Biology subjects

Lin, T.

Publications and source records attributed to Lin, T..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

xOmicsShiny: an R shiny application for cross-omics data analysis and pathway mapping

SummaryWe developed xOmicsShiny, a feature-rich R Shiny-powered application that enables biologists to fully explore omics datasets across experiments and data types, with an emphasis on uncovering biological insights at the pathway level. The data merging feature ensures flexible exploration of cross-omics data, such as transcriptomics, proteomics, metabolomics, and lipidomics. The pathway mapping function covers a broad range of databases, including WikiPathways, Reactome, and KEGG pathways. In addition, xOmicsShiny offers several visualization options and analytical tasks for everyday omics data analysis, namely, PCA, Volcano plot, Venn Diagram, Heatmap, WGCNA, and advanced clustering analyses. The application employs customizable modules to perform various tasks, generating both interactive plots and publication-ready figures. This dynamic, modular design overcomes the issue of slow loading in R Shiny tools and allows it to be readily expanded by the research and developer community. Availability and implementationThe R Shiny application is publicly available at: http://xOmicsShiny.bxgenomics.com. Researchers can upload their own data to the server or use the pre-loaded demo dataset. The source code, under MIT license is provided at https://github.com/interactivereport/xOmicsShiny for local installation. A full tutorial of the application is available at https://interactivereport.github.io/xOmicsShiny/tutorial/docs/index.html. Contactyuhenry.sun@biogen.com or baohong.zhang@biogen.com Supplementary dataSupplementary data are available at bioRxiv online.

bioinformatics↗

bioRxiv2025

Cerebellar Purkinje cell stripe patterns reveal a differential vulnerability and resistance to cell loss during normal aging in mice

Age-related neurodegenerative diseases involve reduced cell numbers and impaired behavioral capacity. Neurodegeneration and behavioral deficits also occur during aging, and notably in the absence of disease. The cerebellum, which modulates movement and cognition, is susceptible to cell loss in both aging and disease. Here, we demonstrate that cerebellar Purkinje cell loss in aged mice is not spatially random but rather occurs in a pattern of parasagittal stripes. We also find that aged mice exhibit impaired motor coordination and more severe tremor compared to younger mice. However, the relationship between patterned Purkinje cell loss and motor dysfunction is not straightforward. Examination of postmortem samples of human cerebella from neurologically typical individuals supports the presence of selective loss of Purkinje cells during aging. These data reveal a spatiotemporal cellular substrate for aging in the cerebellum that may inform how neuronal vulnerability leads to neurodegeneration and the ensuing deterioration of behavior.

neuroscience↗

bioRxiv2025

High-resolution digital dissociation of brain tumors with deep multimodal autoencoder

In single cell biology, the complexity of tissues may hinder lineage cell mapping or tumor microenvi-ronment decomposition, requiring digital dissociation of bulk tissues. Many deconvolution methods focus on transcriptomic assay, not easily applicable to other omics due to ambiguous cell markers and reference-to-target difference. Here, we present MODE, a multimodal autoencoder pipeline linking multi-dimensional features to jointly predict personalized multi-omic profiles and cellular compositions, using pseudo-bulk data constructed by internal non-transcriptomic reference and external scRNA-seq data. MODE was evaluated through rigorous simulation experiments and real multiomic data from multiple tissue types, outperforming nine deconvolution pipelines with superior generalizability and fidelity.

bioinformatics↗

bioRxiv2024

Fish MicroRNA Responses to Thermal Stress: Insights and Implications for Aquaculture and Conservation Amid Global Warming

Under the backdrop of global warming, heat tolerance emerges as an important physiological trait governing the distribution and survival of fish species worldwide. While knowledge on fish heat tolerance and stress has progressed from behavioral studies to transcriptomic analyses, our understanding at the transcriptomic level remains limited. Recently, the highly conserved nature of microRNAs (miRNAs) has introduced new ways of explaining molecular mechanisms of heat stress in fish. Here, we systematically review current research across three main reference databases to explain the universal responses and mechanisms of fish miRNAs to heat stress. An initial screen of 569 articles yielded 13 target papers for comprehensive analysis. Among these, at least 214 differentially expressed genes (DEGs) were identified, with 15 DEGs recurring in at least two studies (12 upregulated, 13 downregulated). The 15 recurrent DEGs were subjected to DIANA mirPath v.3 utilizing the microT-CDS v5.0 database to identify potential target genes. The results indicate that multiple miRNAs target genes, forming a complex network to regulate glucose and energy balance metabolism, maintain homeostasis, and modulate inflammation and immune disorders. Notably, miR-1, miR-122, let-7a, and miR-30b are identified as potential biomarkers of heat stress in fish. Due to their high conservation across species, these miRNAs could be used to monitor the health of wild fish populations, improve selective breeding programs in aquaculture, and guide conservation strategies for species that are vulnerable to climate change. This review provides a framework for further investigation into the molecular mechanisms of fish heat tolerance.

