Biology subjects

Xiao, Y.

Publications and source records attributed to Xiao, Y..

At least 289 records · Page 16Linked to original sources

bioRxiv2021

Structure of SOQ1 lumenal domains identifies potential disulfide exchange for negative regulation of photoprotection, qH

Non-photochemical quenching (NPQ) plays an important role for phototrophs in decreasing photo-oxidative damage. qH is a sustained component of NPQ and depends on the plastid lipocalin (LCNP). A thylakoid membrane-anchored protein SUPPRESSOR OF QUENCHING1 (SOQ1) prevents qH formation by inhibiting LCNP. SOQ1 suppresses qH with its lumen-located C-terminal Trx-like and NHL domains. Here we report crystal structures and biochemical characterization of SOQ1 lumenal domains. Our results show that the Trx-like and NHL domains are stably associated, with the potential redox-active motif located at their interface. Residue E859 essential for SOQ1 function is pivotal for mediating the inter-domain interaction. Moreover, the C-terminal region of SOQ1 forms an independent {beta}-stranded domain, which possibly interacts with the Trx-like domain through disulfide exchange. Furthermore, SOQ1 is susceptible to cleavage at the loops connecting the neighboring domains both in vitro and in vivo, which could be a regulatory process for its suppression function of qH.

plant biology↗

bioRxiv2021

Oligodendrocyte Precursor Cells Sculpt the Visual System by Regulating Axonal Remodeling

Many oligodendrocyte precursor cells (OPCs) do not differentiate to form myelin, suggesting additional roles of this cell population. The zebrafish optic tectum contains OPCs in regions devoid of myelin. Elimination of these OPCs impaired precise control of retinal ganglion cell axon arbor size during formation and maturation of retinotectal connectivity, and in consequence impaired visual acuity. Therefore, OPCs fine-tune neural circuit structure and function independently of their canonical role to make myelin.

neuroscience↗

bioRxiv2021

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasion in vivo

Chromatin remodelers such as the SWI/SNF complex coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in genes encoding the structural subunits of chromatin, such as histone subunits, and chromatin regulating factors (CRFs) are associated with a variety of disease mechanisms including cancer metastasis, in which cancer co-opts cellular invasion programs functioning in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin agents and CRFs that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and enhanced RNA interference (RNAi) vectors, we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Our data specifically implicate the SWI/SNF BAF assembly in the regulation of the G0 cell cycle arrest in the AC, whereas the SWI/SNF PBAF assembly promotes AC invasion via cell cycle-independent mechanisms, including attachment to the basement membrane (BM) and activation of the pro-invasive fos-1/FOS gene. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into how the SWI/SNF assemblies differentially contribute to cellular invasion and how SWI/SNF subunit-specific disruptions may contribute to tumorigeneses and cancer metastasis. SUMMARY STATEMENTCellular invasion through the basement membrane by the C. elegans anchor cell requires both BAF and PBAF SWI/SNF assemblies to arrest the cell cycle and promote the expression of pro-invasive genes.

developmental biology↗

bioRxiv2021

MAPK Pathway Inhibition as A Rational Therapeutic Strategy for MiR-138-5p/PAQR3 Dysregulation-mediated Epirubicin Resistance in Triple-negative Breast Cancer

Anthracyclines, such as epirubicin, activate the mitogen-activated protein kinase (MAPK) pathway in breast cancer (BC). Better predictors of tumor response are needed to guide de-intensification of anthracyclines when used in BC treatment. Here, we aimed to see if MAPK activation was responsible and targetable for epirubicin resistance, and to explore mechanisms and predictive markers for resistance. MAPK pathway inhibitors were used to ameliorate epirubicin resistance. Negative regulators of MAPK were screened to identify the essential gene cascades required for activation of the pathway. In vitro and in vivo approaches were applied to investigate epirubicin resistance. The regulatory miRNA was identified through bioinformatics-based screening and luciferase reporter assay. 114 estrogen receptor negative patients who received epirubicin monotherapy were included to evaluate predictive markers for tumor response. The MAPK pathway was activated in cells resistant to epirubicin; MAPK inhibition ameliorated epirubicin resistance. In triple-negative breast cancer (TNBC), progestin and adipoQ receptor 3 (PAQR3) were the most significantly decreased negative MAPK regulators. PAQR3 increased epirubicin sensitivity and suppressed MAPK activation in resistant cells. MiR-138-5p was increased in epirubicin resistant cells, and was shown to downregulate PAQR3, causing resistance in epirubicin resistant cells. PAQR3 was an independent factor in predicting response to epirubicin (OR=4.86, 95%CI=1.13-20.87, P=0.034), and possessed a high negative predictive value (NPV) (0.93; 95%CI=0.83-0.97). In addition, PAQR3 exhibited a better predictive value in patients older than 50 years (12.92 (95% CI, 1.43-116.78, P = 0.023). The combinative use of PAQR3 and topoisomerase II- (TOP2A) led to an increased specificity (0.70; 95%CI=0.61-0.79), when compared with either PAQR3 or TOP2A alone. MAPK inhibition ameliorated epirubicin resistance. MiR-138-5p-induced PAQR3 reduction causes epirubicin resistance in TNBC via activation of MAPK cascades. PAQR3 is an independent and favorable predictor response to epirubicin in BC.

