Biology subjects

Zhang, Q.

Publications and source records attributed to Zhang, Q..

At least 649 records · Page 36Linked to original sources

bioRxiv2020

Phylogenomics of Brosimum Sw. (Moraceae) and allied genera, including a revised subgeneric system

We present a phylogenomic study of Brosimum and the allied genera Trymatococcus and Helianthostylis, with near-complete taxon sampling. Distributed from Mexico and the Greater Antilles to the Amazon, this clade contains the underutilized crop ramon (bread nut) (Brosimum alicastrum) as well as other species valued for timber or medicinal uses. Target enrichment for 333 genes produced a well-resolved phylogenetic tree and showed that Trymatoccocus and Helianthostylis are nested within Brosimum. We present a revised subgeneric classification of Brosimum based on phylogenetic and morphological considerations, including the reduction of Trymatococcus and Helianthostylis to subgenera. The monophyletic subgenera can be diagnosed based on stipule, pistillode, and cotyledon synapomorphies. Divergence date estimates suggest a Miocene origin for Brosimum, and ancestral area reconstruction indicated that all four subgenera originated and initially diversified in Amazonia before dispersing into other parts of South and Central America. ResumenPresentamos un estudio filogenomico del genero Brosimum y sus aliados, Trymatococcus y Helianthostylis, y que incluye practicamente todas las especies descritas. Su distribucion va desde Mexico y las Antillas Mayores hasta el Amazonas y comprende especies como el ramon (B. alicastrum), un cultivo infrautilizado, y otras especies empleadas como madera o en medicina. La secuenciacion masiva dirigida de 333 marcadores nucleares de copia unica permitio la reconstruccion de una filogenia bien resuelta, en la que se demuestra que Trymatococcus y Helianthostylis estan anidados en Brosimum. Presentamos, por lo tanto, una clasificacion revisada a nivel de especies, teniendo en cuenta los resultados moleculares y las caracteristicas morfologicas, y donde Trymatococcus y Helianthostylis pasan a ser subgeneros de Brosimum. Estos subgeneros monofileticos pueden ser identificados por caracteres de las estipulas y de los pistilodios.

plant biology↗

bioRxiv2020

DENV NS1 and MMP-9 cooperate to induce vascular leakage by altering endothelial cell adhesion and tight junction

Dengue virus (DENV) is a mosquito-borne pathogen that causes a spectrum of diseases including life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage is a common clinical crisis in DHF/DSS patients which is closely associated with increased endothelial permeability. The presence of vascular leakage causes hypotension, circulatory failure or disseminated intravascular coagulation as the disease progresses, which can lead to death under such conditions. However, the mechanisms by which DENV infection caused the vascular leakage are not fully understood. This study reveals a distinct mechanism by which DENV induces endothelial permeability and vascular leakage in human endothelial cells and mice tissues. We initially show that DENV2 promotes the matrix metalloproteinase-9 (MMP-9) expression and secretion in DHF patient serum, peripheral blood mononuclear cells (PBMCs) and macrophages, and further reveal that DENV non-structural protein 1 (NS1) induces MMP-9 expression through activating the nuclear factor {kappa}B (NF-{kappa}B) signaling pathway. Additionally, NS1 inhibits TIMP-1 expression to facilitates the MMP-9 enzymatic activity which alters the adhesion and tight junctions and vascular leakage in human endothelial cells and mouse tissues. Moreover, NS1 recruits MMP-9 to interact with {beta}-catenin and Zona occludins protein-1/2 to degrade the important adhesion and tight junction proteins, thereby inducing endothelial hyperpermeability and vascular leakage in human endothelial cells and mouse tissues. Thus, we reveal that DENV NS1 and MMP-9 cooperatively induce vascular leakage by impairing endothelial cell adhesion and tight junction, and suggest that MMP-9 may serve as a potential target for the treatment of hypovolemia in DSS/DHF patients. Author SummaryDENV is the most common mosquito-transmitted viral pathogen in humans. In general, DENV-infected patients are either asymptomatic or have flu-like symptoms with fever and rash. However, in severe cases of DENV infection, the disease may progress to dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), the leading causes of morbidity and mortality in school-age children in tropical and subtropical regions. DENV-induced vascular leakage is characterized by enhanced vascular permeability without morphological damage to the capillary endothelium. We found that a distinct mechanism of DENV NS1 and MMP-9 cooperatively induce vascular leakage is the main reason leading to death in severe dengue patients. Also, NS1 recruits MMP-9 to degrade {beta}-catenin, ZO-1, ZO-2 to intervene endothelial hyperpermeability in human endothelial cells and mouse vascular. Finally, we reveal that DENV activating NF-{kappa}B signaling pathway induces MMP-9 expression, in patients, mice, PBMC and macrophages though the viral NS1 protein. This study would provide new in signs into the pathogenesis caused by DENV infection, and suggest that MMP-9 may acts as a drug target for the prevention and treatment of DENV-associated diseases.

