Biology subjects

Xia, C.

Publications and source records attributed to Xia, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Associations between common genetic variants and income provide insights about the socioeconomic health gradient

We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic index captures 1 - 4% of income variance, with only one-fourth attributed to direct genetic effects. A phenome-wide association study using this polygenic index showed reduced risks for a broad spectrum of diseases, including hypertension, obesity, type 2 diabetes, coronary atherosclerosis, depression, asthma, and back pain. The income factor showed a substantial genetic correlation (0.92, s.e. = .006) with educational attainment (EA). Accounting for EAs genetic overlap with income revealed that the remaining genetic signal for higher income related to better mental health but reduced physical health benefits and increased participation in risky behaviours such as drinking and smoking.

genetics↗

bioRxiv2023

Beta-catenin inhibition disrupts the homeostasis of osteogenic/adipogenic differentiation leading to the development of glucocorticoid-induced osteonecrosis of femoral head

Glucocorticoid-induced osteonecrosis of the femoral head (GONFH) is a common refractory joint disease characterized by bone damage and the collapse of femoral head structure. However, the exact pathological mechanisms of GONFH remain unknown. Here, we observed abnormal osteogenesis and adipogenesis associated with decreased {beta}-catenin in the necrotic femoral head of GONFH patients. In vivo and in vitro studies further revealed that glucocorticoid exposure disrupted osteogenic/adipogenic differentiation of bone marrow mesenchymal cells (BMSCs) by inhibiting {beta}-catenin signaling in glucocorticoid-induced GONFH rats. Col2+ lineage largely contributes to BMSCs, and was found an osteogenic commitment in the femoral head through 9 months of lineage trace. Specific deletion of {beta}-catenin in Col2+ cells shifted their commitment from osteoblasts to adipocytes, leading to a full spectrum of disease phenotype of GONFH in adult mice. Overall, we uncover that {beta}-catenin inhibition disrupting the homeostasis of osteogenic/adipogenic differentiation contributes to the development of GONFH, and identify an ideal genetic modified mouse model of GONFH.

pathology↗

bioRxiv2023

Population genomic analyses reveal extensive genomic regions within selective sweeps associated with adaptation and demographic history of a wheat fungal pathogen

Plant pathogens can quickly evolve in response to the changing host and environment, resulting in destructive epidemics. The fungus Puccinia striiformis f. sp. tritici (Pst), causing wheat stripe rust disease worldwide, is one such pathogen. In the arms race between pathogens and hosts, changes in host populations exerted continuous selective forces on the dynamics of pathogens. However, the footprints of these selection forces and the demography of Pst remain poorly explored, limited our understanding the evolutionary processes that shape the spread and evolution of pathogens. In this study, we revealed several features of worldwide Pst populations through population genomic analyses. There might be limited gene flow between Pst populations from China and other countries. A slower rate of linkage disequilibrium decay was detected comparing to rust fungi with known sexual reproduction. Furthermore, we detected extensive hard and soft sweeps associated with Pst adaptation. Genes within the selective sweeps were enriched in secreted proteins and effectors and showed functions related to pathogenicity or virulence, temperature tolerance, and fungicide resistance implying that Chinese Pst populations suffered positive selection pressures from host and abiotic factors. Moreover, demographic history indicated Pst populations experienced strong bottlenecks at the beginning of the wheat domestication around 10,000 years ago and during modern agriculture around 100 years ago, suggesting that the crop domestication and breeding programs could continuously contribute to the decline of pathogen effective population sizes. Our results provided insights into the evolution of the Pst genome and highlighted the role of modern agriculture on pathogen demography. Author SummaryWheat stripe rust, as a pathogen of wheat, is capable of inducing significant yield reduction on a global scale. Traditional epidemiological investigations have elucidated the causative agent behind this disease, the wheat stripe rust pathogen, as an organism exhibiting swift adaptive evolution in response to its environment. However, the precise mechanisms underpinning its adaptive strategies and the ensuing alterations in population dynamics remain relatively unexplored. In our research, we have undertaken an analysis encompassing wheat stripe rust samples throughout the world. Employing population genomics methods, we have sought to discern the genomic footprints corresponding to the adaptive process within the pathogen. These genomic footprints have illuminated the operation of positive selection pressures caused by both the host plant and the ecological context. Concurrently, it have provided insights into the population size that the wheat stripe rust pathogen has undergone over millennia. Notably, its change in population size revealed the demographic history associated with wheat domestication.

