microscopically controlled photo illumination apparatus in tissue sections. Applied to mouse embryos, PCL-seq obtains gene expression matrices that align with spatial locations and competitive data quality, featuring around 1.7x105 UMIs and 8,600 genes (irradiation diameter=100{micro}m). PCL-seq can also apply to formalin fixation and paraffin embedding (FFPE) mouse embryo sections, whereas obtained competitive data output and recovered thousands of differentially enriched transcripts from limb and skeleton. Additionally, PCL-seq can achieve subcellular resolution, which was demonstrated for differential expression between nuclear and cytoplasmic. Thus, PCL-seq provides an accessible workflow for spatial transcriptomic analysis in frozen and FFPE tissue at subcellular resolution.

genomics↗

bioRxiv2024

Additive and partially dominant effects contribute to crop heterosis

Heterosis, or hybrid vigor, describes the superior performance of F1 hybrids relative to their parents. Despite its significant importance in crop breeding, the molecular mechanisms underlying heterosis remain debated, mainly attributable to discrepancies across genotypes, traits, tissues, populations, developmental stages, growth environments, and species. In this study, we systematically identified heterosis-associated genes and metabolites from parental molecular differences in rice and functionally validated three genes for heterosis of seedling length. We incorporated these heterosis-associated molecules into network modules and explained the variance of heterosis. The predominant inheritance patterns of these molecules were additive and partially dominant effects, namely at mid-parent levels or values between mid-parent and parental levels, respectively. These two genetic effects contributed to heterosis of 17 agronomic traits in rice, including grain yield and plant height across developmental stages. They also explained yield heterosis in diverse hybrid populations and distinct growth environments in both rice and maize, as well as biomass heterosis in Arabidopsis. Notably, additive and partially dominant effects were associated with parental genomic variants in rice, and the number of these variants correlated significantly with heterosis of agronomic traits. Furthermore, we demonstrated the significant impact of parental genomic, transcriptomic, and metabolomic variation in phenylpropanoid biosynthesis on heterosis for seedling length/plant height. Unlike classical heterosis models primarily focused on genomic sequence variation, our findings provide quantitative insights from genomic downstream information into the molecular mechanisms of plant heterosis, highlighting their potential for improving breeding efficiency of hybrid crops.

plant biology↗

bioRxiv2024

Stratifying variant deleteriousness and trait-modulating effect under human recent adaptation

Despite advances in annotating and interpreting human genetic variants, existing methods to distinguish deleterious/pathogenic from neutral variants still inadequately capture the nuanced impact of genetic variants on fitness and disease susceptibility. In this study, we introduced a new deep learning framework, the FIND model, by stratifying genetic variants into refined categories based on selection pressures and derived allele frequency. FIND demonstrated superior performance over existing genome-wide methods, delivering enhanced resolution in differentiating trait-modulating alleles from those that are pathogenic or neutral. Access to base-wise informative annotations has unveiled novel features that significantly enhance the model interpretability, and FIND has adeptly delineated evolutionary trends in human accelerated regions. Furthermore, applying FIND to the interpretation of clinical variants demonstrates its substantial potential in reclassifying variants of unknown significance. This work advances our understanding of the genetic underpinnings of human adaptation and disease, providing a new tool to explore the complexities of genetic contributions to health.

genetics↗

bioRxiv2024

Coronary Microvascular Dysfunction is Associated with Augmented Lysosomal Signaling in Hypercholesterolemic Mice

Accumulating evidence indicates that coronary microvascular dysfunction (CMD) caused by hypercholesterolemia can lead to myocardial ischemia, with or without obstructive atherosclerotic coronary artery disease (CAD). However, the molecular pathways associated with compromised coronary microvascular function prior to the development of myocardial ischemic injury remain poorly defined. In this study, we investigated the effects of hypercholesterolemia on the function and integrity of the coronary microcirculation in mice and the underlying mechanisms. Mice were fed with a hypercholesterolemic Paigens diet (PD) for 8 weeks. Echocardiography data showed that PD caused CMD, characterized by significant reductions in coronary blood flow and coronary flow reserve (CFR), but did not affect cardiac remodeling or dysfunction. Immunofluorescence studies revealed that PD-induced CMD was associated with activation of coronary arterioles inflammation and increased myocardial inflammatory cell infiltration. These pathological changes occurred in parallel with the upregulation of lysosomal signaling pathways in endothelial cells (ECs). Treating hypercholesterolemic mice with the cholesterol-lowering drug ezetimibe significantly ameliorated PD-induced adverse effects, including hypercholesterolemia, steatohepatitis, reduced CFR, coronary EC inflammation, and myocardial inflammatory cell infiltration. In cultured mouse cardiac endothelial cells (MCECs), 7-ketocholesterol (7K) increased mitochondrial reactive oxygen species (ROS) and inflammatory responses. Meanwhile, 7K induced the activation of TFEB and lysosomal signaling in MCECs, whereas the lysosome inhibitor bafilomycin A1 blocked 7K-induced TFEB activation and exacerbated 7K-induced inflammation and cell death. Interestingly, ezetimibe synergistically enhanced 7K-induced TFEB activation and attenuated 7K-induced mitochondrial ROS and inflammatory responses in MCECs. These results suggest that CMD can develop and precede detectable cardiac functional or structural changes in the setting of hypercholesterolemia, and that upregulation of TFEB-mediated lysosomal signaling in ECs plays a protective role against CMD.