zoology↗

bioRxiv2024

Ophiostomatoid fungi associated with bark beetles infesting Pinus armandii, with characterizations of seven new species from western China

Ophiostomatoid fungi mainly refer to the order Ophiostomatales (Ascomycota), which are known to be symbiotic with bark beetles infesting pine trees. These fungi are primarily associated with Dendroctonus armandi and other bark beetles, significantly impacting the local pines Pinus armandii in western China. However, this fungal diversity must be further explored. This study aims to identify Ophiostomatoid fungi associated with P. armandii in Ningshaan, Shaanxi Province. A total of 225 Ophiostomatalean isolates were obtained from 46 gallery samples, accounting for 77.6 % of the total number of isolated strains. Twenty species were identified based on the phylogenetic analyses of ITS, LSU, {beta}-tubulin, and EF-1, as well as morphological characteristics. These include seven new taxa, Ceratocystiopsis rugosa, Graphilbum prolificum, G. ramosus, Masuyamyces huoditangensis, Ophiostoma flavescens, O. lenta, O. mediotumida, and thirteen known species. This study laid a theoretical foundation for understanding the relationship between the beetles and the ophiostomatalean fungi in the Ningshan region, China.

microbiology↗

bioRxiv2024

Ophiostomatalean fungi associated with bark beetles infesting Pinus koraiensis, including the description of Ceratocystiopsis fushunensis sp. nov. in China

Fungi of Ophiostomatales (Sordariomycetes, Ascomycota) always have a symbiotic relationship with bark beetles (Coleoptera: Scolytinae). In this study, we investigated the fungi associated with Cryphalus piceae and Hylastes sp in Fushun. Based on the four gene fragments of TUB, ITS, LSU, and TEF and morphological characteristics, 206 strains of Ophiostomatales were identified to be distributed in 21 taxa; these included an undescribed taxon. Here, we described it as Ceratocystiopsis fushunensis sp. nov. The results of this study provided valuable information on the relationship between fungi and bark beetles.

microbiology↗

bioRxiv2024

Two new species of Graphium (Microascales, Ascomycota) associated with pine-infesting bark beetles in China

Graphium is a genus of fungi that falls under the order Microascales of Ascomycota. Some species in this genus can establish a unique symbiotic relationship with the pine-infesting bark beetles, while others are typically found in wood or soil habitats. To comprehensively investigate the diversity of species of these fungi, recent field trips were conducted in seven provinces (Fujian, Guangdong, Guizhou, Guangxi, Liaoning, Shaanxi, and Shandong) in China. 96 pure isolates of Graphium were obtained by sequences from 361 samples. Nineteen representative strains were carefully selected to generate sequencing data from four gene regions (ITS, LSU, EF1A and TUBB), then used to construct phylogenetic trees for the genus. The results revealed the discovery of two new species, namely G. armandii sp. nov. and G. massoniana sp. nov., and G. pseudoumiticum was the most common species in various pine hosts.

microbiology↗

bioRxiv2024

Identification of Multi-landscape and Cell Interactions in the Tumor Microenvironment through High-Coverage Single-Cell Sequencing