microbiology↗

bioRxiv2022

A pair of NLRs coordinately modulates NRC3-mediated ETI responses to facilitate age-dependent immunity

Two NLRs (Nucleotide-binding and Leucine-rich repeat Receptors) adjacent to each other on a locus, termed as paired NLRs, may act separately for effector recognition and subsequent signaling activation to mediate effector-triggered immunity (ETI) in many plants. However, it is largely unknown about their distribution and functions in Solanaceae species, in which NLR-Hs (Helpers NLR REQUIRED FOR CELL DEATHs) have been extensively studied. Here, we identified paired NLRs in Solanaceae species and found they harbor paired NLRs ranging from 6 to 100, which are significantly negatively correlated with the numbers of NLR-Hs. N. benthamiana has six paired NLRs, among which silencing of NRCX exhibits phenotypes of dwarfism and accelerated senescence. Importantly, NRCX-silencing phenotypes could be restored by simultaneously silencing its head-to-head NLR pair, thus we named it as NRCY. NRCX/Y pair is specific in Solanaceae species. NRCY contains non-canonical walker B and MHD motifs, but could not induce autoactive cell death in N. benthamiana. Instead of that, silencing NRCY impaired cell death triggered by Sw5b-Nsm and NRC3D480V, indicating NRCY is also an NLR modulator like NRCX. Furthermore, NRCX suppression of Sw5b-Nsm and NRC3-mediated cell death is dependent on NRCY. Remarkably, we found that NRCX and NRCY expressions were induced during plant senescence, while NRCY was induced more than NRCX. Accordingly, the plant resistance was stronger during maturation, indicated NRCX/Y might be involved in age-dependent resistance. Our study reveals one of the paired NLRs coordinately regulates ETI to facilitate age-dependent immunity.

plant biology↗

bioRxiv2022

A compendium of genetic regulatory effects across pig tissues

The Farm animal Genotype-Tissue Expression (FarmGTEx, https://www.farmgtex.org/) project has been established to develop a comprehensive public resource of genetic regulatory variants in domestic animal species, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biology discovery and exploitation in animal breeding and human biomedicine. Here we present results from the pilot phase of PigGTEx (http://piggtex.farmgtex.org/), where we processed 9,530 RNA-sequencing and 1,602 whole-genome sequencing samples from pigs. We build a pig genotype imputation panel, characterize the transcriptional landscape across over 100 tissues, and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We study interactions between genotype and breed/cell type, evaluate tissue specificity of regulatory effects, and elucidate the molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying about 80% of the genetic associations for 207 pig complex phenotypes, and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, corroborating the importance of pigs as a human biomedical model.

genomics↗

bioRxiv2022

High-accuracy protein model quality assessment using attention graph neural networks

Great improvement has been brought to protein tertiary structure prediction through deep learning. It is important but very challenging to accurately rank and score decoy structures predicted by different models. CASP14 results show that existing quality assessment (QA) approaches lag behind the development of protein structure prediction methods, where almost all existing QA models degrade in accuracy when the target is a decoy of high quality. How to give an accurate assessment to high-accuracy decoys is particularly useful with the available of accurate structure prediction methods. Here we propose a fast and effective single-model QA method, QATEN, which can evaluate decoys only by their topological characteristics and atomic types. Our model uses graph neural networks and attention mechanisms to evaluate global and amino acid level scores, and uses specific loss functions to constrain the network to focus more on high-precision decoys and high-precision protein domains. On the CASP14 evaluation decoys, QATEN performs better than other QA models under all correlation coefficients when targeting average LDDT. QATEN shows promising performance when considering only high-accuracy decoys. Compared to the embedded evaluation modules of predicted C-RMSD (pRMSD) in RosettaFold and predicted LDDT (pLDDT) in AlphaFold2, QATEN is complementary and capable of achieving better evaluation on some decoy structures generated by AlphaFold2 and RosettaFold themselves. These results suggest that the new QATEN approach can be used as a reliable independent assessment algorithm for high-accuracy protein structure decoys.

bioinformatics↗

bioRxiv2022

Leveraging Scaffold Information to Predict Protein-ligand Binding Affinity with an Empirical Graph Neural Network

