Biology subjects

Jiang, W.

Publications and source records attributed to Jiang, W..

At least 163 records · Page 9Linked to original sources

bioRxiv2021

Metabolomics and microbiome reveal impacts of rhizosphere metabolites on alfalfa continuous cropping

Alfalfa long-term continuous cropping (CC) can pose a serious threat to alfalfa production. However, the mechanism of alfalfa CC obstacle is unclear as of today. In this study, we determined physic-chemical property, microbial population structure, and metabolite differences of alfalfa rhizosphere soils with CC for 1, 7, and 14-years based on analysis of metabolomics and microbiomics. Shifts of functional microorganisms in rhizosphere soil were analyzed, key metabolites and their effects on alfalfa seeds, seedlings and root rot pathogens were assessed. Based on anlysis, p-coumaric acid and ferulic acid on alfalfa seed and seedling growth and root rot pathogens were basically consistent with the influence of CC obstacles in the field. With the increase of CC years, the microbial community in soils changed from fungal to bacterial, and beneficial microorganisms decreased with the increase of CC years, which echoed the performance of alfalfa CC obstacles. The autotoxicity of p-coumaric acid was the strongest.This study fully proved that the continuous accumulation of autotoxic substances in alfalfa rhizosphere was the key factor causing alfalfa CC obstacles.

microbiology↗

bioRxiv2021

A highly conserved lipase deacylates oxidized phospholipids and ameliorates acute lung injury

Oxidized phospholipids have diverse biological activities, many of which can be pathological, yet how they are inactivated in vivo is not fully understood. Here we present evidence that a previously unsuspected host lipase, acyloxyacyl hydrolase (AOAH), can play a significant role in reducing the pro-inflammatory activities of two prominent products of phospholipid oxidation, 1-palmitoyl-2-glutaryl-sn-glycero-3- phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC). AOAH removed the sn-2 and sn-1 acyl chains from both lipids and reduced their ability to induce macrophage inflammasome activation and cell death in vitro and acute lung injury in vivo. In addition to transforming Gram-negative bacterial lipopolysaccharide from stimulus to inhibitor, its most studied activity, AOAH can inactivate these important danger-associated molecular pattern (DAMP) molecules and reduce tissue inflammation and cell death.

immunology↗

bioRxiv2021

Identifying cellular-to-phenotype associations by elucidating hierarchical relationships in high-dimensional cytometry data

High-throughput single cell technologies hold the promise of discovering novel cellular relationships with disease. However, analytical workflows constructed for these technologies to associate cell proportions with disease often employ unsupervised clustering techniques that overlook the valuable hierarchical structures that have been used to define cell types. We present treekoR, a framework that empirically recapitulates these structures, facilitating multiple quantifications and comparisons of cell type proportions. Our results from twelve case studies reinforce the importance of quantifying proportions relative to parent populations in the analyses of cytometry data -- as failing to do so can lead to missing important biological insights.

bioinformatics↗

bioRxiv2021

ICER controls HIV-1 infection and replication in elite controllers

A rare subset of HIV-infected individuals, termed elite controllers (ECs), can maintain long-term control over HIV replication in the absence of antiretroviral therapy (ART). To elucidate the biological mechanism of resistance to HIV replication at the molecular and cellular levels, we performed RNA sequencing and identified alternative splicing variants from ECs, HIV-infected individuals undergoing ART, ART-naive HIV-infected individuals, and healthy controls. Differential gene expression patterns that are specific to ECs and may influence HIV resistance were identified, including alternative RNA splicing and exon usage variants of the CREM/ICER gene (cAMP-responsive element modulator/inducible cAMP early repressors). The knockout and knockdown of specific ICER exons that were found to be upregulated in ECs resulted in significantly increased HIV infection in CD4+ T cell line and primary CD4+ T cells. Overexpression of ICER isoforms decreased HIV infection in primary CD4+ T cells. Furthermore, ICER regulated HIV-1 LTR promoter activity in a Tat-dependent manner. Together, these results suggest that ICER is an HIV host factor that may contribute to HIV resistance of ECs. These findings will help elucidate the mechanisms of HIV control by ECs and may yield a new approach for treatment of HIV.

