Biology subjects

Chen, X.

Publications and source records attributed to Chen, X..

At least 1,297 records · Page 72Linked to original sources

bioRxiv2020

Single-vessel cerebral blood flow fMRI to map blood velocity by phase-contrast imaging

Current approaches to high-field fMRI provide two means to map hemodynamics at the level of single vessels in the brain. One is through changes in deoxyhemoglobin in venules, i.e., blood oxygenation level-dependent (BOLD) fMRI, while the second is through changes in arteriole diameter, i.e., cerebral blood volume (CBV) fMRI. Here we introduce cerebral blood flow (CBF)-fMRI, which uses high-resolution phase-contrast MRI to form velocity measurements of flow and demonstrate CBF-fMRI in single penetrating microvessels across rat parietal cortex. In contrast to the venule-dominated BOLD and arteriole-dominated CBV fMRI signal, the phase-contrast -based CBF signal changes are highly comparable from both arterioles and venules. Thus, we have developed a single-vessel fMRI platform to map the BOLD, CBV, and CBF from penetrating microvessels throughout the cortex. This high-resolution single-vessel fMRI mapping scheme not only enables the vessel-specific hemodynamic mapping in diseased animal models but also presents a translational potential to map vascular dementia in diseased or injured human brains with ultra-high field fMRI. SummaryWe established a high-resolution PC-based single-vessel velocity mapping method using the high field MRI. This PC-based micro-vessel velocity measurement enables the development of the single-vessel CBF-fMRI method. In particular, in contrast to the arteriole-dominated CBV and venule-dominated BOLD responses, the CBF-fMRI shows similar velocity changes in penetrating arterioles and venules in activated brain regions. Thus, we have built a noninvasive single-vessel fMRI mapping scheme for BOLD, CBV, and CBF hemodynamic parameter measurements in animals.

neuroscience↗

bioRxiv2020

A Human Multi-Lineage Hepatic Organoid Model for Liver Fibrosis

BackgroundTo characterize fibrogenic mechanisms, genome engineering and a human hepatic organoid system was used to produce an in vitro model for human liver fibrosis. Methods and resultsHuman hepatic organoids that were engineered to express the most common causative mutation for Autosomal Recessive Polycystic Kidney Disease (ARPKD) developed the key features of ARPKD liver pathology (abnormal bile ducts and hepatic fibrosis) in only 21 days. Second harmonic generation microscopy confirmed that the ARPKD mutation increased collagen abundance and thick collagen fiber production in hepatic organoids; and we demonstrated that these changes mirrored that occurring in ARPKD liver tissue. Transcriptomic and other analyses indicated that the ARPKD mutation generates cholangiocytes with increased TGF{beta}-associated pathway activation, which are actively involved in collagen fiber generation. The abnormal cholangiocytes promote the expansion of collagen-producing myofibroblasts with markedly increased PDGFR{beta} protein expression and an activated STAT3 signaling pathway. Moreover, the transcriptome of ARPKD organoid myofibroblasts resembled that of myofibroblasts in liver tissue obtained from patients with commonly occurring acquired forms of liver fibrosis. The involvement of the PDGFRB pathway was confirmed by the anti-fibrotic effect observed when ARPKD organoids were treated with PDGFRB inhibitors. ConclusionsBesides providing mechanistic insight into the pathogenesis of congenital (and possibly acquired) forms of liver fibrosis, ARPKD organoids could also be used to test the anti-fibrotic efficacy of potential anti-fibrotic therapies.

