Biology subjects

Li, D.

Publications and source records attributed to Li, D..

At least 577 records · Page 32Linked to original sources

bioRxiv2020

Exploration of target spaces in the human genome for protein and peptide drugs

MotivationProtein and peptide drugs, after decades of development have grown into a major drug class of the marketplace. Target identification and validation is crucial for their discovery, and bioinformatics estimation of candidate targets based on characteristics of successful target proteins will help improve efficiency and success rate of target selection. However, owing to the development history of the pharmaceutical industry, previous systematic exploration of target space mainly focused on traditional small-molecule drugs, whereas that for protein and peptide drugs is blank. Here we systematically explored target spaces in the human genome specially for protein and peptide drugs. ResultsWe found that compared with other proteins, targets of both successful protein and peptide drugs have their own characteristics in many aspects and are also significantly different from those of traditional small-molecule drugs. Further based on these features, we developed effective genome-wide target estimation models respectively for protein and peptide drugs.

bioinformatics↗

bioRxiv2020

Lectin-like Intestinal Defensin Inhibits 2019-nCoV Spike binding to ACE2

The burgeoning epidemic caused by novel coronavirus 2019 (2019-nCoV) is currently a global concern. Angiotensin-converting enzyme-2 (ACE2) is a receptor of 2019-nCoV spike 1 protein (S1) and mediates viral entry into host cells. Despite the abundance of ACE2 in small intestine, few digestive symptoms are observed in patients infected by 2019-nCoV. Herein, we investigated the interactions between ACE2 and human defensins (HDs) specifically secreted by intestinal Paneth cells. The lectin-like HD5, rather than HD6, bound ACE2 with a high affinity of 39.3 nM and weakened the subsequent recruitment of 2019-nCoV S1. The cloak of HD5 on the ligand-binding domain of ACE2 was confirmed by molecular dynamic simulation. A remarkable dose-dependent preventive effect of HD5 on 2019-nCoV S1 binding to intestinal epithelial cells was further evidenced by in vitro experiments. Our findings unmasked the innate defense function of lectin-like intestinal defensin against 2019-nCoV, which may provide new insights into the prevention and treatment of 2019-nCoV infection.

microbiology↗

bioRxiv2020

Potentiating the anti-tumor response of tumor infiltrated T cells by NAD+ supplementation

Tumor immunotherapies have provided clinical benefits, yet great potential remains for optimizing therapeutic effects. Here, we show that low NAD+ levels restrict the function of tumor infiltrating T lymphocytes (TILs). TILs harvested from human ovarian tumor tissues showed decreased NAD+ levels compared with T cells from paired peripheral blood samples. The combination of whole-genome CRISPR and large-scale metabolic inhibitor screens implicated the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. Further isotopic labeling and LC-MS studies confirmed that NAD+ depletion suppressed mitochondrial energy biosynthesis in T cells. Excitingly, NAD+ supplementation significantly enhanced the tumor cell-killing efficacy of CAR-T cells ex vivo, and extended animal survive in both adoptive CAR-T model and immune checkpoint blockade treatment models in vivo. This study demonstrates an over-the-counter nutrient supplement NAD+ could robustly boost the efficacy of T cell-based immunotherapy and provides insights into the cellular basis of T cell metabolic reprogramming in treating cancers. One Sentence SummaryNAD+ supplementation during cancer immunotherapies significantly enhances T cell activation and tumor killing capacity.

immunology↗

bioRxiv2020

The dominance hierarchy of the female Yunnan snub-nosed monkeys (Rhinopithecus bieti)

Dominance hierarchies are common in social mammals, especially primates. The formation of social hierarchies is conducive to solving the problem of the allocation of scarce resources among individuals. From August 2015 to July 2016, we observed a wild, provisioned Yunnan snub-nosed monkey (Rhinopithecus bieti) group at Xiangguqing in Baimaxueshan National Nature Reserve, Yunnan Province, China. Aggressive and submissive behaviors were used to investigate dominance hierarchies between female individuals in the same one-male unit (OMU), and the grooming reciprocity index was used to detect reciprocal relationships between these females within the OMU. The results showed that loose social hierarchies exist among the females in each OMU, and more dominant individuals have higher grooming incomes. These results are consistent with the aggressive-submissive hypothesis and the resource control hypothesis.