Single-cell RNA sequencing (scRNA-seq) is a widely used method for classifying cell types and states and revealing disease mechanisms. However, most contemporary scRNA-seq platforms fail to explore the multilandscape of RNA. Here, we designed a microfluidic chip that combines oligo-dT primers and Random Bridging Co-labeling (RBCL) RNA sequencing to develop an innovative Chigene scRNA-seq technology that can identify gene expression, mutations, and RNA splicing landscapes at the single-cell level. The Chigene scRNA-seq platform demonstrated exceptional performance, with minimal doublet rates of 0.94% (Chigene V1) and 1.93% (Chigene V2). Both versions exhibit high sensitivity, with Chigene V2 achieving nearly 100% RNA coverage and detecting over 1800 genes per cell on average. Targeted capture of single-cell gene mutations enhances mutation detection sensitivity. Moreover, this Chigene V2 platform has been validated in clinical samples for its ability to detect mutations, gene fusions and alternative splicing. The reliability of the platform was further corroborated via known functional gene mutation (CDKN1A) and fusion (FGFR3-TACC). To validate this methods potential for discovering novel gene mutations in clinical samples, our investigation revealed an intriguing cell subpopulation carrying an ARHGAP5 mutation in urothelial carcinoma. These cells exhibited high-frequency mRNA splicing and exhibited specific crosstalk with T cells, distinguishing them from the subpopulation with the ARHGAP5 wild-type phenotype. Overall, this method provides a robust scRNA-seq platform suitable for comprehensive analyses of clinical specimens at different genetic information levels, thereby offering significant potential in the discovery of novel genes and interactions at the single-cell level.

genomics↗

bioRxiv2024

Targeting DBS to the centrolateral thalamic nucleus improves movement in a lesion-based model of acquired cerebellar dystonia in mice

Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a "dystonia network" consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical areas in the network - the basal ganglia, thalamus, and cerebellum - lead to a dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts instigates dystonia; and how network modulation interacts with symptom latency remain as unexplored questions. Here, we present an electrolytic lesioning paradigm that bilaterally targets the cerebellar outflow tracts. We found that lesioning these tracts, at the junction of the superior cerebellar peduncles and the medial and intermediate cerebellar nuclei, resulted in acute, severe dystonia. We observed that dystonia is reduced with one hour of DBS of the centrolateral thalamic nucleus, a first order node in the network downstream of the cerebellar nuclei. In contrast, one hour of stimulation at a second order node in the short latency, disynaptic projection from the cerebellar nuclei, the striatum, did not modulate the dystonia in the short-term. Our study introduces a robust paradigm for inducing acute, severe dystonia, and demonstrates that targeted modulation based on network principles powerfully rescues motor behavior. These data inspire the identification of therapeutic targets for difficult to manage acquired dystonia.

neuroscience↗

bioRxiv2024

psudo: Exploring Multi-Channel Biomedical Image Data with Spatially and Perceptually Optimized Pseudocoloring

Over the past century, multichannel fluorescence imaging has been pivotal in myriad scientific breakthroughs by enabling the spatial visualization of proteins within a biological sample. With the shift to digital methods and visualization software, experts can now flexibly pseudocolor and combine image channels, each corresponding to a different protein, to explore their spatial relationships. We thus propose psudo, an interactive system that allows users to create optimal color palettes for multichannel spatial data. In psudo, a novel optimization method generates palettes that maximize the perceptual differences between channels while mitigating confusing color blending in overlapping channels. We integrate this method into a system that allows users to explore multi-channel image data and compare and evaluate color palettes for their data. An interactive lensing approach provides on-demand feedback on channel overlap and a color confusion metric while giving context to the underlying channel values. Color palettes can be applied globally or, using the lens, to local regions of interest. We evaluate our palette optimization approach using three graphical perception tasks in a crowdsourced user study with 150 participants, showing that users are more accurate at discerning and comparing the underlying data using our approach. Additionally, we showcase psudo in a case study exploring the complex immune responses in cancer tissue data with a biologist. CCS ConceptsO_LIHuman-centered computing [->] Visualization systems and tools; C_LI