microbiology↗

bioRxiv2020

The draft genome sequence of herbaceous diploid bamboo Raddia distichophylla

Bamboos are important non-timber forest plants widely distributed in the tropical and subtropical regions of Asia, Africa, America, and Pacific islands. They comprise the Bambusoideae in the grass family (Poaceae), including approximately 1,700 described species in 127 genera. In spite of the widespread uses of bamboo for food, construction and bioenergy, the gene repertoire of bamboo still remains largely unexplored. Raddia distichophylla (Schrad. ex Nees) Chase, belonging to the tribe Olyreae (Bambusoideae, Poaceae), is diploid herbaceous bamboo with only slightly lignified stems. In this study, we report a draft genome assembly of the approximately [~]589 Mb whole-genome sequence of R. distichophylla with a contig N50 length of 86.36 Kb. Repeated sequences account for [~]49.08% of the genome, of which LTR retrotransposons occupy [~]35.99% of whole genome. A total of 30,763 protein-coding genes were annotated in the R. distichophylla genome with an average transcript size of 2,887 bp. Access to this herbaceous bamboo genome sequence will provide novel insights into biochemistry, molecular-assisted breeding programs and germplasm conservation for bamboo species world-wide.

genomics↗

bioRxiv2020

MpsLDA-ProSVM: predicting multi-label protein subcellular localization by wMLDAe dimensionality reduction and ProSVM classifier

Proteins play a significant part in life processes such as cell growth, development, and reproduction. Exploring protein subcellular localization (SCL) is a direct way to better understand the function of proteins in cells. Studies have found that more and more proteins belong to multiple subcellular locations, and these proteins are called multi-label proteins. They not only play a key role in cell life activities, but also play an indispensable role in medicine and drug development. This article first presents a new prediction model, MpsLDA-ProSVM, to predict the SCL of multi-label proteins. Firstly, the physical and chemical information, evolution information, sequence information and annotation information of protein sequences are fused. Then, for the first time, use a weighted multi-label linear discriminant analysis framework based on entropy weight form (wMLDAe) to refine and purify features, reduce the difficulty of learning. Finally, input the optimal feature subset into the multi-label learning with label-specific features (LIFT) and multi-label k-nearest neighbor (ML-KNN) algorithms to obtain a synthetic ranking of relevant labels, and then use Prediction and Relevance Ordering based SVM (ProSVM) classifier to predict the SCLs. This method can rank and classify related tags at the same time, which greatly improves the efficiency of the model. Tested by jackknife method, the overall actual accuracy (OAA) on virus, plant, Gram-positive bacteria and Gram-negative bacteria datasets are 98.06%, 98.97%, 99.81% and 98.49%, which are 0.56%-9.16%, 5.37%-30.87%, 3.51%-6.91% and 3.99%-8.59% higher than other advanced methods respectively. The source codes and datasets are available at https://github.com/QUST-AIBBDRC/MpsLDA-ProSVM/.

bioinformatics↗

bioRxiv2020

Transgenerational inheritance of abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse induced by in utero arsenic exposure

Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. However, little is known about the transgenerational effects of arsenic exposure. We hypothesize that prenatal arsenic exposure may result in impaired spermatogenesis in subsequent generations of male mice. To test our hypothesis, we treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that transient exposure of the F0 gestating female to arsenic can result in decreased sperm quality and histological abnormalities in testes of male offspring in the F1 and F3 generations. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3 generations. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly higher than in the control males in both F1 and F3 generations. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19.

pharmacology and toxicology↗

bioRxiv2020

A framework for detecting and quantifying relationship alterations in microbial community