immunology↗

bioRxiv2021

Classical swine fever virus NS5A inhibits NF-κB signaling by targeting NEMO

The NS5A non-structural protein of classical swine fever virus (CSFV) is a multifunctional protein involved in viral genomic replication, protein translation and regulation of cellular signaling pathways, and assembly of infectious virus particles. Previous report showed that NS5A inhibited nuclear factor kappa B (NF-{kappa}B) signaling induced by poly(I:C); however, the mechanism was not elucidated. Here, we report that NS5A interacts with NF-{kappa}B essential modulator (NEMO),a regulatory subunit of the I{kappa}B kinase (IKK) complex, and that the zinc finger domain of NEMO essential for NEMO ubiquitination and IKK activation is required for the interaction of NEMO with NS5A. Viral infection or NS5A expression by itself reduced the protein level of NEMO. Mechanistic analysis revealed that NS5A mediated proteasomal degradation of NEMO. Ubiquitination assay showed that NS5A induced K27-but not K48-linked polyubiquitination of NEMO. In addition, NS5A blocked k63-linked polyubiquitination of NEMO, thereby inhibiting activation of IKK and NF-{kappa}B. These findings indicate that NS5A inhibits NF-{kappa}B signaling by mediating proteasomal degradation of NEMO and blocking k63-linked polyubiquitination of NEMO, thereby revealing a novel mechanism by which CSFV inhibits host innate immunity. ImportanceClassical swine fever (CSF) is a economically important swine viral disease leading to hemorrhagic fever and immuno-suppression. In order to successfully infect and replicate in a host cell, viruses have evolved various strategies to antagonize host innate immunity. It is known that CSFV non-structural protein Npro interacts with interferon regulatory factor 3 (IRF3) and mediates its proteasomal degradation, thereby inhibiting the production of type I interferon. However, no other mechanism by which CSFV antagonizes host innate immunity has so far been reported. Here, we show that NS5A inhibits NF-{kappa}B signaling by mediating proteasomal degradation of NEMO and by blocking k63-linked polyubiquitination of NEMO, thereby revealing a novel mechanism by which CSFV antagonizes host innate immunity.

microbiology↗

bioRxiv2021

Somatic genetics analysis of sleep in adult mice

Classical forward and reverse mouse genetics approaches require germline mutations and, thus, are unwieldy to study sleep functions of essential genes or redundant pathways. It is also time-consuming to conduct electroencephalogram/electromyogram-based mouse sleep screening owning to labor-intensive surgeries and genetic crosses. Here, we describe a highly accurate SleepV (video) system and adeno-associated virus (AAV)-based adult brain chimeric (ABC)- expression/knockout (KO) platform for somatic genetics analysis of sleep in adult mice. A pilot ABC-expression screen identifies CREB and CRTC1, of which constitutive or inducible expression significantly reduces quantity and quality of non-rapid eye movement sleep. Whereas ABC-KO of exon 13 of Sik3 by AAV-Cre injection in Sik3-E13flox/flox adult mice phenocopies Sleepy (Sik3Slp/+) mice, ABC-CRISPR of Slp/Sik3 reverses hypersomnia of Sleepy mice, indicating a direct role of SLP/SIK3 kinase in sleep regulation. Multiplex ABC-CRISPR of both orexin/hypocretin receptors causes narcolepsy-like episodes, enabling one-step analysis of redundant genes in adult mice. Finally, ABC-expression/KO screen identifies Ankrd63 and NR1 as two potentially new sleep regulators. Therefore, this somatic genetics approach should facilitate high-throughput analysis of sleep regulatory genes, especially for essential or redundant genes, in adult mice by skipping the mouse development and genetic crosses.

neuroscience↗

bioRxiv2021

Structure-based design of a highly stable, covalently-linked SARS-CoV-2 spike trimer with improved structural properties and immunogenicity

The continued threat of SARS-CoV-2 to global health necessitates development of improved research tools and vaccines. We present an improved SARS-CoV-2 spike ectodomain, "VFLIP", bearing five proline substitutions, a flexible cleavage site linker, and an inter-protomer disulfide bond. VFLIP displays significantly improved stability, high-yield production and retains its trimeric state without exogenous trimerization motifs. High-resolution cryo-EM and glycan profiling reveal that the VFLIP quaternary structure and glycosylation mimic the native spike on the viral surface. Further, VFLIP has enhanced affinity and binding kinetics relative to other stabilized spike proteins for antibodies in the Coronavirus Immunotherapeutic Consortium (CoVIC), and mice immunized with VFLIP exhibit potent neutralizing antibody responses against wild-type and B.1.351 live SARS-CoV-2. Taken together, VFLIP represents an improved tool for diagnostics, structural biology, antibody discovery, and vaccine design.

