Biology subjects

Ren, X.

Publications and source records attributed to Ren, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2020

Experimental Stroke Induces Chronic Gut Dysbiosis and Neuroinflammation in Male Mice

Recent literature implicates gut epithelia mucosa and intestinal microbiota as important players in post-stroke morbidity and mortality. As most studies have focused on the acute effects of stroke on gut dysbiosis, our study objective was to measure chronic, longitudinal changes in the gut microbiota and intestinal pathology following ischemic stroke. We hypothesized that mice with experimental ischemic stroke would exhibit chronic gut dysbiosis and intestinal pathology up to 36 days post-stroke compared to sham controls. Male C57BL/6J mice were subjected to 60 minutes of transient middle cerebral artery occlusion (tMCAO) or sham surgery. To determine the long-term effects of tMCAO on gut dysbiosis, fecal boli were collected pre- and post-tMCAO on days 0, 3, 14, and 28. Bioinformatics analysis demonstrate significant differences in abundance among Firmicutes and Bacteroidetes taxa at the phylum, family, and species levels in tMCAO compared to sham mice that persisted up to one month post-stroke. The most persistent changes in post-stroke microbial abundance were a decrease in bacteria family S24-7 and significant increases in Ruminococcaceae. Overall, these changes resulted in a persistently increased Firmicutes:Bacteroidetes ratio in stroke animals. Intestinal histopathology showed evidence of chronic intestinal inflammation that included marked increases in immune cell infiltration with mild-moderate epithelial hyperplasia and villous blunting. Increased astrocyte and microglial activity were also detected one-month post-stroke. These results demonstrate that acute, post-stroke disruption of the gut-brain-microbiota axis progresses to chronic gut dysbiosis, intestinal inflammation, and chronic neuroinflammation. Clinical PerspectivesO_LIThe microbiota-gut-brain axis, recently implicated in several neurological disorders, remains largely unexplored at chronic time points post-tMCAO. C_LIO_LIOur results demonstrate chronic gut dysbiosis, prolonged behavioral deficits, and persistent cerebral and intestinal inflammation post-tMCAO in male C57BL/6J mice. C_LIO_LIThese results suggest that manipulation of microbiota may help reduce poor outcomes after stroke and lead to improved post-stroke functional recovery. C_LI

neuroscience↗

bioRxiv2020

Layered Feedback Control Improves Robust Functionality across Heterogeneous Cell Populations

Realizing homeostatic control of metabolites or proteins is one of the key goals of synthetic circuits. However, if control is only implemented internally in individual cells, cell-cell heterogeneity may break the homeostasis on population level since cells do not contribute equally to the production or regulation. New control structures are needed to achieve robust functionality in heterogeneous cell populations. Quorum sensing (QS) serves as a collective mechanism by releasing and sensing small and diffusible signaling molecules for group decision-making. We propose a layered feedback control structure that includes a global controller using quorum sensing and a local controller via internal signal-receptor systems. We demonstrate with modeling and simulation that the global controller drives contributing cells to compensate for disturbances while the local controller governs the fail-mode performance in non-contributing cells. The layered controller can tolerate a higher portion of non-contributing cells or longer generations of mutant cells while maintaining metabolites or proteins level within a small error range, compared with only internal feedback control. We further discuss the potential of such layered structures in robust control of cell population size, population fraction and other population-dependent functions.

synthetic biology↗

bioRxiv2020

An emergent clade of SARS-CoV-2 linked to returned travellers from Iran

The SARS-CoV-2 epidemic has rapidly spread outside China with major outbreaks occurring in Italy, South Korea and Iran. Phylogenetic analyses of whole genome sequencing data identified a distinct SARS-CoV-2 clade linked to travellers returning from Iran to Australia and New Zealand. This study highlights potential viral diversity driving the epidemic in Iran, and underscores the power of rapid genome sequencing and public data sharing to improve the detection and management of emerging infectious diseases.