animal behavior and cognition↗

bioRxiv2020

Cryo-EM structure of catalytic ribonucleoprotein complex RNase MRP

RNase MRP is an essential eukaryotic ribonucleoprotein complex involved in the maturation of rRNA and the regulation of the cell cycle. RNase MRP is related to the ribozyme-based RNase P, but it has evolved to have distinct cellular roles. We report a cryo-EM structure of the S. cerevisiae RNase MRP holoenzyme solved to 3.0 [A]. We describe the structure of this 450 kDa complex, interactions between its components, and the organization of its catalytic RNA. We show that while the catalytic center of RNase MRP is inherited from the ancestral enzyme RNase P, the substrate binding pocket of RNase MRP is significantly altered by the addition of unique RNA and protein elements, as well as by RNA-driven protein remodeling. One Sentence SummaryChanges in peripheral RNA elements and RNA-driven protein remodeling result in diversification of related catalytic RNPs

biochemistry↗

bioRxiv2020

Rhamnolipid production from waste cooking oil using newly isolated halotolerant Pseudomonas aeruginosa M4

This study isolated a novel halotolerant Pseudomonas aeruginosa M4, that was able to degrade oil and produce rhamnolipids. Various carbon sources, nitrogen sources, inoculum ratio, pH, and temperature were tested to optimize the oil degradation conditions. The highest oil degradation rate of 85.20 % and lipase activity of 23.86 U/mL were obtained under the optimal conditions (5% inoculum at 35 {degrees}C and pH 8). The components of degradation products at different times were analyzed to explore the mechanism of oil degradation by GC-MS. Short chain fatty acid of acetic and n-butyric acids were the primary degradation intermediates. P. aeruginosa M4 had good salt tolerance up to 70 g/L. The maximum rhamnolipid concentration of 1119.87 mg/L was produced when P. aeruginosa M4 used waste cooking oil as the sole carbon source. Rhamnose precursors were synthesized from glycerol, a hydrolysis product of waste cooking oil. R-3-hydroxyalkanoate precursors were synthesized de novo using acetyl-CoA produced from {beta}-oxidation of fatty acids. The findings show that P. aeruginosa M4 is a valuable biosurfactant producer in the treatment of waste cooking oil. Key PointsP. aeruginosa isolation, oil degradation mechanism, rhamnolipid production from WCO

microbiology↗

bioRxiv2020

Relatively semi-conservative replication and a folded slippage model for simple repeat sequences

Simple sequence repeats (SSRs) are found ubiquitously in almost all genome, and their formation mechanism is ambiguous yet. Here, the SSRs were analyzed in 55 randomly selected segments of genomes from a fairly wide range of species, with introducing more open standard for extensively mining repeats. A high percentage of repeats were discovered in these segments, which is inconsistent with the current theory suggested that repeats tend to disappear over long-term evolution. Therefore, a mechanism is most probably responsible for continually producing repeats during replication to balance continuous repeat disappearance, which may makes the replicating process relatively semi-conservative. To improve the current straight-line slippage model, we proposed a folded slippage model involving the geometric space of nucleotides and hydrogen bond stability to explain the high-percent SSR occurrence, which can describe SSR expansion and contraction more reasonably. And analysis of external forces in the folding template strands suggested that the microsatellites tend to expand than contract. Our research may provide implements for contributions of microsatellites to genome evolution and complement semi-conservative replication.

molecular biology↗

bioRxiv2020

Lower Soil Carbon Loss Due to Persistent Microbial Adaptation to Climate Warming

Soil microbial respiration is an important source of uncertainty in projecting future climate and carbon (C) cycle feedbacks. Despite intensive studies for two decades, the magnitude, direction, and duration of such feedbacks are uncertain, and their underlying microbial mechanisms are still poorly understood. Here we examined the responses of soil respiration and microbial community structure to long-term experimental warming in a temperate grassland ecosystem. Our results indicated that the temperature sensitivity of soil microbial respiration (i.e., Q10) persistently decreased by 12.0{+/-}3.7% across 7 years of warming. Integrated metagenomic and functional analyses showed that microbial community adaptation played critical roles in regulating respiratory acclimation. Incorporating microbial functional gene abundance data into a microbially-enabled ecosystem model significantly improved the modeling performance of soil microbial respiration by 5-19%, compared to the traditional non-microbial model. Model parametric uncertainty was also reduced by 55-71% when gene abundances were used. In addition, our modeling analyses suggested that decreased temperature sensitivity could lead to considerably less heterotrophic respiration (11.6{+/-}7.5%), and hence less soil C loss. If such microbially mediated dampening effects occur generally across different spatial and temporal scales, the potential positive feedback of soil microbial respiration in response to climate warming may be less than previously predicted.