MotivationProtein-ligand binding affinity prediction is an important task in structural bioinformatics for drug discovery and design. Although various scoring functions have been proposed, it remains challenging to accurately evaluate the binding affinity of a protein-ligand complex with known bound structure due to the potential preference of scoring system. In recent years, deep learning techniques have been applied to scoring functions without sophisticated feature engineering. Nevertheless, existing methods cannot model the differential contribution of atoms in various regions of proteins, and the relationship between atom properties and intermolecular distance is also not fully explored. ResultsWe propose a novel empirical graph neural network for accurate protein-ligand binding affinity prediction (EGNA). Graphs of protein, ligand and their interactions are constructed based on different regions of each bound complex. Proteins and ligands are effectively represented by graph convolutional layers, enabling the EGNA to capture interaction patterns precisely by simulating empirical scoring functions. The contributions of different factors on binding affinity can thus be transparently investigated. EGNA is compared with the state-of-the-art machine learning-based scoring functions on two widely used benchmark datasets. The results demonstrate the superiority of EGNA and its good generalization capability. Availability and implementationThe web server and source code of EGNA is available at www.csbio.sjtu.edu.cn/bioinf/EGNA and https://github.com/chunqiux/EGNA. Contacthbshen@sjtu.edu.cn or 2008xypan@sjtu.edu.cn Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2022

Cryo-EM structures reveal the activation and substrate recognition mechanism of human enteropeptidase

The enteropeptidase (EP) initiates the intestinal digestion by proteolytic processing of trypsinogen, generating catalytic active trypsin. The dysfunction of EP will cause a series of pancreatic diseases, the most severe of which is acute necrotizing pancreatitis. However, the molecular mechanism of EP activation and substrate recognition remain elusive due to the lack of structural information, hampering the structure-based research of EP and even further EP-targeted drug design. Here we report cryo-EM structures of human EP in multiple states, covering the functional cycle spanning from inactive to active state and eventually to the substrate binding state, with the inactive core region reached an atomic 2.7-[A]-resolution. The heavy chain of EP exhibits a clamping configuration with the CUB2 domain serving for substrate recognition. The N-terminus of light chain induces the surface loop remodeling from inactive to active conformation, resulting in a highly dynamic and active EP. Then the heavy chain performs like a hinge to ensure the flexibility of light chain for substrate recruitment and subsequent cleavage. Our study provides structural insights of EP remodeling and heavy chain dynamics while performing enzymatic function, facilitating our understanding of the pathogenies of EP-related pancreatitis and the EP-targeted treatment of pancreatitis.

cell biology↗

bioRxiv2021

Lateral plate mesoderm cell-based organoid system for NK cell regeneration from human pluripotent stem cells

Human pluripotent stem cell (hPSC)-induced NK (iNK) cells are a promising "off-the-shelf" cell product for universal immune therapy. Conventional methods for iNK cell regeneration from hPSCs include embryonic body-formation and feeder-based expansion steps, which bring instability, time-consuming, and high costs for manufacture. In this study, we develop an embryonic body-free, organoid aggregate method for NK cell regeneration from hPSCs. In a short time window of 27-day induction, millions of hPSC input can produce over billions of iNK cells without the necessity of NK cell-expansion feeders. The iNK cells highly express classical toxic granule proteins, apoptosis-inducing ligands, as well as abundant activating and inhibitory receptors. Functionally, the iNK cells eradicate human tumor cells by mechanisms of direct cytotoxity, apoptosis, and antibody-dependent cellular cytotoxicity. This study provides a reliable scale-up method for regenerating human NK cells from hPSCs, which promotes the universal availability of NK cell products for immune therapy.

immunology↗

bioRxiv2021

Conservation and divergence in cortical cellular organization between human and mouse revealed by single-cell transcriptome imaging

The human cerebral cortex has tremendous cellular diversity and complex cellular organization that are essential for brain function. How different types of cells are organized and interact with each other in the human cortex, and how cellular organizations and interaction patterns vary across species are, however, unclear. Here, we performed spatially resolved single-cell expression profiling of 4,000 genes in human middle and superior temporal gyrus using multiplexed error-robust fluorescence in situ hybridization (MERFISH). We identified >100 neuronal and non-neuronal cell populations with distinct transcriptional signatures, generated a molecularly defined and spatially resolved cell atlas of these brain regions, and analyzed cell-cell interactions in a cell-type-specific manner. Comparison with the mouse cortex showed conservation in the laminar organization of cells and substantial divergence in cell-cell interactions between human and mouse. Notably, our data revealed a drastic increase in interactions between neurons and non-neuronal cells in the human cortex, uncovered human-specific cell-cell interaction patterns, and identified potential ligand-receptor basis of microglia-neuron interactions.

neuroscience↗

bioRxiv2021

Hoxb5 reprograms murine multipotent blood progenitors into hematopoietic stem cell-like cells