microbiology↗

bioRxiv2020

DeepDigest: prediction of protein proteolytic digestion with deep learning

In shotgun proteomics, it is essential to accurately determine the proteolytic products of each protein in the sample for subsequent identification and quantification, because these proteolytic products are usually taken as the surrogates of their parent proteins in the further data analysis. However, systematical studies about the commonly used proteases in proteomics research are insufficient, and there is a lack of easy-to-use tools to predict the digestibilities of these proteolytic products. Here, we propose a novel sequence-based deep learning model - DeepDigest, which integrates convolutional neural networks and long-short term memory networks for digestibility prediction of peptides. DeepDigest can predict the proteolytic cleavage sites for eight popular proteases including trypsin, ArgC, chymotrypsin, GluC, LysC, AspN, LysN and LysargiNase. Compared with traditional machine learning algorithms, DeepDigest showed superior performance for all the eight proteases on a variety of datasets. Besides, some interesting characteristics of different proteases were revealed and discussed.

bioinformatics↗

bioRxiv2020

Stiffness of Nanoparticulate Mineralized Collagen Scaffolds Triggers Osteogenesis via Mechanotransduction and Canonical Wnt Signaling

The ability of the extracellular matrix (ECM) to instruct progenitor cell differentiation has generated excitement for the development of materials-based regenerative solutions. We previously described a nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) material capable of inducing in vivo skull regeneration approaching 60% of the biomechanical properties of native calvarium without exogenous growth factors or ex vivo progenitor cell-priming, suggesting promise as a first-generation material for skull regeneration. Here, we evaluated the contribution of titrating stiffness to osteogenicity by comparing non-crosslinked (NX-MC) and crosslinked (MC) forms of MC-GAG. While both materials were osteogenic, MC demonstrated an increased expression of osteogenic markers and mineralization compared to NX-MC. Both materials were capable of autogenously activating the canonical bone morphogenetic protein receptor (BMPR) signaling pathway with phosphorylation of Smad1/5 (small mothers against decapentaplegic-1/5). However, unlike NX-MC, hMSCs cultured on MC demonstrated significant elevations in the major mechanotransduction mediators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) expression coincident with {beta}-catenin activation in the canonical Wnt signaling pathway. Inhibition of YAP/TAZ activation reduced osteogenic marker expression, mineralization, and {beta}-catenin activation in MC with a much lesser of an effect on NX-MC. YAP/TAZ inhibition also resulted in a reciprocal increase in Smad1/5 phosphorylation as well as BMP2 expression. Our results indicate that increasing MC-GAG stiffness induces osteogenic differentiation via the mechanotransduction mediators YAP/TAZ and the canonical Wnt signaling pathway, whereas the canonical BMPR signaling pathway is activated in a manner independent of mechanical cues.

bioengineering↗

bioRxiv2020

Establishment of a marine nematode model for animal functional genomics, environmental adaptation and developmental evolution

Nematodes play key roles in marine ecosystem. Although oceans cover 71% of the Earths surface, none of marine model nematode has been reported. Here, we constructed the first inbred line of free-living marine nematode Litoditis marina, sequenced and assembled its genome. Furthermore, we successfully applied CRISPR/Cas9 genome editing in L. marina. Comparative genomics revealed that immunity and oxygen regulation genes are expanded, which is probably central to its sediment adaptation. While L. marina exhibits massive gene contractions in NHRs, chemoreceptors, xenobiotics detoxification and core histones, which could explain the more defined marine environment. Our experiments showed that dozens of H4 genes in Caenorhabditis elegans might contribute to its adaptation to the complex terrestrial environments, while two H4 genes in L. marina are involved in salinity stress adaptation. Additionally, ninety-two conserved genes appear to be positively selected in L. marina, which may underpin its osmotic, neuronal and epigenetic changes in the sea. With short generation time, highly inbred lines, and genomic resources, our report brings L. marina a promising marine animal model, and a unique satellite marine model to the well-known biomedical model nematode C. elegans. This study will underpin ongoing work on animal functional genomics, environmental adaptation and developmental evolution.