ecology↗

bioRxiv2020

Preserving Vascular Integrity Protects Mice Against Multidrug-Resistant Gram-Negative Bacterial Infection

The rise in multidrug resistant (MDR) organisms portends a serious global threat to the healthcare system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB) including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization and National Institutes of Healths high priority MDR pathogens for targeted development of new therapies. Here we show that stabilizing the hosts vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, CPKP pneumonia. We show that pharmacological inhibition of ARF6-GTP phenocopies endothelial-specific Arf6 disruption in enhancing survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small molecule inhibitors is by restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of TLR4/MyD88/ARNO/ARF6 pathway. By targeting the hosts vasculature with small molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and re-emerging pathogens.

microbiology↗

bioRxiv2020

phyr: An R package for phylogenetic species-distribution modelling in ecological communities

O_LIModel-based approaches are increasingly popular in ecological studies. A good example of this trend is the use of joint species distribution models to ask questions about ecological communities. However, most current applications of model-based methods do not include phylogenies despite the well-known importance of phylogenetic relationships in shaping species distributions and community composition. In part, this is due to lack of accessible tools allowing ecologists to fit phylogenetic species distribution models easily. C_LIO_LITo fill this gap, the R package phyr (pronounced fire) implements a suite of metrics, comparative methods and mixed models that use phylogenies to understand and predict community composition and other ecological and evolutionary phenomena. The phyr workhorse functions are implemented in C++ making all calculations and model estimations fast. C_LIO_LIphyr can fit a variety of models such as phylogenetic joint-species distribution models, spatiotemporal-phylogenetic autocorrelation models, and phylogenetic trait-based bipartite network models. phyr also estimates phylogenetically independent trait correlations with measurement error to test for adaptive syndromes and performs fast calculations of common alpha and beta phylogenetic diversity metrics. All phyr methods are united under Brownian motion or Ornstein-Uhlenbeck models of evolution and phylogenetic terms are modelled as phylogenetic covariance matrices. C_LIO_LIThe functions and model formula syntax we propose in phyr serves as a simple and unified framework that ignites the use of phylogenies to address a variety of ecological questions. C_LI

ecology↗

bioRxiv2020

Exploring the coronavirus epidemic using the new WashU Virus Genome Browser

Since its debut in mid-December, 2019, the novel coronavirus (2019-nCoV) has rapidly spread from its origin in Wuhan, China, to several countries across the globe, leading to a global health crisis. As of February 7, 2020, 44 strains of the virus have been sequenced and uploaded to NCBIs GenBank [1], providing insight into the viruss evolutionary history and pathogenesis. Here, we present the WashU Virus Genome Browser, a web-based portal for viewing virus genomic data. The browser is home to 16 complete 2019-nCoV genome sequences, together with hundreds of related viral sequences including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and Ebola virus. In addition, the browser features unique customizability, supporting user-provided upload of novel viral sequences in various formats. Sequences can be viewed in both a track-based representation as well as a phylogenetic tree-based view, allowing the user to easily compare sequence features across multiple strains. The WashU Virus Genome Browser inherited many features and track types from the WashU Epigenome Browser, and additionally incorporated a new type of SNV track to address the specific needs of viral research. Our Virus Browser portal can be accessed at https://virusgateway.wustl.edu, and documentation is available at https://virusgateway.readthedocs.io/.

genomics↗

bioRxiv2020

Consensus mutagenesis and ancestral reconstruction provide insight into the substrate specificity and evolution of the front-end Δ6-desaturase family

Marine algae are a major source of omega ({omega})-3 long-chain polyunsaturated fatty acids ({omega}3-LCPUFAs), which are conditionally essential nutrients in humans and a target for industrial production. The biosynthesis of these molecules in marine algae begins with the desaturation of fatty acids by {Delta}6-desaturases and enzymes from different species display a range of specificities towards {omega}3 and {omega}6 LCPUFAs. In the absence of a molecular structure, the structural basis for the variable substrate specificity of {Delta}6-desaturases is poorly understood. Here we have conducted a consensus mutagenesis and ancestral protein reconstruction-based analysis of the {Delta}6-desaturase family, focusing on the {omega}3-specific {Delta}6-desaturase from Micromonas pusilla (Mp{Delta}6des) and the bispecific ({omega}3/{omega}6) {Delta}6-desaturase from Ostreococcus tauri (Ot{Delta}6des). Our characterization of consensus amino acid substitutions in Mp{Delta}6des revealed that residues in diverse regions of the protein, such as the N-terminal cytochrome b5 domain, can make important contributions to determining substrate specificity. Ancestral protein reconstruction also suggests that some extant {Delta}6-desaturases, such as Ot{Delta}6des, could have adapted to different environmental conditions by losing specificity for {omega}3-LCPUFAs. This dataset provides a map of regions within {Delta}6-desaturases that contribute to substrate specificity and could facilitate future attempts to engineer these proteins for use in biotechnology.