cell biology↗

bioRxiv2024

Biallelic pathogenic variants in DNAH3 cause male infertility in humans and mice

Axonemal protein complexes, including the outer and inner dynein arms (ODA/IDA), are highly ordered structures of the sperm flagella that drive sperm motility. Deficiencies in several axonemal proteins have been associated with male infertility, which is characterized by asthenozoospermia or asthenoteratozoospermia. Dynein axonemal heavy chain 3 (DNAH3) resides in the IDA and is highly expressed in the testis. However, the relationship between DNAH3 and male infertility is still unclear. Herein, we identified biallelic variants of DNAH3 in four unrelated Han Chinese infertile men with asthenoteratozoospermia through whole-exome sequencing (WES). These variants contributed to deficient DNAH3 expression in the patients sperm flagella. Importantly, the patients represented the anomalous sperm flagellar morphology, and the flagellar ultrastructure was severely disrupted. Intriguingly, Dnah3 knockout (KO) male mice were also infertile, especially showing the severe reduction in sperm movement with the abnormal IDA and mitochondrion structure. Mechanically, nonfunctional DNAH3 expression resulted in decreased expression of IDA-associated proteins in the spermatozoa flagella of patients and KO mice, including DNAH1, DNAH6, and DNALI1, the deletion of which has been involved in disruption of sperm motility. Moreover, the infertility of patients with DNAH3 variants and Dnah3 KO mice could be rescued by intracytoplasmic sperm injection (ICSI) treatment. Our findings indicated that DNAH3 is a novel pathogenic gene for asthenoteratozoospermia and may further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.

genetics↗

bioRxiv2023

Divergence in herbivore resistance during the invasion of a global plant invader

O_LISuccessful plant invasions are often explained with adaptation to novel environments. However, invasive species often occupy broad niches within their native and introduced ranges, and a true understanding of microevolution during invasion therefore requires broad sampling of ranges, ideally with a knowledge of introduction history. C_LIO_LIWe tested for genetic differentiation in herbivore resistance among 128 introduced (Europe, North America) and native (China, Japan) populations of the invasive Japanese knotweed (Reynoutria japonica) in two common gardens in the native range. C_LIO_LIIn both common gardens we found that resistance traits of introduced populations differed from most Chinese native populations, but not from populations in Japan, the putative sources of introduction. Compared to Chinese populations, introduced European populations had thicker leaves with a lower C:N ratio but higher flavonoids contents. In the native range, variation in herbivore resistance was much more strongly associated with climate of origin than in introduced populations. C_LIO_LIOur results support the idea that founder effects played a key role in the invasion of knotweed into Europe and North America, with introduction of particular resistance phenotypes from Japan. Our study also demonstrates how knowledge of introduction history can avoid drawing wrong conclusions from observed biogeographic divergence. C_LI

ecology↗

bioRxiv2023

FOXA2 is essential for maintaining the urea cycle in acute liver failure

Hepatic encephalopathy is a lethal complication of acute liver failure (ALF), and is caused by hyperammonemia. Ammonia clearance by the liver requires an intact and complete urea cycle comprising six enzymes, including the rate-limiting enzyme carbamoyl phosphate synthetase I (CPS1). To date, the detailed regulation of CPS1 transcription in order to maintain urea cycle in physiological condition and ALF remains largely unknown. This study scrutinizes the role of pioneer factor forkhead box A 2 (FOXA2) in the regulation of CPS1 transcription, urea cycle performance and hyperammonemia. Physiologically, CPS1 transcription requires FOXA2 to maintain chromatin accessibility on its enhancers, which is essential for CCAAT enhancer-binding protein-alpha (C/EBP) binding to activate gene transcription. In ALF, hepatic C/EBP expression is inhibited by inflammatory mediators such as TGF-{beta} and TNF-. In this setting, retinoic acid receptor synergizes with FOXA2 to maintain CPS1 transcriptions. Once ALF patients suffer from massive hepatic necrosis, liver progenitor cells initiate a transcription network comprising FOXA2 and C/EBP to perform the urea cycle and prevent hyperammonemia. In ALF, hepatic encephalopathy occurs in patients lacking hepatic FOXA2 expression. In mice with acetaminophen-induced ALF, injection of Foxa2-AAV8 maintains urea cycle and prevents hyperammonemia. Taken together, FOXA2 is essential for maintaining the urea cycle. Pharmaceutical induction of hepatic FOXA2 expression might represent a novel approach to treat hepatic encephalopathy in ALF. One Sentence SummaryPioneer factor FOXA2 synergizes with C/EBP or RAR to maintain urea cycle in acute liver failure