genomics↗

bioRxiv2020

RNAAgeCalc: A multi-tissue transcriptional age calculator

We introduced RNAAgeCalc, a versatile across-tissue and tissue-specific transcriptional age calculator. We utilized GTEx database to identify 1,616 common age-related genes based on meta-analysis of transcriptional age signature across multi-tissues. Additionally, tissue-specific age-related genes were obtained from differential expression analysis on individual tissues. By performing across-tissue transcriptional age prediction, we showed that our 1,616 common age-related genes outperformed other prior age related gene signatures. Furthermore, we utilized TCGA database to demonstrate that the transcriptional age acceleration computed from our within-tissue predictor was significantly correlated with mutation burden, mortality risk and cancer stage. RNAAgeCalc is available at http://www.ams.sunysb.edu/~pfkuan/softwares.html#RNAAgeCalc.

bioinformatics↗

bioRxiv2020

Reconstruction of cell spatial organization based on ligand-receptor mediated self-assembly

Single-cell RNA sequencing (scRNA-seq) has revolutionized transcriptomic studies by providing unprecedented cellular and molecular throughputs, but spatial information of individual cells is lost during tissue dissociation. While imaging-based technologies such as in situ sequencing show great promise, technical difficulties currently limit their wide usage. Since cellular spatial organization is inherently encoded by cell identity and can be reconstructed, at least in part, by ligand-receptor interactions, here we present CSOmap, a computational strategy to infer cellular interaction from scRNA-seq. We show that CSOmap can successfully recapitulate the spatial organization of tumor microenvironments for multiple cancers and reveal molecular determinants of cellular interactions. Further, CSOmap readily simulates perturbation of genes or cell types to gain novel biological insights, especially into how immune cells interact in the tumor microenvironment. CSOmap can be widely applicable to interrogate cellular organizations based on scRNA-seq data for various tissues in diverse systems.

bioinformatics↗

bioRxiv2020

Exosome-mediated apoptosis pathway during WSSV infection in crustacean mud crab

MicroRNAs are regulatory molecules that can be packaged into exosomes to modulate recipients cellular response, while their role during viral infection is beginning to be appreciated. However, the involvement of exosomal miRNAs during immunoregulation in invertebrates has not been addressed. Here, we found that exosomes released from WSSV-injected mud crabs could suppress viral invasion by inducing apoptosis of hemocytes. Besides, miR-137 and miR-7847 were found to be less packaged in mud crab exosomes during viral infection, with both miR-137 and miR-7847 shown to be negative apoptosis regulators by targeting the apoptosis-inducing factor (AIF). Moreover, our data revealed that AIF did not only translocate to the nucleus to induce DNA fragmentation, but could also competitively bind to HSP70 to disintegrate the HSP70-Bax (Bcl-2-associated X protein) complex, which eventually activated the mitochondria apoptosis pathway via free Bax. Therefore, our findings provides a novel mechanism underlying the crosstalk between exosomal miRNAs and apoptosis pathway in innate immunity in invertebrates.

immunology↗

bioRxiv2020

Landscape of transcript isoforms in single T cells infiltrating in non-small cell lung cancer

Single cell RNA-seq has enabled high-resolution characterization of molecular signatures of tumor-infiltrating lymphocytes. However, analyses at the transcript isoform level are rarely reported. As alternative splicing is critical to T cell differentiation and activation, here we proposed a computational method named as IDEA to comprehensively detect and annotate differentially used isoforms across cell subtypes. We applied IDEA on a scRNA-seq dataset of 12,346 T cells from non-small cell lung cancer. We found most genes tend to dominantly express one isoform in single T cells, enabling typing T cells according to the isotypes given a gene. Isotype analysis suggested that tumor-infiltrating T cells significantly preferred specific isotypes for 245 genes in CD8+ T cells and 456 genes in CD4+ T cells. Functional annotation suggests that the preferred isoforms involved in coding/non-coding switches, transcription start site changes, gains/losses of domains and subcellular translocation. Clonal analysis revealed that isoform switching occurred during T cell activation/differentiation. Our analysis provides precise characterization of the molecular events in tumor-infiltrating T cells and sheds new lights into the regulatory mechanisms of tumor-infiltrating T cells.