microbiology↗

bioRxiv2021

An inter-channel cooperative mechanism mediates PIEZO1's exquisite mechanosensitivity

The bowl-shaped structure of PIEZO channels is predicted to flatten in response to mechanical stimuli, gating their pore open. However, how this unique structure allows them to detect exquisitely small changes in membrane tension remains unclear. Here, using pressure clamp electrophysiology, modeling, and molecular dynamics simulations, we show that the single channel open probability of PIEZO1 increases weakly with respect to pressure-induced tension. In contrast, when multiple channels are present in a membrane patch, channel open probability increases steeply as a function of the number of open channels. These cooperative effects are consistent with an inter-channel energetic repulsion due to the local membrane deformation created by the non-planar PIEZO structure. When channels open, this deformation shrinks, allowing open channels to diffuse closer to each other, thus delaying closure. This study reveals how PIEZO1 channels acquire their exceptional mechanosensitivity and suggests a possible mechanism by which cells could rapidly tune mechanosensitivity.

biophysics↗

bioRxiv2021

Aerodynamics and motor control of ultrasonic vocalizations for social communication in mice and rats

Rodent ultrasonic vocalizations (USVs) are crucial to their social communication and a widely used translational tool for linking gene mutations to behavior. To maximize the causal interpretation of experimental treatments, we need to understand how neural control affects USV production. However, both the aerodynamics of USV production and its neural control remain poorly understood. Here we test three intralaryngeal whistle mechanisms - the wall and alar edge impingement, and shallow cavity tone - by combining in vitro larynx physiology and individual-based 3D airway reconstructions with fluid dynamics simulations. Our results show that in the mouse and rat larynx USVs are produced by a glottal jet impinging on the thyroid inner wall. Furthermore, we implemented an empirically based motor control model that predicts motor gesture trajectories of USV call types. Our work provides a quantitative neuromechanical framework to evaluate the contributions of brain and body in shaping USVs, and a first step in linking descending motor control to USV production.

neuroscience↗

bioRxiv2021

Extended Graphical Lasso for Multiple Interaction Networks for High Dimensional Computational Data

There has been a spate of interest in association networks in biological and medical research, for example, genetic interaction networks. In this paper, we propose a novel method, the extended joint hub graphical lasso (EDOHA), to estimate multiple related interaction networks for high dimensional omics data across multiple distinct classes. To be specific, we construct a convex penalized log likelihood optimization problem and solve it with an alternating direction method of multipliers (ADMM) algorithm. The proposed method can also be adapted to estimate interaction networks for high dimensional compositional data such as microbial interaction networks. The performance of the proposed method in the simulated studies shows that EDOHA has remarkable advantages in recognizing class-specific hubs than the existing comparable methods. We also present three applications of real datasets. Biological interpretations of our results confirm those of previous studies and offer a more comprehensive understanding of the underlying mechanism in disease. Author summaryReconstruction of multiple association networks from high dimensional omics data is an important topic, especially in biology. Previous studies focused on estimating different networks and detecting common hubs among all classes. Integration of information over different classes of data while allowing difference in the hub nodes is also biologically plausible. Therefore, we propose a method, EDOHA, to jointly construct multiple interaction networks with capacity in finding different hub networks for each class of data. Simulation studies show the better performance over conventional methods. The method has been demonstrated in three real world data.

systems biology↗

bioRxiv2021

Free energy and kinetics of cAMP permeation through connexin26 hemichannel with and without voltage