cancer biology↗

bioRxiv2021

BRAF inhibitors reprogram cancer-associated fibroblasts to drive matrix remodeling and therapeutic escape in melanoma

The tumor stroma and its cellular components are known to play an important role in tumor resilience towards treatment. Here, we report a novel resistance mechanism in melanoma that is elicited by BRAF inhibitors (BRAFi)-induced non-canonical nuclear {beta}-catenin signaling in cancer-associated fibroblasts (CAFs). Our study reveals that BRAFi leads to an expanded CAF population with increased {beta}-catenin nuclear accumulation and enhances their biological properties. This CAF subpopulation is essential for melanoma cells to grow and resist to BRAFi/MEK inhibitors (MEKi). Mechanistically, BRAFi induces BRAF and CRAF dimerization and subsequently the activation of ERK signaling in CAFs, leading to the inactivation of the {beta}-catenin destruction complex. By RNA-Seq, periostin (POSTN) is identified as a major downstream effector of {beta} catenin in CAFs and can compensate for the loss of {beta}-catenin in CAFs in conferring melanoma cell BRAFi/MEKi resistance. Moreover, POSTN reactivates the ERK pathway, which is inhibited by BRAFi/MEKi, in melanoma cells through PI3K/AKT signaling. Our data underscore the roles of BRAFi-induced CAF reprogramming in matrix remodeling and therapeutic escape of melanoma cells and reveal POSTN as an important matrix target to eliminate BRAFi/MEKi resistance in melanoma.

cancer biology↗

bioRxiv2021

Characterizing white matter alterations in drug-naïve de novo Parkinsons disease with diffusion MRI

Parkinsons disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and non-motor symptoms, often with the motor dysfunction initiated unilaterally. Knowledge regarding disease-related alterations in white matter pathways can effectively help improve the understanding of the disease and propose targeted treatment strategies. Microstructural imaging techniques, including diffusion tensor imaging (DTI), allows inspection of white matter integrity to study the pathogenesis of various neurological conditions. Previous voxel-based analyses with DTI measures, such as fractional anisotropy and mean diffusivity have uncovered changes in brain regions that are associated with PD, but the conclusions were inconsistent, partially due to small patient cohorts and the lack of consideration for clinical laterality onset, particularly in early PD. Fixel-based analysis (FBA) is a recent framework that offers tract-specific insights regarding white matter health, but very few FBA studies on PD exist. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug-naive de novo PD cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to both functional degeneration and the creation of compensatory networks in the early stage.

neuroscience↗

bioRxiv2021

Rapid spread of a symbiotic virus in a major crop pest following wide-scale adoption of Bt-cotton in China

Bacillus thuringiensis (Bt) crops have been widely planted and the effects of Bt-crops on populations of the target and non-target insect pests were well studied. However, the effects of Bt-crops exposure on microorganisms that interact with crop pests havent previously been quantified. Here, we use laboratory and field data to show that infection of Helicoverpa armigera with a symbiotic densovirus (HaDV2) is associated with its enhanced growth and resistance to Bt-cotton. Moreover, field monitoring showed a much higher incidence of cotton bollworm infection with HaDV2 in regions cultivated with Bt-cotton than in regions without it, with the rate of densovirus infection increasing with increasing use of Bt-cotton. RNA-seq suggested resistance to both baculovirus and Cry1Ac were enhanced via the immune-related pathways. These suggest that the exposure to Bt-crops has selected for beneficial interactions between the target pest and a symbiotic microorganism that enhances its performance on Bt-crops under field conditions.