biochemistry↗

bioRxiv2020

Genetic diversity and evolution of Hantaan virus in China and its neighbors

BackgroudHantaan virus (HTNV), as one of the pathogenic hantaviruses of HFRS, has raised serious concerns in Eurasia. China and its neighbors, especially Russia and South Korea, are seriously suffered HTNV infections. Recent studies reported genetic diversity and phylogenetic features of HTNV in different parts of China, but the analyses from the holistic perspective are rare. Methodology and Principal FindingsTo better understand HTNV genetic diversity and dynamics, we analyzed all available complete sequences derived from the S and M segments with bio-informatic tools. Our study revealed 11 phylogroups and sequences showed obvious geographic clustering. We found 42 significant amino acid variants sites and 18 of them located in immune epitopes. Nine recombination events and seven reassortment isolates were deteced in our study. Sequences from Guizhou were highly genetic divergent, characterized by the emergence of multiple lineages, recombination and reassortment events. We found that HTNV probably emerged in Zhejiang about 1,000 years ago and the population size expanded from 1980s to 1990s. Bayesian stochastic search variable selection analysis revealed that Heilongjiang, Shaanxi and Guizhou played important roles in HTNV evolution and migration. Conclusions/SignificanceThese findings reveal the original and evolution features of HTNV which might assist in understanding Hantavirus epidemics and would be useful for disease prevention and control. Author summaryHemorrhagic Fever with Renal Syndrome (HFRS) and Hantavirus Pulmonary Syndrome (HPS) are endemic zoonotic infectious diseases caused by hantaviruses that belong to the Family Bunyaviridae. Hantaviruses have gained worldwide attention as etiological agents of emerging zoonotic diseases, with fatality rates ranging from <10% up to 60%. However, our knowledge about the emergence and evolution of HTNV is limited. To get more information about HTNV genetic diversity and phylogenetic features in holistic perspective, we investigated the genetic diversity and spatial distribution of HTNV using all available whole genomic sequences of S and M segments. We also gain insights into the genetic diversity and spatial-temporal dynamics of HTNV. These data can augment traditional approach to infectious disease surveillance and control.

evolutionary biology↗

bioRxiv2020

Bayesian copy number detection and association in large-scale studies

Germline copy number variants (CNVs) increase risk for many diseases, yet detection of CNVs and quantifying their contribution to disease risk in large-scale studies is challenging. We developed an approach called CNPBayes to identify latent batch effects, to provide probabilistic estimates of integer copy number across the estimated batches, and to fully integrate the copy number uncertainty in the association model for disease. We demonstrate this approach in a Pancreatic Cancer Case Control study of 7,598 participants where the major sources of technical variation were not captured by study site and varied across the genome. Candidate associations aided by this approach include deletions of 8q24 near regulatory elements of the tumor oncogene MYC and of Tumor Supressor Candidate 3 (TUSC3). This study provides a robust Bayesian inferential framework for estimating copy number and evaluating the role of copy number in heritable diseases.

genetics↗

bioRxiv2020

Accumulation of ammonium owing to the metabolic imbalance of carbon and nitrogen might inhibit the central metabolism in Methylomonas sp. ZR1