The connexin family is a diverse group of highly regulated non-{beta}-barrel wide-pore channels permeable to biological signaling molecules. Despite their critical roles in mediating selective molecular signaling in health and disease, the molecular basis of permeation through these pores remains unclear. Here, we report the thermodynamics and kinetics of binding and transport of a second messenger, adenosine-3,5-cyclophosphate (cAMP), through a connexin26 hemichannel. Inward and outward fluxes of cAMP were first obtained from 4 s simulations with voltages and multiple cAMPs in solution. The results are compared with the intrinsic potential of mean force (PMF) and the mean first passage times (MFPTs) of a single cAMP in the absence of voltage, obtained from a total of 16.5 s of multi-replica Voronoi-tessellated Markovian milestoning simulations. The computed transit times through the pore correspond well to existing experimental data. Both voltage simulations and milestoning simulations revealed two cAMP binding sites with binding constants and dissociation rates computed from PMF and MFPTs. The protein dipole inside the pore produces an asymmetric PMF, reflected in unequal cAMP MFPTs in each direction once within the pore. The free energy profiles under voltages derived from intrinsic PMF provided a unified understanding of directional transition rates with/without voltage, and revealed the unique role of channel polarity and the mobile electrolyte within a wide pore on the total free energy. In addition, we show how these factors influence the cAMP dipole vector during permeation, and how cAMP affects the local and non-local pore diameter in a position-dependent manner. Significance StatementConnexins are wide-pore channels permeable to cellular signaling molecules. They mediate molecular signaling crucial in physiology, pathology, and development; mutations in connexins cause human pathologies. However, the fundamental structural, thermodynamic, and kinetic determinants of molecular permeability properties are unknown. Using multiple molecular dynamics simulation techniques, we report, for the first time, an in-depth investigation of the free energy and the directional transition rates of an important biological signaling molecule, cAMP, through a connexin channel. We reveal the energetics and binding sites that determine the cAMP flux, and the effects of mobile ions and external electrical field on the process. The results provide a basis for understanding the unique features of molecular flux through connexins and other non-{beta}-barrel wide-pore channels.

biophysics↗

bioRxiv2021

Correcting statistical bias in correlation-based kinship estimators

Accurate estimate of relatedness is important for genetic data analyses, such as association mapping and heritability estimation based on data collected from genome-wide association studies. Inaccurate relatedness estimates may lead to spurious associations and biased heritability estimations. Individual-level genotype data are often used to estimate kinship coefficient between individuals. The commonly used sample correlation-based genomic relationship matrix (scGRM) method estimates kinship coefficient by calculating the average sample correlation coefficient among all single nucleotide polymorphisms (SNPs), where the observed allele frequencies are used to calculate both the expectations and variances of genotypes. Although this method is widely used, a substantial proportion of estimated kinship coefficients are negative, which are difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists bias in the estimated kinship coefficient using the scGRM method when the observed allele frequencies are regarded as true frequencies. This leads to negative bias for the average estimate of kinship among all individuals, which explains the estimated negative kinship coefficients. Based on this observation, we propose an unbiased estimation method, UKin, which can reduce the bias. We justify our improved method with rigorous mathematical proof. We have conducted simulations as well as two real data analyses to demonstrate that both bias and root mean square error in kinship coefficient estimation can be reduced by using UKin. Further simulations indicate that the power in association mapping can also be improved by using our unbiased kinship estimates to adjust for cryptic relatedness. Author summaryInference of relatedness plays an important role in genetic data analysis. Many methods have been proposed to estimate kinship coefficients, including the commonly used genomic relationship matrix method. However, a substantial proportion of the kinship coefficients estimated by this method are negative, which is difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists a negative bias in this approach. To correct for this bias, we propose a new kinship coefficient estimation method, UKin, which is unbiased without requiring extra genetic information nor added computational complexity. The better performance of UKin in reducing bias and root mean squared error is demonstrated through theory, simulations and analysis of data from the young-onset breast cancer and familial intracranial aneurysm studies.

genetics↗

bioRxiv2020

Gapless indica rice genome reveals synergistic effects of active transposable elements and segmental duplications that promote rice genome evolution

The ultimate goal of genome assembly is a high-accuracy gapless genome. Here we report a new assembly pipeline which we have used to produce a gapless genome for the indica rice cultivar Minghui 63. The 395.82 Mb final assembly is composed of 12 contigs with a contig N50 size of 31.82 Mb. All chromosomes are now gapless, with each chromosome represented by a single contig. This is the first gapless genome assembly achieved for higher plants or animals. BUSCO evaluation showed that gene regions of our assembly have higher completeness than the current rice reference genome (IRGSP-1.0). Compared with japonica rice, indica has more transposable elements (TEs) and segmental duplications (SDs), the latter of which produce many duplicated genes that can affect plant traits through dose effect or sub-/neo-functionalization. The insertion of TEs can also affect the expression of duplicated genes, which may drive evolution of these genes. We also found the expansion of NBS-LRR disease resistance genes and cZOGT growth-related genes in SDs, suggesting that SDs contribute to the adaptative evolution of rice disease resistance and developmental processes. Our findings suggest that active TEs and SDs together provide synergistic effects to promote rice genome evolution.

genomics↗

bioRxiv2020

Hippocampal Asymmetry of Regional Development and Structural Covariance in Preterm Neonates