ecology↗

bioRxiv2021

Experimental and mathematical insights on the interactions between poliovirus and a defective interfering genome

1During replication, RNA viruses accumulate genome alterations, such as mutations and deletions. The interactions between individual variants can determine the fitness of the virus population and, thus, the outcome of infection. To investigate the effects of defective interfering genomes (DI) on wild-type (WT) poliovirus replication, we developed an ordinary differential equation model. We experimentally determined virus and DI replication during co-infection, and use these data to infer model parameters. Our model predicts, and our experimental measurements confirm, that DI replication and encapsidation are the most important determinants for the outcome of the competition. WT replication inversely correlates with DI replication. Our model predicts that genome replication and effective DI genome encapsidation are critical to effectively inhibit WT production, but an equilibrium can be established which enables WT to replicate, albeit to reduce levels.

microbiology↗

bioRxiv2020

MaPPeRTrac: A Massively Parallel, Portable, and Reproducible Tractography Pipeline

Large-scale diffusion MRI tractography remains a significant challenge. Users must orchestrate a complex sequence of instructions that requires many software packages with complex dependencies and high computational cost. We developed MaPPeRTrac, a probabilistic tractography pipeline that simplifies and vastly accelerates this process on a wide range of high performance computing (HPC) environments. It fully automates the entire tractography pipeline, from management of raw MRI machine data to edge density imaging (EDI) of the structural connectome. Dependencies are containerized with Docker or Singularity and de-coupled from code to enable rapid proto-typing and modification. Data artifacts are strictly organized with the Brain Imaging Data Structure (BIDS) to ensure that they are findable, accessible, interoperable, and reusable following FAIR principles. The pipeline takes full advantage of HPC resources using the Parsl parallel programming frame-work, resulting in the creation of connectome datasets of unprecedented size. MaPPeRTrac is publicly available and tested on commercial and scientific hardware, so that it may accelerate brain connectome research for a broader user community.

neuroscience↗

bioRxiv2020

Structural basis for piRNA-targeting

Piwi proteins use PIWI-interacting RNAs (piRNAs) to identify and silence the transposable elements (TEs) pervasively found in animal genomes. The Piwi targeting mechanism is proposed to be similar to targeting by Argonaute proteins, which employ microRNA (miRNA) guides to repress cellular mRNAs, but has not been characterized in detail. We present cryo-EM structures of a Piwi-piRNA complex with and without target RNAs and analysis of target recognition. Resembling Argonaute, Piwi identifies targets using the piRNA seed-region. However, Piwi creates a much weaker seed so that prolonged target association requires further piRNA-target pairing. Beyond the seed, Piwi creates wide central cleft wide for unencumbered piRNA-target pairing, enabling long-lived Piwi-piRNA-target interactions that are tolerant of mismatches. Piwi ensures targeting fidelity by blocking propagation of the piRNA-target duplex in the absence of faithful seed pairing, and by requiring extended piRNA-target pairing to reach an endonucleolytically active conformation. This mechanism allows Piwi to minimize off-targeting cellular mRNAs and adapt piRNA sequences to evolving genomic threats.

molecular biology↗

bioRxiv2020

Effect of the BMPR-II-SMAD3/MRTF complex on proliferation and migration of ASMCs and the mechanism in asthma.

Phenotype transformation of airway smooth muscle (ASM) is the key feature of airway remodelling in asthma. A variety of smooth muscle-specific genes and proteins, including SMAD3, BMPR-II, and MRTF, are involved in airway remodelling in asthma. Bone morphogenetic protein (BMP) signalling plays an important role in the physiological and pathological processes of asthma. As a receptor of BMP signalling, BMPR-II has important roles in variety of cellular processes. However, the understanding of the roles and underlying mechanism of BMPR-II in airway smooth muscle cells (ASMCs) in asthma remains incomplete. First, we observed significant increases in BMPR-II, SMAD3 and MRTF in asthmatic ASMCs at both the mRNA and protein levels. Second, we observed that silencing of siBMPR-II and siMRTF inhibits proliferation, migratory capacity and intracellular Ca2+ concentration in ASMCs. Furthermore, our results revealed these three factors, BMPR-II, SMAD3 and MRTF, form a complex that affects the bioactivities of ASMCs. Taken together, this study indicates that the BMPR-II-SMAD3/MRTF signalling pathway is involved in the process of ASM remodelling, providing novel avenues for the identification of new therapeutic modalities.