The expression of transcription factor Hoxb5 specifically marks the functional hematopoietic stem cells (HSC) in mice. However, our recent work demonstrated that ectopic expression of Hoxb5 exerted little effect on HSC but could convert B cell progenitors into functional T cells in vivo. Thus, cell type- and development stage-specific roles of Hoxb5 in hematopoietic hierarchy await more extensive exploration. Here, with a mouse strain engineered with conditional expression of Hoxb5, we unveiled that induced expression of Hoxb5 in mouse multipotent progenitor cells (MPP) led to the generation of a de novo Sca1+cKit+Mac1+CD48+ (Mac1+CD48+SK) cell type, which has the ability to repopulate long-term multi-lineage hematopoiesis in serial transplant recipients. RNA-seq analyses showed that Mac1+CD48+SK cells exhibited an acquired machinery of DNA replication and cell division, which resembled nature fetal liver HSC cells (FL HSC). In short, our current study uncovers that Hoxb5 is able to empower MPP with self-renewal potential, thereby providing new strategies to reprogram blood progenitor cells into HSC-like cells.

cell biology↗

bioRxiv2021

Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors

Regeneration of humoral immunity from pluripotent stem cells (PSCs) is a crucial aim in translational medicine. However, reconstitution of complete, sustained, and functional B lymphopoiesis from PSCs has not yet been developed. Here, we successfully achieved regenerative B lymphopoiesis in B-cell deficient animals transplanted with PSC-derived hematopoietic progenitors (iHPCs) guided by synergistic expression of Runx1, Hoxa9, and Lhx2. Upon transplantation, the iHPCs immediately gave rise to pro/pre-B cells in recipients bone marrow, which were able to further differentiate into the entire B cell lineages, including innate B-1a, B-1b, MZ B cells, as well as adaptive FO B cells. In responding to antigen stimuli, the regenerative B cells produced adaptive humoral immune responses, sustained a prolonged antigen-specific antibody production, and formed immune-memory. Particularly, the regenerative B cells in spleen showed developing patterns of immunoglobulin chain-switch and hyper-mutation via a cross-talk with the host T follicular helper cells, which eventually formed T cell-dependent humoral responses. This study provides de novo evidence that B lymphopoiesis can be regenerated from PSCs via a HSC-independent approach, which provides insights into treating B-cell related humoral deficiencies using PSCs as unlimited cell resource.

immunology↗

bioRxiv2021

BrainEXP-NPD: a database of transcriptomic profiles of human brains of six neuropsychiatric disorders

BackgroundSpatio-temporal gene expression has been widely used to study gene functions and biological mechanisms in diseases. Numerous microarray and RNA sequencing data focusing on brain transcriptomes in neuropsychiatric disorders have accumulated. However, their consistency, reproducibility has not been properly evaluated. Except for a few psychiatric disorders, like schizophrenia, bipolar disorder and autism, most have not been compared to each other for cross-disorder comparisons. MethodsWe organized 48 human brain transcriptome datasets from six sources. The original brain donors include patients with schizophrenia (SCZ, N=427), bipolar disorder (BD, N=312), major depressive disorder (MDD, N=219), autism spectrum disorder (ASD, N=53), Alzheimers disease (AD, N=765), Parkinsons disease (PD, N=163) as well as controls as unaffected by such disorders (CTRL, N=6,378), making it a total of 8,317 samples. Raw data included multiple brain regions of both sexes, with ages ranging from embryonic to seniors. After standardization, quality control, filtering and removal of known and unknown covariates, we performed comprehensive meta- and mega-analyses, including gene differential expression and gene co-expression network. ResultsA total of 6922, 3011, 2703, 4389, 3507, 4279 significantly differentially expressed genes (FDR q < 0.05) were detected in the comparisons of 6 brain regions of SCZ-CTRL, 5 brain regions of BD-CTRL, 6 brain regions of MDD-CTRL, 4 brain regions of ASD-CTRL, 7 brain regions of AD-CTRL, and 6 brain regions of PD-CTRL, respectively. Most differentially expressed genes were brain region-specific and disease-specific. SCZ and BD have a maximal transcriptome similarity in striatum ({rho}=0.42) among the four brain regions, as measured by Spearmans correlation of differential expression log2 FC values. SCZ and MDD have a maximal transcriptome similarity in hippocampus ({rho}=0.30) among the five brain regions. BD and MDD have a maximal transcriptome similarity in frontal cortex ({rho}=0.45) among the five brain regions. Other disease pairs have a less transcriptome similarity ({rho}<0.1) in all brain regions. PD is negatively correlated with SCZ, BD, and MDD in cerebellum and striatum. We also performed coexpression network analyses for different disorders and controls separately. We developed a database named BrainEXP-NPD (http://brainexpnpd.org:8088/BrainEXPNPD/), to provide a userfriendly web interface for accessing the data, and analytical results of meta- and mega-analyses, including gene differential expression and gene co-expression networks between cases and controls on different brain regions, sexes and age groups. Discussion: BrainEXP-NPD compiled the largest collection of brain transcriptomic data of major neuropsychiatric disorders and presented lists of differentially expressed genes and coexpression modules in multiple brain regions of six major disorders.