cell biology↗

bioRxiv2020

High Throughput Computational Mouse Genetic Analysis

BackgroundGenetic factors affecting multiple biomedical traits in mice have been identified when GWAS data that measured responses in panels of inbred mouse strains was analyzed using haplotype-based computational genetic mapping (HBCGM). Although this method was previously used to analyze one dataset at a time; but now, a vast amount of mouse phenotypic data is now publicly available, which could lead to many more genetic discoveries. ResultsHBCGM and a whole genome SNP map covering 53 inbred strains was used to analyze 8462 publicly available datasets of biomedical responses (1.52M individual datapoints) measured in panels of inbred mouse strains. As proof of concept, causative genetic factors affecting susceptibility for eye, metabolic and infectious diseases were identified when structured automated methods were used to analyze the output. One analysis identified a novel genetic effector mechanism; allelic differences within the mitochondrial targeting sequence affected the subcellular localization of a protein. We also found allelic differences within the mitochondrial targeting sequences of many murine and human proteins, and these could affect a wide range of biomedical phenotypes. ImplicationsThese initial results indicate that genetic factors affecting biomedical responses could be identified through analysis of very large datasets, and they provide an early indication of how this type of augmented intelligence can facilitate genetic discovery.

bioinformatics↗

bioRxiv2020

The Contribution of Brain Structural and Functional Variance in Predicting Age, Sex and Treatment

Structural and functional neuroimaging have been widely used to track and predict demographic and clinical variables, including treatment outcomes. However, it is often difficult to directly establish and compare the respective weights and contributions of brain structure and function in prediction studies. The present study aimed to directly investigate respective roles of brain structural and functional indices, along with their contributions in the prediction of demographic variables (age/sex) and clinical changes of schizophrenia patients. The present study enrolled 492 healthy people from Southwest University Adult Lifespan Dataset (SALD) for demographic variables analysis and 42 patients with schizophrenia from West China Hospital for treatment analysis. We conducted a model fit test with two variables (one voxel-based structural metric and another voxel-based functional metric) and then performed a variance partitioning on the voxels that can be predicted sufficiently. Permutation tests were applied to compare the contribution difference between each pair of structural and functional measurements. We found that voxel-based structural indices had stronger predictive value for age and sex, while voxel-based functional metrics showed stronger predictive value for treatment. Therefore, through variance partitioning, we could clearly and directly explore and compare the voxel-based structural and functional indices on particular variables. In sum, for long-term change variable (age) and constant biological feature (sex), the voxel-based structural metrics would contribute more than voxel-based functional metrics; but for short-term change variable (schizophrenia treatment), the functional metrics could contribute more.

neuroscience↗

bioRxiv2020

mRNA translation control by Dhx36 binding to 5' UTR G-quadruplex structures is essential for skeletal muscle stem cell regenerative functions

Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells, also called satellite cells (SCs), that are normally quiescent. When stimulated by damage, SCs activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that Dhx36, a helicase that unwinds RNA quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. We find that Dhx36 (initially named RHAU) is barely expressed at quiescence and is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs revealed Dhx36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling showed that Dhx36 promotes mRNA translation via 5UTR rG4 binding. Furthermore, we demonstrate that Dhx36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5UTR rG4 structures and identify Gnai2 as a downstream effector of Dhx36 for SC expansion. Altogether our findings uncover Dhx36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration through binding and unwinding rG4 structures at 5UTR of target mRNAs.

cell biology↗

bioRxiv2020

Integrating barcoded neuroanatomy with spatial transcriptional profiling reveals cadherin correlates of projections shared across the cortex

Functional circuits consist of neurons with diverse axonal projections and gene expression. Understanding the molecular signature of projections requires high-throughput interrogation of both gene expression and projections to multiple targets in the same cells at cellular resolution, which is difficult to achieve using current technology. Here, we introduce BARseq2, a technique that simultaneously maps projections and detects multiplexed gene expression by in situ sequencing. We determined the expression of cadherins and cell-type markers in 29,933 cells, and the projections of 3,164 cells in both the mouse motor cortex and auditory cortex. Associating gene expression and projections in 1,349 neurons revealed shared cadherin signatures of homologous projections across the two cortical areas. These cadherins were enriched across multiple branches of the transcriptomic taxonomy. By correlating multi-gene expression and projections to many targets in single neurons with high throughput, BARseq2 provides a path to uncovering the molecular logic underlying neuronal circuits.

neuroscience↗

bioRxiv2020

Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial {beta}- and peroxisomal {omega}-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.

cancer biology↗

bioRxiv2020

Qualitative and quantitative bioanalytical methods validation of aristolochic acid DNA adducts and application in human formalin-fixed paraffin-embedded hepatocellular carcinoma tissues