The metabolic intermediates of nitrogen source have been proved to have multiple functions on the metabolism of mehthanotrophs. In this study, accumulation and assimilation mechanism of the nitrate metabolic intermediate ammonium in the fast growing Methylomonas sp. ZR1 was analyzed. Although, nitrate salt was the best nitrogen source supporting the growth of ZR1, its metabolic intermediate ammonium would accumulate and inhibit ZR1. Kinetic studies indicated that accumulation of NH4+ was deduced from the imbalance of nitrogen and carbon metabolism. Compensation of carbon skeleton -keto-glutaramate could effectively relieve the inhibition of NH4+ to ZR1, which further approved the assumption. qPCR analysis indicated a third ammonium assimilation pathway Glycine synthesis system may function in ZR1 under high ammonium tension. In the presence of ammonium, ZR1 might employ two strategies to relieve the ammonium stress, one was assimilating the excess ammonium, and another one was cutting off the nitrogen reduction reactions. Investigation of the nitrogen metabolism and its influence to the carbon metabolism is meaningful to systematically understand and control the C1 feedstock bioconversion process in methanotrophs. ImportanceThe nitrogen metabolism in methanotrophs has long been concerned. However, there are lots of research problems yet to be solved. In this study, the accumulation and assimilation mechanism of the nitrogen metabolic intermediate ammonium in the fast growing Methylomonas sp. ZR1 was analyzed. Owing to the imbalance metabolism of carbon and nitrogen source, ammonium would accumulate to high concentrations to inhibit cell growth. Compensation of carbon skeleton was an effective strategy to relieve the inhibition of NH4+. A third ammonium assimilation pathway related genes were proved actively expressing in ZR1 when it confronted with high ammonium tension. When confronted with ammonium tension, ZR1 might employ different strategies to relieve the ammonium stress according to the edible carbon source. Revealing the endogenous ammonium accumulation mechanism and its metabolic adjustment effect on the central metabolism of methanotrophs, was meaningful to reveal the complex coordination metabolic mechanism of nitrogen and carbon in methanotrophs.

physiology↗

bioRxiv2020

Crowdsourcing digital health measures to predict Parkinson's disease severity: the Parkinson's Disease Digital Biomarker DREAM Challenge

Mobile health, the collection of data using wearables and sensors, is a rapidly growing field in health research with many applications. Deriving validated measures of disease and severity that can be used clinically or as outcome measures in clinical trials, referred to as digital biomarkers, has proven difficult. In part due to the complicated analytical approaches necessary to develop these metrics. Here we describe the use of crowdsourcing to specifically evaluate and benchmark features derived from accelerometer and gyroscope data in two different datasets to predict the presence of Parkinsons Disease (PD) and severity of three PD symptoms: tremor, dyskinesia and bradykinesia. Forty teams from around the world submitted features, and achieved drastically improved predictive performance for PD status (best AUROC=0.87), as well as tremor (best AUPR=0.75), dyskinesia (best AUPR=0.48) and bradykinesia (best AUPR=0.95) severity.

bioengineering↗

bioRxiv2020

Information theory tests critical predictions of plant defense theory for specialized metabolism

Different plant defense theories have provided important theoretical guidance in explaining patterns in plant specialized metabolism, but their critical predictions remain to be tested. Here, we systematically explored the metabolomes of Nicotiana attenuata, from single plants to populations, as well as of closely-related species, using unbiased MS/MS analyses and processed the abundances of compound-spectrum-based MS features within an information theory framework to test critical predictions of Optimal Defense (OD) and Moving Target (MT) theories. Information components of herbivory-elicited plant metabolomes were fully consistent with the OD theory predictions and contradicted the main prediction of the MT theory. From micro- to macro-evolutionary scales, jasmonate signaling was identified as the master determinant of OD while ethylene signaling provided fine-tuning for herbivore-specific responses annotated via MS/MS molecular networks. One-sentence summaryInformation theory tests defense theory predictions by providing a common currency for comparison of specialized metabolomes

plant biology↗

bioRxiv2020

Global post-translational modification profiling of HIV-1-infected cells reveals mechanisms of host cellular pathway remodeling

Viruses must effectively remodel host cellular pathways to replicate and evade immune defenses, and they must do so with limited genomic coding capacity. Targeting post-translational modification (PTM) pathways provides a mechanism by which viruses can broadly and rapidly transform a hostile host environment into a hospitable one. We used quantitative proteomics to measure changes in two PTM types - phosphorylation and ubiquitination - in response to HIV-1 infection with viruses harboring targeted deletions of a subset of HIV-1 genes. PTM analysis revealed a requirement for Aurora kinase A activity in HIV-1 infection and furthermore revealed that AMP-activated kinase activity is modulated during infection via HIV-1 Vif-mediated degradation of B56-containing protein phosphatase 2A (PP2A). Finally, we demonstrated that the Cullin4A-DDB1-DCAF1 E3 ubiquitin ligase ubiquitinates histone H1 somatic isoforms and that HIV-1 Vpr inhibits this process, leading to defects in DNA repair. Thus, global PTM profiling of infected cells serves as an effective tool for uncovering specific mechanisms of host pathway modulation.

microbiology↗