bioinformatics↗

bioRxiv2021

WRKY33-mediated indole glucosinolate metabolic pathway confers host resistance against Alternaria brassicicola

The tryptophan (Trp)-derived plant secondary metabolites, including camalexin, 4-hydroxy-indole-3-carbonylnitrile (4OH-ICN), and indole glucosinolate (IGS), show broad-spectrum antifungal activity. However, the upstream regulators of these metabolic pathways among different plant species in response to fungus infection are rarely studied. In this study, our results revealed a positive role of WRKY33 in host resistance to Alternaria brassicicola by directly regulating the transcription of genes involved in the biosynthesis and atypical hydrolysis of IGS both in Arabidopsis and Chinese kale. Indole-3-yl-methylglucosinolate (I3G) and 4-methoxyindole-3-yl-methylglucosinolate (4MI3G) are the main components of IGS. WRKY33 induces the expression of MYB51 and CYP83B1 which promotes the biosynthesis of I3G, the precursor of 4MI3G. Moreover, it also directly activates the expression of CYP81F2, IGMT1, and IGMT2 to drive side chain modification of I3G to produce 4MI3G, which is in turn hydrolyzed by PEN2. However, Chinese kale showed a more severe symptom than Arabidopsis when infected by Alternaria brassicicola. Comparative analyses of the origin and evolution of Trp-metabolism indicate that the loss of camalexin biosynthesis in Brassica crops during evolution might attenuate the resistance of crops to Alternaria brassicicola. As a result, IGS metabolic pathway mediated by WRKY33 becomes essential for Chinese kale to deter Alternaria brassicicola. Our results highlight the differential regulation of Trp-derived camalexin and IGS biosynthetic pathways in plant immunity between Arabidopsis and Brassica crops. One-sentence SummaryPathogen-responsive WRKY33 directly regulates indole glucosinolates biosynthesis and atypical hydrolysis, conferring to host resistance to Alternaria brassicicola in Arabidopsis and Brassica crops.

plant biology↗

bioRxiv2021

Structural and immunological identification and antiviral infection experiment of the dominant cytotoxic T lymphocyte epitopes of the oncogenic Marek's disease virus

Mareks disease (MD) is a serious cancer caused by MDV in chickens, and it is also the first tumor disease that could be controlled by an attenuated vaccine in the world. However, the attenuated vaccine is able to inhibit only the formation of tumors but cannot prevent the infection of oncogenic viruses; instead, it leads to mutations and the emergence of a number of virulent strains. In this paper, the crystal structures of chicken MHC class I (pBF2*1501) molecules bound with 8-mer and 9-mer MDV peptides were solved. The results showed that the conformations of the 8-mer and 9-mer peptides in the antigen-binding groove (ABG) of pBF2*1501 are different; the ABG-8-mer is flat, and the ABG-9-mer has the "featured" M-type epitope morphology. Based on these results, multiple MDV epitopes were confirmed using the tetramer technique, and the immunoprotective effect of dominant epitope was confirmed using the protein adjuvant HSP108-N333 in BF2*1501-expressing chickens. The results showed that the two epitopes have obvious protective effects after a standard immunization program. After challenge, the mortality rate was only 20%, and the protective index (PI) reached 33% in the epitope group. The results verified that a single epitope could induce extremely strong specific antitumor T lymphocyte immunity. The results show that three key factors are crucial to obtain the best antitumor effect: accurate identification of dominant cytotoxic T lymphocyte (CTL) epitopes, efficient protein adjuvant and MHC matching. Meanwhile, the results also provided obvious advantages for the development of multiple epitope vaccines for tumor diseases. ImportanceMareks disease (MD) is the first tumor disease that can be controlled by an attenuated vaccine. However, the attenuated vaccine cannot prevent the infection of the oncogenic virus and instead leads to the emergence of a number of mutated virulent strains. First, the mechanism of the chicken BF2*1501 preferentially presents 9-mer peptide was clarified. Based on this result, multiple MDV epitopes were confirmed, and the dominant epitopes were identified. Subsequently, two epitope groups showed obvious protective effects after a standard immunization program, and the protective index (PI) of one of the epitope groups reached over 30%. The results showed that a single epitope could induce strong and efficient antitumor CTL immunity. Overall, three key factors are crucial to obtain the best antitumor effect: accurate identification of dominant epitopes, efficient protein adjuvant and MHC matching. Our results provide an obvious strategy for the development of multiple epitope vaccines in tumor diseases.