molecular biology↗

bioRxiv2023

Ggnbp2 regulates synaptic development and autophagy in motor neurons

AbstractGenome-wide association studies (GWAS) have identified numerous candidate ALS risk variants, but their cellular functions are often unknown. Recent studies have identified a variant of GGNBP2 that results in increased expression. To better understand how this gene might contribute to disease, we investigated the function of Drosophila Ggnbp2 (dGgnbp2) in motor neurons. Loss of function studies showed that dGgnbp2 is required for motor neuron synaptic development. A human transgene completely rescued these phenotypes indicating that the gene is functionally conserved between humans and flies. Overexpression of dGgnbp2 caused severe locomotor defects in adult flies, consistent with ALS pathology. At the cellular level, dGgnbp2 regulated autophagy, a process commonly defective in ALS. Both overexpression and removal of dGgnbp2 reduced levels of the phosphorylated lipid, PI(3)P, an essential component of autophagosomes. Our study provides strong evidence that Ggnbp2 functions in motor neurons to regulate a cellular process commonly defective in ALS. TeaserThis study investigated the function of the ALS risk variant GGNBP2, in flies, and showed that it regulates autophagy in motor neurons.

neuroscience↗

bioRxiv2023

Expression of Filaments of the Geobacter Extracellular Cytochrome OmcS in Shewanella oneidensis

The physiological role of Geobacter sulfurreducens extracellular cytochrome filaments is a matter of debate and the development of proposed electronic device applications of cytochrome filaments awaits methods for large-scale cytochrome nanowire production. Functional studies in Geobacter sulfurreducens are stymied by the broad diversity of redox-active proteins on the outer cell surface and the redundancy and plasticity of extracellular electron transport routes. G. sulfurreducens is a poor chassis for producing cytochrome nanowires for electronics because of its slow, anaerobic growth. Here we report that filaments of the G. sulfurreducens cytochrome OmcS can be heterologously expressed in Shewanella oneidensis. Multiple lines of evidence demonstrated that a strain of S. oneidensis, expressing the G. sulfurreducens OmcS gene on a plasmid, localized OmcS on the outer cell surface. Atomic force microscopy revealed filaments with the unique morphology of OmcS filaments emanating from cells. Electron transfer to OmcS appeared to require a functional outer-membrane porin-cytochrome conduit. The results suggest that S. oneidensis, which grows rapidly to high culture densities under aerobic conditions, may be a suitable for development of a chassis for producing cytochrome nanowires for electronics applications and may also be good model microbe for elucidating cytochrome filament function in anaerobic extracellular electron transfer.

synthetic biology↗

bioRxiv2023

A novel method for quantitation of AAV genome integrity and residual DNAs using duplex digital PCR

Recombinant adeno-associated virus (rAAV) vectors have become a reliable strategy for delivering gene therapies. As rAAV capsid content is known to be heterogeneous, assays for rAAV characterization are critical for assessing the efficacy and safety of drug products. Multiplex droplet digital PCR (ddPCR) has emerged as a popular molecular approach for characterizing capsid content due to its high level of throughput, accuracy, and replicability. Despite growing popularity, tools to accurately analyze multiplexed data are scarce. Here, we introduce a novel model to estimate genome integrity from duplex ddPCR assays. This work demonstrates that use of a Poisson-multinomial mixture distribution significantly improves the accuracy and quantifiable range of duplex ddPCR assays over currently available models.

molecular biology↗

bioRxiv2023

How Myosin VI Traps its Off-State, is Activated and Dimerizes

Myosin VI (Myo6) is the only minus-end directed nanomotor on actin, allowing it to uniquely contribute to numerous cellular functions. As for other nanomotors, proper functioning of Myo6 relies on precise spatio-temporal control of motor activity via a poorly defined off-state and interactions with partners. Our structural, functional, and cellular studies reveal key features of myosin regulation and indicate that not all partners can activate Myo6. TOM1 and Dab2 cannot bind the off-state while, GIPC1 binds Myo6, releases its auto-inhibition and triggers proximal dimerization. Myo6 partners thus differentially recruit Myo6. We solved a crystal structure of the proximal dimerization domain, and show that its disruption compromises endocytosis in HeLa cells, emphasizing the importance of Myo6 dimerization. Finally, we show that the L926Q deafness mutation disrupts Myo6 auto-inhibition and indirectly impairs proximal dimerization. Our study thus demonstrates the importance of partners in the control of Myo6 auto-inhibition, localization, and activation.

biochemistry↗

bioRxiv2023

Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.

cell biology↗