Premature birth is associated with high prevalence of neurodevelopmental impairments in surviving infants. The hippocampus is known to be critical for learning and memory, the putative role of hippocampus dysfunction remains poorly understood in preterm neonates. Particularly, hemispherical asymmetry of the hippocampus has been well-noted, either structurally or functionally. How the preterm birth impairs the hippocampal development, and to what extent the hippocampus was impaired by preterm birth asymmetrical has not been well studied. In this study, we compared regional and local hippocampal development in term born neonates (n=361) and prematurely born infants at term-born equivalent age on MRI studies (n = 53) using T2 MRI images collected from the Developing Human Connectome Project (dHCP); We compared 1) volumetric growth; 2) shape development in the hippocampal hemispheres using Laplace-Beltrami eigen-projection and boundary deformation between the two groups; and 3) structural covariance between hippocampal vertices and the cortical thickness in cerebral cortex regions. We demonstrated that premature infants have smaller volume for the right hippocampi, while no difference was observed for the left hippocampi. Lower thickness was observed in the hippocampal head in both hemispheres for preterm neonates compared to full-term peers, while an accelerated hippocampal thickness growth rate was found in left hippocampus only. Structural covariance analysis demonstrated that in premature infants, the structural covariance between hippocampi and limbic lobe were severely impaired compared to healthy term neonates only in left hemisphere. These data suggest that the development of the hippocampus during the third trimester may be altered following early extrauterine exposure, with high degree of asymmetry. These findings suggested that the hippocampus shows high degree of vulnerability, particularly asymmetrical vulnerability or plasticity, in preterm neonates at the term-born equivalent age compared to full-term healthy controls.

neuroscience↗

bioRxiv2020

The C. elegans homolog of TMEM132D, a human panic-disorder and anxiety risk gene, modulates neuronal morphogenesis through the WAVE-regulatory complex

TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Belonging to a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt the interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of selective WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.

genetics↗

bioRxiv2020

The bone microenvironment invigorates metastatic seeds for further dissemination

Metastasis has been considered as the terminal step of tumor progression. However, recent clinical studies suggest that many metastases are seeded from other metastases, rather than primary tumors. Thus, some metastases can further spread, but the corresponding pre-clinical models are lacking. By using several approaches including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. Importantly, dissemination from the bone microenvironment appears to be more aggressive compared to that from mammary tumors and lung metastases. We further uncovered that this metastasis-promoting effect is independent from genetic selection, as single cell-derived cancer cell populations (SCPs) exhibited enhanced metastasis capacity after being extracted from the bone microenvironment. Taken together, our work revealed a previously unappreciated effect of the bone microenvironment on metastasis evolution, and suggested a stable reprogramming process that engenders cancer cells more metastatic.

cancer biology↗

bioRxiv2020

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

Immunomodulatory agents dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-191-16. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome. To answer these questions, we designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs action. Here we present our findings, including genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasones immunosuppressive effects. Our findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.

pharmacology and toxicology↗

bioRxiv2020

Target lipidomics reveals associations between serum sphingolipids and insulin sensitivity by the glucose clamp

BackgroundThis study aimed to systematically investigate the associations between serum sphingolipids and insulin sensitivity as well as insulin secretion. This study also aimed to reveal potential predictors for insulin sensitivity or give perceptive insight into disease processes. MethodsWe conducted a lipidomics evaluation of molecularly distinct SPs in the serum of 86 consecutive Chinese adults with or without obesity and diabetes using electrospray ionization mass spectrometry coupled with liquid chromatography. The GIR30 was measured under steady conditions to assess insulin sensitivity by the gold standard hyperinsulinemic-euglycemic clamp. We created the ROC curves to detect the serum SMs diagnostic value and establish the diagnosis of insulin sensitivity. ResultsDifferential correlation network analysis illustrated correlations amongst lipids, insulin sensitivity, insulin secretion and other clinical indexes. Total and subspecies of serum SMs and globotriaosylceramides (Gb3s) were positively related to GIR30, free FAs (FFA 16:1, FFA20:4), some long chain GM3 and complex ceramide GluCers showed strong negative correlations with GIR30. Notably, ROC curves showed that SM/Cer and SM d18:0/26:0 may be good serum lipid predictors of diagnostic indicators of insulin sensitivity close to conventional clinical indexes such as 1/HOMA-IR (all areas under the curve >0.80) based on GIR30 as standard diagnostic criteria. ConclusionsThese results provide novel associations between serum sphingolipid between insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. We further identify two specific SPs that may represent prognostic biomarkers for insulin sensitivity.

physiology↗