cancer biology↗

bioRxiv2019

Automatic and fast encoding of representational uncertainty underlies probability distortion

Humans do not have an accurate representation of probability information in the environment but distort it in a surprisingly stereotyped way ("probability distortion"), as shown in a wide range of judgment and decision-making tasks. Many theories hypothesize that humans automatically compensate for the uncertainty inherent in probability information ("representational uncertainty") and probability distortion is a consequence of uncertainty compensation. Here we examined whether and how the representational uncertainty of probability is quantified in the human brain and its relevance to probability distortion behavior. Human subjects kept tracking the relative frequency of one color of dot in a sequence of dot arrays while their brain activity was recorded by magnetoencephalography (MEG). We found converging evidence from both neural entrainment and time-resolved decoding analysis that a mathematically- derived measure of representational uncertainty is automatically computed in the brain, despite it is not explicitly required by the task. In particular, the encodings of relative frequency and its representational uncertainty respectively occur at latencies of approximately 300 ms and 400 ms. The relative strength of the brain responses to these two quantities correlates with the probability distortion behavior. The automatic and fast encoding of the representational uncertainty provides neural basis for the uncertainty compensation hypothesis of probability distortion. More generally, since representational uncertainty is closely related to confidence estimation, our findings exemplify how confidence might emerge prior to perceptual judgment.

neuroscience↗

bioRxiv2019

Host fruit as a suitable bacteria growth substrate that promotes larval development of Bactrocera dorsalis (Diptera: Tephritidae)

The ability of a host plant to act as a substrate or media for larval development may depend on how good it is at offering suitable nutrients for bacterial growth. In this study, we hypothesized that the suitability of a fruit type for fruit fly larval development is positively correlated with the ability of that fruit to act as a substrate/media for fruit fly symbiotic bacterial growth. We allowed a single female fruit fly to lay eggs on five different host fruits, then we monitored the larval development parameters across five generations and analyzed the bacterial community structure of larvae developing in 2 of these hosts (apple and banana) at the first and fifth generations. Results indicate that the larval length and dry weight did not vary significantly across experimental generations, but were greatly affected by fruit types and larval stages. The larval development time was extended considerably in apple and tomato but shortened in banana and mango. There was a significant shift in bacterial community structure and composition across fruits and generations. The bacterial community of larvae within the same fruit (apple and banana) clustered and was similar to the parental female (with the predominance of Proteobacteria), but there was a shift at the fifth generation (dominance of Firmicutes). Banana offered a suitable better development and growth to larvae and bacteria, respectively, compared to apple in which reduced larval development and bacterial growth were recorded. Although additional experiments are needed to adequately show that the differences in microbiome seen in fruit fly larval guts are the actual driver of different developmental outcomes of larvae on the different fruits, at the very least, our study has provided intriguing data suggesting interaction between the diets and gut microbial communities on insect development.\n\nImportance and Significance of the studyTephritid fruit flies entertain complex interactions with gut bacteria. These bacteria are known to provide nutritional benefits to their hosts, by supplementing missing nutrients from the host diets and regulating energy balance. Foraging for food is a risky exercise for the insect which is exposed to ecological adversities, including predators. Therefore, making beneficial choice among available food substrates is a question of survival for the flies and bacteria as well. Our study demonstrates interactions between the host fly and its intestinal bacteria in sustaining the larval development while foraging optimally on different fruit types. These findings add a novel step into our understanding of the interactions between the gut microbial communities and B. dorsalis and provide avenues for developing control strategies to limit the devastative incidence of the fly.

microbiology↗

bioRxiv2019

ROGUE: an entropy-based universal metric for assessing the purity of single cell population