pharmacology and toxicology↗

bioRxiv2024

Spatial organization of PI3K-PI(3,4,5)P3-AKT signaling by focal adhesions

The class I PI3K-AKT signaling pathway is the master regulator of cell survival, growth, and proliferation, and among the most frequently mutated pathways in cancer. However, where and how the PI3K-AKT signaling is spatially activated and organized in mammalian cells remain poorly understood. Here, we identified focal adhesions (FAs) as the subcellular signaling hubs organizing the activation of PI3K-PI(3,4,5)P3-AKT signaling in mammalian cells. We found that class IA PI3Ks are preferentially and dynamically recruited to FAs for activation, resulting in localized production of the critical signaling lipid PI(3,4,5)P3 around FAs. As the effector protein of PI(3,4,5)P3, AKT molecules are dynamically recruited around FAs for activation. Mechanistically, the spatial recruitment/activation of PI3K-PI(3,4,5)P3-AKT cascade are regulated by the activated FAK. Furthermore, combined inhibition of class I PI3K and FAK results in a more potent inhibitory effect on cancer cells. Thus, our results unveil a growth-factor independent, compartmentalized organization mechanism for PI3K-PI(3,4,5)P3-AKT signaling.

cell biology↗

bioRxiv2024

Dynamic Localization of Leukemia Stem Cells via CXCL12 Regulates Leukemia Progression

The processes that govern leukemia progression and remission are poorly understood. Our research reveals that the CXCL12 gradient, traditionally associated with LSC quiescence and survival, critically determines LSC localization and associated behavior. Specifically, CXCL12 guides LSCs to either the quiescent niche in the metaphysis, characterized by N-cadherin-expressing mesenchymal stromal cells (N-cad+ MSCs), or the proliferative niche in the central marrow (CM), marked by sinusoidal endothelial cells and associated stromal cells. We identified that the CXCL12 gradient is finely regulated by the interplay between dipeptidyl peptidase 4 (DPP4) on LSCs and glypican-3 (GPC3) on N-cad+ MSCs. DPP4 deactivates CXCL12, while GPC3 inhibits DPP4, resulting in a higher CXCL12 concentration in the metaphysis and a lower concentration in the CM. This differential gradient facilitates leukemia progression by promoting LSC quiescence and survival in the metaphysis versus relative proliferation and apoptosis in the CM. Depletion of Dpp4 from LSCs or Cxcl12 from N-cad+ MSCs disrupts this gradient, mobilizing LSCs from the metaphysis to the CM and significantly hindering leukemia development. Our findings redefine the role of CXCL12 in LSC behavior and provide a clearer understanding of leukemia progression. This novel insight highlights the potential for targeted therapeutic strategies that disrupt the CXCL12 gradient to treat minimal residual LSCs, offering a promising path toward a lasting cure for acute myeloid leukemia (AML).

cancer biology↗

bioRxiv2024

CREEPING STEM1 Regulates Directional Auxin Transport for Lodging Resistance in Soybean

Soybean, a staple crop on a global scale, frequently encounters challenges due to lodging under high planting densities, which results in significant yield losses. Despite extensive research, the fundamental genetic mechanisms governing lodging resistance in soybeans remain elusive. In this study, we identify and characterize the Creeping Stem 1 (CS1) gene, which plays a crucial role in conferring lodging resistance in soybeans. The CS1 gene encodes a HEAT-repeat protein that modulates hypocotyl gravitropism by regulating amyloplast sedimentation. Functional analysis reveals that the loss of CS1 activity disrupts polar auxin transport, vascular bundle development, and the biosynthesis of cellulose and lignin, ultimately leading to premature lodging and aberrant root development. Conversely, increasing CS1 expression significantly enhances lodging resistance and improves yield under conditions of high planting density. Our findings shed light on the genetic mechanisms that underlie lodging resistance in soybeans and highlight the potential of CS1 as a valuable target for genetic engineering to improve crop lodging resistance and yield.

plant biology↗

bioRxiv2024

Proteasome inhibition induces DNA methylation alteration by attenuating the synthesis of DNA methyltransferase 1 and 3B in colorectal cancer