Mutation signature of aristolochic acid (AA) found in urothelial or hepatocellular carcinoma causes public concern about the cancer risk of AA. In contrast, direct evidence based on the reliable bioanalytical method for the exposure of AA is still lacking and not universal. Here, we strictly complied with the qualitative and quantitative guidance for forensic toxicological analysis: In the sample preprocessing, DNA from formalin-fixed and paraffin-embedded (FFPE) tissues was digested to single nucleotide by a series of enzymes with 70% enzymatic digestion efficiency. After protein precipitation, the samples were submitted to an ABI6500+ mass spectrometer for LC-MS/MS analysis. Ion pairs 543.2/427.2 and 543.2/395.2 of dA-AAI were selected from 5 ion pairs due to their higher LC-MS/MS response. Both these ion pairs have excellent selectivity and specificity in rat liver DNA matrix, and a linear regression range from 5 pg/mL to 200 pg/mL with the best fit and determination coefficient (r) greater than 0.99. The intra and inter batch accuracy and precision of these two ion pairs are also acceptable with less than 15% variation. The total recovery for ion pair 543.2/427.2 and 543.2/395.2 of dA-AAI was 90.06% and 90.76%, respectively. Our method has a minor matrix effect and good stability under different temperature and time conditions. With signal to noise ratio [≥] 3, 2 ion pairs (< 50 % relative abundance variation), the lower limit of quantification (LLOQ) of our method is set to 5 pg/mL([~]3.6 AAI-DNA adducts per 108 DNA bases). By using this validated bioanalytical method of dA-AAI, 165 human HCC FFPE tissues were analyzed, the total ratio of samples with peak543.2/427.2 is 17.0% (28/165), with peak543.2/395.2 is 9.09% (15/165) which yields the total ratio of samples combined peak543.2/427.2 and peak543.2/395.2 is 7.27% (12/165). Two samples are higher than 5 pg/mL under the qualitative requirements. In conclusion, we first reported a fully validated methods to analyze the DNA adducts level of aristolochic acid, which could be qualitatively and quantitatively applied to the investigation of AA exposure in the human and other species.

pharmacology and toxicology↗

bioRxiv2020

Host immunity increases Mycobacterium tuberculosis reliance on cytochrome bd oxidase

In order to sustain a persistent infection, Mycobacterium tuberculosis (Mtb) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc1/aa3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the cytochrome bd oxidase is specifically required for resisting the adaptive immune response. While the bd oxidase was dispensable for growth in resting macrophages and the establishment of infection in mice, this complex was necessary for optimal fitness after the initiation of adaptive immunity. This requirement was dependent on lymphocyte-derived interferon gamma (IFN{gamma}), but did not involve nitrogen and oxygen radicals that are known to inhibit respiration in other contexts. Instead, we found that{Delta} cydA mutants were hypersusceptible to the low pH encountered in IFN{gamma}-activated macrophages. Unlike wild type Mtb, cytochrome bd-deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochrome bc1/aa3 complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome bc1/aa3 inhibitor, Q203, is dramatically enhanced at low pH. This work identifies a critical interaction between host immunity and pathogen respiration that influences both the progression of the infection and the efficacy of potential new TB drugs. Author SummaryTuberculosis, caused by Mycobacterium tuberculosis (Mtb) is a serious global health problem that is responsible for over one million deaths annually, more than any other single infectious agent. In the host, Mtb can adapt to a wide variety of immunological and environmental pressures which is integral to its success as a pathogen. Accordingly, the respiratory capacity of Mtb is flexible. The electron transport chain of Mtb has two terminal oxidases, the cytochrome bc1/aa3 super complex and cytochrome bd, that contribute to the proton motive force and subsequent production of energy in the form of ATP. The bc1/aa3 super complex is required for optimal growth during infection but the role of cytochrome bd is unclear. Here we report that the cytochrome bd oxidase is required for resisting the adaptive immune response, in particular, acidification of the phagosome induced by lymphocyte-derived IFN{gamma}. We found that the cytochrome bd oxidase is specifically required under acidic conditions, where the bc1/aa3 complex is preferentially inhibited. Additionally, we show that acidic conditions increased the potency of Q203, a cytochrome bc1/aa3 inhibitor and candidate tuberculosis therapy. This work defines a new link between the host immune response and the respiratory requirements of Mtb that affects the potency of a potential new therapeutic.