Single-cell RNA sequencing (scRNA-seq) is a versatile tool for discovering and annotating cell types and states, but the determination and annotation of cell subtypes is often subjective and arbitrary. Often, it is not even clear whether a given cluster is uniform. Here we present an entropy-based statistic, ROGUE, to accurately quantify the purity of identified cell clusters. We demonstrated that our ROGUE metric is generalizable across datasets, and enables accurate, sensitive and robust assessment of cluster purity on a wide range of simulated and real datasets. Applying this metric to fibroblast and B cell datasets, we identified additional subtypes and demonstrated the application of ROGUE-guided analyses to detect true signals in specific subpopulations. ROGUE can be applied to all tested scRNA-seq datasets, and has important implications for evaluating the quality of putative clusters, discovering pure cell subtypes and constructing comprehensive, detailed and standardized single cell atlas.

bioinformatics↗

bioRxiv2019

Highly efficient transgenesis with miniMos in Caenorhabditis briggsae

C. briggsae as a companion species for C. elegans has played an increasingly important role in study of evolution of development, gene regulation and genome. Aided by the isolation of its sister spices, it has recently been established as a model for speciation study. To take full advantage of the species for comparative study, an effective transgenesis method especially those with single copy insertion is important for functional comparison. Here we modified a transposon-based transgenesis methodology that had been originally developed in C. elegans but worked marginally in C. briggsae. By incorporation of a heat shock step, the transgenesis efficiency in C. briggsae with single copy insertion is comparable to that in C. elegans. We used the method to generate 54 independent insertions mostly consisting of a mCherry tag over the C. briggsae genome. We demonstrated the use of the tags in identifying interacting loci responsible for hybrid male sterility between C. briggsae and C. nigoni when combined with the GFP tags we generated previously. Finally, we demonstrated that C. briggsae has developed native immunity against the C. elegans toxin, PEEL-1, but not SUP-35, making the latter a potential negative selection marker against extrachromosomal array.\n\nSummaryNematode C. briggsae has been used for comparative study against C. elegans over decades. Importantly, a sister species has recently been identified, with which C. briggsae is able to mate and produce viable hybrid progeny. This opens the possibility of using nematode species as a model for speciation study for the first time. To take full advantage of C. briggsae for comparative study, an effective transgenesis method to generate single copy insertion is important especially for functional comparison. An attempt was made previously to generate single copy insertion with transposon-based transgenesis methodology, which had been originally developed in C. elegans but with limited success in C. briggsae. Here we modified the transposon-based methodology by incorporation of a heat shock step, which allows us to achieve a much higher transgenesis efficiency in C. briggsae with single copy insertion. We used the method to generate 54 independent insertions mostly consisting of a mCherry tag over the C. briggsae genome. We demonstrated the use of the tags in identifying interacting loci responsible for hybrid male sterility between C. briggsae and C. nigoni when combined with the GFP tags we generated previously. Finally, we demonstrated that C. briggsae has developed native immunity against the C. elegans toxin, PEEL-1, but not SUP-35, making the latter a potential negative selection marker against extrachromosomal array. Taken together, the modified transgenesis methodology and the transgenic strains generated in this study are expected to further facilitate C. briggsae as a model for comparative study or speciation study.