cell biology↗

bioRxiv2020

Remote Digital Psychiatry: MindLogger for Mobile Mental Health Assessment and Therapy

BackgroundUniversal access to assessment and treatment of mental health and learning disorders remains a significant and unmet need. There is a vast number of people without access to care because of economic, geographic, and cultural barriers as well as limited availability of clinical experts who could help advance our understanding of mental health. ObjectiveTo create an open, configurable software platform to build clinical measures, mobile assessments, tasks, and interventions without programming expertise. Specifically, our primary requirements include: an administrator interface for creating and scheduling recurring and customized questionnaires where end users receive and respond to scheduled notifications via an iOS or Android app on a mobile device. Such a platform would help relieve overwhelmed health systems, and empower remote and disadvantaged subgroups in need of accurate and effective information, assessment, and care. This platform has potential to advance scientific research by supporting the collection of data with instruments tailored to specific scientific questions from large, distributed, and diverse populations. MethodsWe conducted a search for tools that satisfy the above requirements. We designed and developed a new software platform called "MindLogger" that exceeds the above requirements. To demonstrate the tools configurability, we built multiple "applets" (collections of activities) within the MindLogger mobile application and deployed several, including a comprehensive set of assessments underway in a large-scale, longitudinal, mental health study. ResultsOf the hundreds of products we researched, we found 10 that met our primary requirements above with 4 that support end-to-end encryption, 2 that enable restricted access to individual users data, 1 that provides open source software, and none that satisfy all three. We compared features related to information presentation and data capture capabilities, privacy and security, and access to the product, code, and data. We successfully built MindLogger mobile and web applications, as well as web browser-based tools for building and editing new applets and for administering them to end users. MindLogger has end-to-end encryption, enables restricted access, is open source, and supports a variety of data collection features. One applet is currently collecting data from children and adolescents in our mental health study, and other applets are in different stages of testing and deployment for use in clinical and research settings. ConclusionsWe have demonstrated the flexibility and applicability of the MindLogger platform through its deployment in a large-scale, longitudinal, mobile mental health study, and by building a variety of other mental health-related applets. With this release, we encourage a broad range of users to apply the MindLogger platform to create and test applets to advance health care and scientific research. We hope that increasing availability of applets designed to assess and administer interventions will facilitate access to health care in the general population.

neuroscience↗

bioRxiv2020

High-resolution electrochemistry of the extracellular electron transfer of Escherichia coli

Escherichia coli is one of the most important model bacteria in microorganism research and is broadly encountered in nature. In the present study, a wild-type E. coli strain K-12 was used for electrochemical investigations. Differential pulse voltammetry showed five pairs of redox peaks both for K-12 cells and the supernatant with potentials (anodic/cathodic) at -0.450/-0.378, -0.125/-0.105, -0.075/-0.055, +0.192/+0.264, and +0.300/+0.414 V (vs. Ag/AgCl), respectively. Chronoamperometry indicates that K-12 cells can produce immediate current by addition of glucose. The current production from K-12 can be 8-fold enhanced by 10.0 M exogenetic vitamin K3, but addition of 10.0 M riboflavin did not enhance the current production. Medium replacement experiments show that 50 % of the K-12 biofilm current was produced via direct extracellular electron transfer pathways. The study provides new insight in the voltammetry of strain K-12 and confirms that E. coli is an electrochemically active bacterium. E. coli has the potential to serve as a model bacterium for studying microbial extracellular electron transfer mechanisms.

microbiology↗

bioRxiv2020

Development of a Novel Index to Characterise Arterial Dynamics Using Ultrasound Imaging

Abdominal aortic aneurysms (AAA) are associated with systemic inflammation and endothelial dysfunction. We previously reported flow mediated dilatation (FMD) of the brachial artery as a predictor of AAA growth. We hence hypothesised that other physical characteristics of the brachial artery correlate with AAA growth. Using a prospectively cohort of AAA patients, we devised a brachial artery relaxation index (BARI) and examined its role as a biomarker for AAA growth. However, no correlation between BARI and future aneurysm growth was observed (p=0.5). Therefore, our investigations did not substantiate the hypothesis that other physical characteristics of the brachial artery predicts AAA growth.