microbiology↗

bioRxiv2020

An Industrial-Grade Brain Imaging-Based Deep Learning Classifier

Beyond detecting brain lesions or tumors, comparatively little success has been attained in identifying brain disorders such as Alzheimers disease (AD), based on magnetic resonance imaging (MRI). Many machine learning algorithms to detect AD have been trained using limited training data, meaning they often generalize poorly when applied to scans from previously unseen populations. Therefore, we built a practical brain MRI-based AD diagnostic classifier using deep learning/transfer learning on a dataset of unprecedented size and diversity. A retrospective MRI dataset pooled from more than 217 sites/scanners constituted one of the largest brain MRI samples to date (85,721 scans from 50,876 participants) between January 2017 and August 2021. Next, a state-of-the-art deep convolutional neural network, Inception-ResNet-V2, was built as a sex classifier with high generalization capability. The sex classifier achieved 94.9% accuracy and served as a base model in transfer learning for the objective diagnosis of AD. After transfer learning, the model fine-tuned for AD classification achieved 90.9% accuracy in leave-sites-out cross-validation on the Alzheimers Disease Neuroimaging Initiative (ADNI, 6,857 samples) dataset and 94.5%/93.6%/91.1% accuracy for direct tests on three unseen independent datasets (AIBL, 669 samples / MIRIAD, 644 samples / OASIS, 1,123 samples). When this AD classifier was tested on brain images from unseen mild cognitive impairment (MCI) patients, MCI patients who converted to AD were 3 times more likely to be predicted as AD than MCI patients who did not convert (65.2% vs 20.6%). Predicted scores from the AD classifier showed significant correlations with illness severity. In sum, the proposed AD classifier offers a medical-grade marker that has potential to be integrated into AD diagnostic practice.

neuroscience↗

bioRxiv2020

Sodium leak channel as a therapeutic target for neuronal sensitization in neuropathic pain

Neuropathic pain affects up to 10% of the total population and no specific target is ideal for therapeutic need. The sodium leak channel (NALCN), a voltage-independent cation channel, mediates the background Na+ leak conductance and controls neuronal excitability and rhythmic behaviors. Here, we show that increases of NALCN expression and function in dorsal root ganglion (DRG) and dorsal spinal cord contribute to chronic constriction injury (CCI)-induced neuropathic pain in rodents. NALCN current and neuronal excitability in acutely isolated DRG neurons and spinal cord slices of rats were increased after CCI which were decreased to normal levels by NALCN-siRNA. Accordingly, pain-related symptoms were significantly alleviated by NALCN-siRNA-mediated NALCN knockdown and completely reversed by NALCN-shRNA-mediated NALCN knockdown in rats or by conditional NALCN knockout in mice. Our results indicate that increases in NALCN expression and function contribute to CCI-induced neuronal sensitization; therefore, NALCN may be a novel therapeutic target for neuropathic pain.

neuroscience↗

bioRxiv2020

Characterization of histone inheritance patterns in the Drosophila female germline

Stem cells have the unique ability to undergo asymmetric division which produces two daughter cells that are genetically identical, but commit to different cell fates. The loss of this balanced asymmetric outcome can lead to many diseases, including cancer and tissue dystrophy. Understanding this tightly regulated process is crucial in developing methods to treat these abnormalities. Here, we report that produced from a Drosophila female germline stem cell asymmetric division, the two daughter cells differentially inherit histones at key genes related to either maintaining the stem cell state or promoting differentiation, but not at constitutively active or silenced genes. We combined histone labeling with DNA Oligopaints to distinguish old versus new histone distribution and visualize their inheritance patterns at single-gene resolution in asymmetrically dividing cells in vivo. This strategy can be widely applied to other biological contexts involving cell fate establishment during development or tissue homeostasis in multicellular organisms.