immunology↗

bioRxiv2021

Crystal structure of the classical MHC-I molecule: insights into the MHC-I system in antiviral diseases in dogs

Only one classical MHC-I locus (aka DLA-88) evolved in dogs, and thus far, a total of 76 DLA-88 alleles can be divided into two categories. The first category consists of 60 alleles, and the second category consists of 16 alleles. The main difference between the two categories is the insertion of an amino acid in the 2 region of DLA-88 alleles. To elucidate the structure of the first category, in this study, the crystal structure of pDLA-88*001:01 was determined for the first time. The 3D structure and topological characteristics of the ABG of pDLA-88*001:01 with a CDV peptide were analyzed. The viral presentation profile and the binding motif of viruses presented by pDLA-88*001:01 were determined. Most importantly, there were no amino acid insertions in the 2 region of the first category, which changed the conformation of the D pocket and the docking of the TCR. The results suggest obvious differences between the two categories. Because of the variation in the 2 region, pDLA-88*001:01 showed distinctive features in the two categories. Due to the peptide-binding motif of pDLA-88*001:01, more than 320 high-affinity viral peptides were predicted from dog H7N9, CPV, CMV, CMV, and CDV strains. The results reveal that there are two kinds of structural MHC-I systems in dogs that are responsible for CTL immunity against viral diseases. The results provide knowledge for designing viral epitope vaccines in canines. ImportanceDLA plays an important role in the acquired immunity of organism. In previous study, the pMHC-I structure of dog was analyzed with DLA-88 self-peptide. In this study, we screened several viral peptides which can bind to DLA-88 and resolved the structure of the DLA-88 complex binding the CDV peptide. This study enriches the study of canine MHC-I molecular-presenting polypeptide-activated TCR, which is of great significance for the study of canine cellular immunity and anti-viral vaccine development.

immunology↗

bioRxiv2020

Proteomic and functional analyses of the periodic membrane skeleton in neurons

Actin, spectrin, and associated molecules form a membrane-associated periodic skeleton (MPS) in neurons. The molecular composition and functions of the MPS remain incompletely understood. Here, using co-immunoprecipitation and mass spectrometry, we identified hundreds of candidate MPS-interacting proteins that span diverse functional categories. We validated representative proteins in several of these categories, including previously unknown MPS structural components, as well as motor proteins, cell adhesion molecules, ion channels, and signaling proteins, demonstrating periodic distributions of [~]20 proteins in neurons using super-resolution imaging. Genetic perturbations of the MPS and its interacting proteins further suggested functional roles of the MPS in axon-axon and axon-dendrite interactions and in axon diameter regulation, and implicated the involvement of MPS interactions with cell adhesion molecules and non-muscle myosin in these roles. These results provide new insights into the interactome of the MPS, and suggest new functions of the MPS in neurons.

neuroscience↗

bioRxiv2020

A comprehensive catalogue of regulatory variants in the cattle transcriptome

Characterization of genetic regulatory variants acting on the transcriptome of livestock is essential for interpreting the molecular mechanisms underlying traits of economic value and for increasing the rate of genetic gain through artificial selection. Here, we build a cattle Genotype-Tissue Expression atlas (cattle GTEx, http://cgtex.roslin.ed.ac.uk/) as part of the pilot phase of Farm animal GTEx (FarmGTEx) project for the research community based on publicly available 11,642 RNA-Seq datasets. We describe the landscape of the transcriptome across over 100 tissues and report hundreds of thousands of genetic associations with gene expression and alternative splicing for 24 major tissues. We evaluate the tissue-sharing patterns of these genetic regulatory effects, and functionally annotate them using multi-omics data. Finally, we link gene expression in different tissues to 43 economically important traits using both transcriptome-wide association study (TWAS) and colocalization analyses to decipher the molecular regulatory mechanisms underpinning such agronomic traits in cattle.

genomics↗