Proteasome is an essential organelle in guarding cellular protein homeostasis. Here, we report that inhibition of proteasome leads to alterations in DNA methylation patterns in colorectal cancer (CRC) by surpressing the synthesis of DNA methyltransferases (DNMTs). We found that treating CRC cells with proteasome inhibitors results in attenuated translation of DNMT1 and DNMT3B, mediated by the inactivation of AKT and mammalian target of rapamycin (mTOR), which is dependent on the accumulation of p300, an acetyltransferase that inhibits AKT through acetylation modification. Furthermore, we demonstrated that downregulation of DNMT1 and DNMT3B confers protection against proteasome inhibitor treatment, potentially through reprogramming the transcriptome of CRC cells, highlighting the significant role of DNMTs in response to disruptions in protein homeostasis. Interestingly, the proteasome inhibitor-induced downregulation of DNMT1 and DNMT3B appears to be CRC specific, notwithstanding the underlying mechanism remains unclear. Altogether, our findings reveal an epigenetic effect of proteasome on DNA methylation in CRC through its regulation of DNA methyltransferase synthesis.

cancer biology↗

bioRxiv2024

Transformer-based modeling of Clonal Selection and Expression Dynamics (TraCSED) reveals resistance signatures in breast cancer

Understanding transcriptional heterogeneity in cancer cells and its implication for treatment response is critical to identify how resistance occurs and may be targeted. Such heterogeneity can be captured by in vitro studies through clonal barcoding methods. We present TraCSED (Transformer-based modeling of Clonal Selection and Expression Dynamics), a dynamic deep learning approach for modeling clonal selection. Using single-cell gene expression and the fitness of barcoded clones, TraCSED identifies interpretable gene programs and the timepoints at which they are associated with clonal selection. When applied to cells treated with either giredestrant, an estrogen receptor (ER) antagonist and degrader, or palbociclib, a CDK4/6 inhibitor, time-dependent resistance pathways are revealed. For example, ER activity is associated with positive selection around day four under palbociclib treatment and this adaptive response can be suppressed by combining the drugs. Yet, in the combination treatment, one clone still emerged. Clustering based on partial least squares regression found that high baseline expression of both SNHG25 and SNCG genes was the primary marker of positive selection to co-treatment and thus potentially associated with innate resistance - an aspect that traditional differential analysis methods missed. In conclusion, TraCSED enables associating pathways with phenotypes in a time-dependent manner from scRNA-seq data.

cancer biology↗

bioRxiv2024

Genotype-environment-driven dysbiosis in the skin microbiome of ichthyosis

Monogenic skin disorders such as ichthyosis introduce multiple sources of disturbance to the skin, including the direct biochemical consequences of the genotype, the phenotypic changes in skin physiology, and an altered skin microbiome. The association between changes in the skin microbiome and the diseases genotypic and phenotypic effects are of both ecological and clinical interest but are historically obscured by 1) the limited resolution of metagenomic profiles, and 2) additional sources of variation such as age and topical/oral treatments. Here we characterize the skin microbiome from seven ichthyosis genotypes, at species, strain, and metabolic pathway levels. Critically, we assess the association between these microbiome features and the ichthyosis genotype and phenotype while adjusting for contextual host covariables. We show that the ichthyosis genotype, especially that caused by mutations in TGM1, and the ichthyosis phenotype, particularly transepidermal water loss (TEWL), and personal covariables, such as topical emollients and oral retinoids, collectively, and sometimes antagonistically, influence the species community, strain population, and metabolic potential of the skin microbiome. One Sentence SummarySpecies, strain, and the composition of metabolic pathways of the cutaneous microbiome in ichthyosis are influenced by the mutation genotype of ichthyosis, phenotypic features of ichthyosis such as transepidermal water loss, scaling, and skin hydration, and host age and treatment.

microbiology↗

bioRxiv2024

Is subjective perceptual similarity metacognitive?

Perceptual similarity is a cornerstone for human learning and generalization. However, in assessing perceptual similarity between two stimuli, it is not well-defined which features or combinations of features one should focus on. The problem has accordingly been considered ill-posed, implying a lack of a clear ground-truth basis for similarity judgments. We hypothesized that the stimuli rated as subjectively similar are those that are, in fact, more challenging for oneself to discern in practice, in near-threshold settings (e.g., psychophysics experiments). Therefore, an individuals perceptual discrimination capacities can serve as a quasi-objective ground truth for determining whether two stimuli should be judged as similar. To test this idea, we asked participants to rank the similarity of face pairs and also separately measured their discrimination capacity for those pairs. We found a positive association between perceptual discrimination capacity and subjective perceptual dissimilarity, with this association being specific to each individual. The results indicate that perceptual similarity judgments reflect and predict ones own perceptual discrimination capacities. Overall, although subjective, similarity judgments are normative in that they are grounded in ones perceptual capacities, which can be measured through a psychophysical task with objective responses.

neuroscience↗