developmental biology↗

bioRxiv2020

BARcode DEmixing through Non-negative Spatial Regression (BarDensr)

Modern spatial transcriptomics methods can target thousands of different types of RNA transcripts in a single slice of tissue. Many biological applications demand a high spatial density of transcripts relative to the imaging resolution, leading to partial mixing of transcript rolonies in many voxels; unfortunately, current analysis methods do not perform robustly in this highly-mixed setting. Here we develop a new analysis approach, BARcode DEmixing through Non-negative Spatial Regression (BarDensr): we start with a generative model of the physical process that leads to the observed image data and then apply sparse convex optimization methods to estimate the underlying (demixed) rolony densities. We apply Bar-Densr to simulated and real data and find that it achieves state of the art signal recovery, particularly in densely-labeled regions or data with low spatial resolution. Finally, BarDensr is fast and parallelizable. We provide open-source code as well as an implementation for the NeuroCAAS cloud platform. Author SummarySpatial transcriptomics technologies allow us to simultaneously detect multiple molecular targets in the context of intact tissues. These experiments yield images that answer two questions: which kinds of molecules are present, and where are they located in the tissue? In many experiments (e.g., mapping RNA expression in fine neuronal processes), it is desirable to increase the signal density relative to the imaging resolution. This may lead to mixing of signals from multiple RNA molecules into single imaging voxels; thus we need to demix the signals from these images. Here we introduce BarDensr, a new computational method to perform this demixing. The method is based on a forward model of the imaging process, followed by a convex optimization approach to approximately invert mixing induced during imaging. This new approach leads to significantly improved performance in demixing imaging data with dense expression and/or low spatial resolution.

genomics↗

bioRxiv2020

Asymmetric histone inheritance regulates stem cell fate in Drosophila midgut

A fundamental question in developmental biology is how distinct cell fates are established and maintained through epigenetic mechanisms in multicellular organisms. Here, we report that preexisting (old) and newly synthesized (new) histones H3 and H4 are asymmetrically inherited by the distinct daughter cells during asymmetric division of Drosophila intestinal stem cells (ISCs). By contrast, in symmetrically dividing ISCs that produce two self-renewed stem cells, old and new H3 and H4 show symmetric inheritance patterns. These results indicate that asymmetric histone inheritance is tightly associated with the distinct daughter cell fates. To further understand the biological significance of this asymmetry, we express a mutant histone that compromises asymmetric histone inheritance pattern. We find increased symmetric ISC division and ISC tumors during aging under this condition. Together, our results demonstrate that asymmetric histone inheritance is important for establishing distinct cell identities in a somatic stem cell lineage, consistent with previous findings in asymmetrically dividing male germline stem cells in Drosophila. Therefore, this work sheds light on the principles of histone inheritance in regulating stem cell fate in vivo.

developmental biology↗

bioRxiv2020

Human Embryonic Stem Cell-derived Lung Organoids: a Model for SARS-CoV-2 Infection and Drug Test

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we demonstrated that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids. Ciliated cells, alveolar type 2 (AT2) cells and rare club cells were virus target cells. Electron microscopy captured typical replication, assembly and release ultrastructures and revealed the presence of viruses within lamellar bodies in AT2 cells. Virus infection induced more severe cell death in alveolar organoids than in airway organoids. Additionally, RNA-seq revealed early cell response to SARS-CoV-2 infection and an unexpected downregulation of ACE2 mRNA. Further, compared to the transmembrane protease, serine 2 (TMPRSS2) inhibitor camostat, the nucleotide analog prodrug Remdesivir potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model for SARS-CoV-2 infection and drug discovery.

microbiology↗

bioRxiv2020

Impaired learning and memory ability induced by a bilaterally hippocampal injection of streptozotocin in mice: involved with the adaptive changes of synaptic plasticity