bioengineering↗

bioRxiv2020

Ethacridine inhibits SARS-CoV-2 by inactivating viral particles in cellular models

SARS-CoV-2 is the coronavirus that causes the respiratory disease COVID-19, which is now the third-leading cause of death in the United States. The FDA has recently approved remdesivir, an inhibitor of SARS-CoV-2 replication, to treat COVID-19, though recent data from the WHO shows little to no benefit with use of this anti-viral agent. Here we report the discovery of ethacridine, a safe antiseptic use in humans, as a potent drug for use against SARS-CoV-2 (EC50 ~ 0.08 M). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescent assay. Interestingly, the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Indeed, ethacridine is effective in various cell types, including primary human nasal epithelial cells. Taken together, these data identify a promising, potent, and new use of the old drug possessing a distinct mode of action for inhibiting SARS-CoV-2.

microbiology↗

bioRxiv2020

Three-dimensional biofilm growth supports a mutualism involving matrix and nutrient sharing

Life in a three-dimensional structure such as a biofilm is typical for many bacteria, yet little is known about how strains with different genotypes interact in this context. Here, to systematically explore gene knockdowns across various three-dimensional contexts, we created arrayed libraries of essential-gene CRISPRi knockdowns in the model biofilm-forming bacterium Bacillus subtilis and measured competitive fitness during colony co-culture with a wild type-like parent on different media and at different knockdown levels. Partial knockdown led to a wide range of fitness phenotypes, with targeting of translation-related genes often leading to lower growth rates and rapid out-competition by the parent. Several knockdowns competed differentially in biofilms versus non-biofilm colonies, in some cases due to lack of a particular nutrient in one medium. Cells depleted for the alanine racemase AlrA died in monoculture, but co-cultures survived via nutrient sharing in a biofilm but not in liquid. This rescue was enhanced in biofilm co-culture with a parent unable to produce extracellular matrix, due to a mutualism involving nutrient and matrix sharing. Including alrA, we identified several examples of mutualism involving matrix sharing that occurred in a three-dimensional biofilm colony but not when growth was constrained to two dimensions. These findings demonstrate that growth in a three-dimensional biofilm can promote genetic diversity through sharing of secreted factors, and illustrate the role of matrix production in determining trajectories for biofilm evolution that may be relevant to pathogens and other environmental bacteria.

microbiology↗

bioRxiv2020

Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

Circadian clocks regulate [~]24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms. SIGNIFICANCEAlmost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate [~]24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.

neuroscience↗

bioRxiv2020

PEA polymer-coated nanotopography delivers solid-state BMP2, enhances mesenchymal stem cell adhesion, prevents bacterial biofilm formation and protects cells from quorum sensing virulence factors

Post-operative infection is a major complication in patients recovering from orthopaedic surgery. As such, there is a clinical need to develop biomaterials for use in regenerative surgery that can promote mesenchymal stem cell (MSC) osteospecific differentiation and that can prevent infection caused by biofilm-forming pathogens. Nanotopographical approaches to pathogen control are being identified, including in orthopaedic materials such as titanium and its alloys. These topographies use high aspect ratio nanospikes or nanowires to prevent bacterial adhesion but these features puncture adhering cells, thus also reducing MSC adhesion. Here, we use a poly(ethyl acrylate) (PEA) polymer coating on titanium nanowires to spontaneously organise fibronectin (FN) and to deliver bone morphogenetic protein 2 (BMP2) to enhance MSC adhesion and osteospecific signalling. This nanotopography when combined with the PEA coating enhanced osteogenesis and reduced adhesion of Pseudomonas aeruginosa in culture. Using a novel MSC-Pseudomonas aeruginosa co-culture, we also show that the coated nanotopographies protect MSCs from cytotoxic quorum sensing and signalling molecules. We conclude that the PEA polymer-coated nanotopography can both support MSCs and prevent pathogens from adhering to a biomaterial surface, thus protecting from biofilm formation and bacterial infection and supporting osteogenic repair.

bioengineering↗