genetics↗

bioRxiv2019

The bounded rationality of probability distortion: the bounded log-odds model

AO_SCPLOWBSTRACTC_SCPLOWIn decision-making under risk (DMR) participants choices are based on probability values systematically different from those that are objectively correct. Similar systematic distortions are found in tasks involving relative frequency judgments (JRF). These distortions limit performance in a wide variety of tasks and an evident question is, why do we systematically fail in our use of probability and relative frequency information? We propose a Bounded Log-Odds Model (BLO) of probability and relative frequency distortion based on three assumptions: (1) log-odds: probability and relative frequency are mapped to an internal log-odds scale, (2) boundedness: the range of representations of probability and relative frequency are bounded and the bounds change dynamically with task, and (3) variance compensation: the mapping compensates in part for uncertainty in probability and relative frequency values. We compared human performance in both DMR and JRF tasks to the predictions of the BLO model as well as eleven alternative models each missing one or more of the underlying BLO assumptions (factorial model comparison). The BLO model and its assumptions proved to be superior to any of the alternatives. In a separate analysis, we found that BLO accounts for individual participants data better than any previous model in the DMR literature. We also found that, subject to the boundedness limitation, participants choice of distortion approximately maximized the mutual information between objective task-relevant values and internal values, a form of bounded rationality. SO_SCPLOWIGNIFICANCEC_SCPLOW SO_SCPLOWTATEMENTC_SCPLOWPeople distort probability in decision under risk and many other tasks. These distortions can be large, leading us to make markedly suboptimal decisions. There is no agreement on why we distort probability. Distortion changes systematically with task, hinting that distortions are dynamic compensations for some intrinsic "bound" on working memory. We first develop a model of the bound and the compensation process and then report an experiment showing that the model accounts for individual human performance in decision under risk and relative frequency judgments. Last, we show that the particular compensation in each experimental condition serve to maximize the mutual information between objective decision variables and their internal representations. We distort probability to compensate for our own working memory limitations.

neuroscience↗

bioRxiv2019

SciBet: An ultra-fast classifier for cell type identification using single cell RNA sequencing data

Fast, robust and technology-independent computational methods are needed for supervised cell type annotation of single-cell RNA sequencing data. We present SciBet, a Bayesian classifier that accurately predicts cell identity for newly sequenced cells or cell clusters. We enable web client deployment of SciBet for rapid local computation without uploading local data to the server. This user-friendly and cross-platform tool can be widely useful for single cell type identification.

bioinformatics↗

bioRxiv2019

Structural basis for tetherin antagonism as a barrier to zoonotic lentiviral transmission

Tetherin is a host defense that physically prevents escape of virions from the plasma membrane. Human tetherin lacks the motif DIWK antagonized by SIV, the antecedent of HIV. Here, we reconstituted the AP-2 clathrin adaptor complex with a simian tetherin and SIV Nef and determined its structure by cryo-EM. Nef refolds the first -helix of the {beta}2 subunit of AP-2 to a {beta} hairpin, creating a binding site for the DIWK sequence. The tetherin binding site in Nef is distinct from those of MHC-I, CD3, and CD4, but overlaps the site for SERINC5 restricting viral infectivity. The structure explains the dependence of SIVs on the host tetherin DIWK sequence and the consequent barrier to human transmission.

biochemistry↗

bioRxiv2019

Alterations of the pulmonary immunity are independent of spontaneous pneumonia in an experimental model of ischemic stroke

Stroke-associated pneumonia (SAP) is a major cause of mortality in patients who have suffered from severe ischemic stroke. Although multi-factorial in nature, stroke-induced immunosuppression plays a key role in the development of SAP. Previous studies of focal ischemic stroke induction, using a murine model of transient middle cerebral artery occlusion (tMCAO) have shown that severe brain damage results in massive apoptosis and functional defects of lymphocytes in the spleen, thymus, and peripheral blood. However, how immune alternations in remote tissues lead to a greater susceptibility to lung infections is not well-understood. Importantly, how ischemic stroke alters immune-cell fates, and the expression of cytokines and chemokines in the lungs that directly impact pulmonary immunity, has not been characterized. We report here that ischemic stroke increases the percentage of alveolar macrophages, neutrophils, and CD11b+ dendritic cells (DCs), but reduces the percentage of CD4+ T cells, CD8+ T cells, B cells, natural killer (NK) cells, and eosinophils in the lungs. The depletion of immune cells in the lungs is not caused by apoptosis, cell infiltration to the brain, or spontaneous pneumonia following ischemic stroke as previously described, but correlates with a significant reduction in the levels of multiple chemokines in the lungs, including: CCL3, CCL4, CCL5, CCL17, CCL20, CCL22, CXCL5, CXCL9, and CXCL10. These findings suggest that ischemic stroke negatively impacts pulmonary immunity to become more susceptible for SAP development. Further investigation into the mechanisms that control pulmonary immune alternations following ischemic stroke may identify novel diagnostic or therapeutic targets for SAP.

immunology↗