BackgroundAlzheimers disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability and loss of self-sufficiency. ObjectiveTo establish an AD mice model, investigate the behavioral performance, and explore the potential mechanism. MethodsStreptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL /6 mice to establish the AD model. Behavioral changes (anhedonia and despair, balance and motor coordination, locomotion, and learning and memory) were examined and the serum concentrations of insulin and nesfatin-1 were measured by ELISA. The activation of hippocampal microglia was assessed by immunohistochemistry and the protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the prefrontal cortex (PFC) was detected via western blotting. ResultsThe STZ model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-{beta}-catenin/{beta}-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3{beta} (ser9)/GSK-3{beta} were reduced in the hippocampus. ConclusionA bilateral hippocampal microinjection of STZ could successfully duplicate an AD mice model, as indicated by the impaired learning and memory and the alternated synaptic plasticity, together with the hyperactive inflammatory response in the hippocampus and the imbalanced abundance of serum insulin and nesfatin-1. Apart from these, the mechanism might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=99 SRC="FIGDIR/small/235481v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@181c9a9org.highwire.dtl.DTLVardef@1deaa4forg.highwire.dtl.DTLVardef@17f3f09org.highwire.dtl.DTLVardef@1037c21_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Characterization of the gut DNA and RNA viromes in a cohort of Chinese residents and visiting Pakistanis

BackgroundTrillions of viruses inhabit the gastrointestinal tract. Some of them have been well-studied on their roles in infection and human health, but the majority remain unsurveyed. It has been established that the composition of the gut virome is highly variable based on the changes of diet, physical state, and environmental factors. However, the effect of host genetic factors, e.g. ethnic origin, on the gut virome is rarely investigated. Methods and ResultsHere, we characterized and compared the gut virome in a cohort of local Chinese residents and visiting Pakistani individuals, each group containing 24 healthy adults and 6 children. Using metagenomic shotgun sequencing and assembly of fecal samples, a huge number of viral operational taxonomic units (vOTUs) were identified for profiling the DNA and RNA viromes. National background contributed a primary variation to individuals gut virome. Compared with the Chinese adults, the Pakistan adults showed higher macrodiversity and different compositional and functional structures in their DNA virome and lower diversity and altered composition in their RNA virome. The virome variations of Pakistan children were inherited from the that of the adults but also tended to share similar characteristics with the Chinese cohort. We also analyzed and compared the bacterial microbiome between two cohorts and further revealed numerous connections between virus and bacterial host. Statistically, the gut DNA and RNA viromes were covariant to some extent (p<0.001), and they both influenced the holistic bacterial composition and vice versa. ConclusionsThis study provides an overview of gut viral community in Chinese and visiting Pakistanis and proposes a considerable role of ethnic origin in shaping the virome.

microbiology↗

bioRxiv2020

Statistical model integrating interactions into genotype-phenotype association mapping: an application to reveal 3D-genetic basis underlying Autism

Biological interactions are prevalent in the functioning organisms. Correspondingly, statistical geneticists developed various models to identify genetic interactions through genotype-phenotype association mapping. The current standard protocols in practice test single variants or single regions (that contain multiple local variants) sequentially along the genome, followed by functional annotations that involve various aspects including interactions. The testing of genetic interactions upfront is rare in practice due to the burden of testing a huge number of combinations, which lead to the multiple-test problem and the risk of overfitting. In this work, we developed interaction-integrated linear mixed model (ILMM), a novel model that integrates a priori knowledge into linear mixed models. ILMM enables statistical integration of genetic interactions upfront and overcomes the problems associated with combination searching. Three dimensional (3D) genomic interactions assessed by Hi-C experiments have led to unprecedented biological discoveries. However, the contribution of 3D genomic interactions to the genetic basis of complex diseases has yet to be quantified. Using 3D interacting regions as a priori information, we conducted both simulations and real data analysis to test ILMM. By applying ILMM to whole genome sequencing data for Autism Spectrum Disorders, or ASD (MSSNG) and transcriptome sequencing data (GTEx), we revealed the 3D-genetic basis of ASD and 3D-eQTLs for a substantial proportion of gene expression in brain tissues. Moreover, we have revealed a potential mechanism involving distal regulation between FOXP2 and DNMT3A conferring the risk of ASD. Software is freely available in our GitHub: https://github.com/theLongLab/Jawamix5

genetics↗