Dysbiosis of gut microbiota is associated with the pathogenesis of human disease. Observing shifts in the microbe abundance cannot fully reveal underlying perturbations. Examining the relationship alteration (RA) in microbiome between different healthy status provides additional hints about the pathogenesis of human disease. However, no methods were designed to directly detect and quantify the RA between different conditions. Here, we present PM2RA (Profile Monitoring for Microbial Relationship Alteration), an analysis framework to identify and quantify the microbial RAs. The performance of PM2RA were evaluated in synthetic data, and found to show higher specificity and sensitivity than the co-occurrence-based methods. Analyses of real microbial dataset show that PM2RA is robust for quantifying microbial RA across different datasets in several diseases. By applying PM2RA, we identified both previously reported and novel microbes implicated in multiple diseases. The PM2RA is implemented as a web-based application available at http://www.pm2ra-xingyinliulab.cn/.

microbiology↗

bioRxiv2020

RDoC Mechanisms of Transdiagnostic Polygenic Risk for Trajectories of Depression: From Early Adolescence to Adulthood

There is substantial heterogeneity in the development of depression across early adolescence into adulthood. Yet, little is known about the risk factors underlying individual differences in the development of depression. For instance, despite the discovery of genetic variants for depression, there is also significant genetic overlap between depression and other mental disorders. Thus, depression may have etiologically complex (i.e., transdiagnostic) origins when accounting for its heterogeneous developmental presentations. This study examined the association between a transdiagnostic polygenic score for psychopathology (p-factor PGS) and depressive trajectories, spanning early adolescence into adulthood, in the National Longitudinal Study of Adolescent to Adult Health. We also examined whether the Research Domains Criteria (RDoC) negative valence (i.e., negative emotionality), positive valence (i.e., novelty seeking), and cognitive systems (i.e., picture vocabulary) could explain how the p-factor PGS eventuates into the various pathways of depressive development. Four trajectories of depression were identified: low depression (78.9%), low increasing (7.3%), high declining (8.2%), and early adult peaked (5.7%). The p-factor PGS was only associated with the trajectory that showed increasing depression over time - low increasing. There was also a specific indirect effect by which the association of p-factor PGS on early adult peaked and high declining depression was partially mediated by negative emotionality, but not by picture vocabulary or novelty seeking. Our findings reinforce the crucial role of development in genetically-informed RDoC models of depression, as there appear to be distinct correlates and risk factors that underlie the various developmental pathways of depression. Clinical implications were also discussed. General Scientific SummaryThere are individual differences in how depression symptoms progress over time, but little is known about the risk factors that underlie these various patterns of development. This study suggests that there are distinct correlates and risk factors that underlie the various developmental pathways of depression. We found that transdiagnostic polygenic risks for psychopathology are directly associated with worsening patterns of adolescent to adult depression and indirectly associated with the less severe patterns of depression via negative emotionality.

genetics↗

bioRxiv2020

SARS-CoV-2 neutralizing serum antibodies in cats: a serological investigation

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, and rapidly spread worldwide. Previous studies suggested cat could be a potential susceptible animal of SARS-CoV-2. Here, we investigated the infection of SARS-CoV-2 in cats by detecting specific serum antibodies. A cohort of serum samples were collected from cats in Wuhan, including 102 sampled after COVID-19 outbreak, and 39 prior to the outbreak. 15 of 102 (14.7%) cat sera collected after the outbreak were positive for the receptor binding domain (RBD) of SARS-CoV-2 by indirect enzyme linked immunosorbent assay (ELISA). Among the positive samples, 11 had SARS-CoV-2 neutralizing antibodies with a titer ranging from 1/20 to 1/1080. No serological cross-reactivity was detected between the SARS-CoV-2 and type I or II feline infectious peritonitis virus (FIPV). Our data demonstrates that SARS-CoV-2 has infected cat population in Wuhan during the outbreak.

microbiology↗

bioRxiv2020

Paxillin Promotes ATP-induced Activation of P2X7 Receptor and NLRP3 Inflammasome

The stimulation of P2X7 receptor by extracellular ATP leads to activation of NLRP3 inflammasome and release of pro-inflammatory cytokines. Here, we reveal a distinct mechanism by which Paxillin promotes ATP-induced activation of P2X7 receptor and NLRP3 inflammasome. Extracellular ATP induces Paxillin phosphorylation and facilitates Paxillin-NLRP3 interaction. Interestingly, Paxillin enhances NLRP3 deubiquitination and activates NLRP3 inflammasome upon ATP treatment and K+ efflux. Moreover, we reveal that UPS13 is a key enzyme for Paxillin-mediated NLRP3 deubiquitination upon ATP treatment. Notably, extracellular ATP promotes Paxillin and NLRP3 migration from cytosol to plasma membrane and facilitates P2X7-Paxillin interaction and Paxillin-NLRP3 association, resulting in the formation of P2X7-Paxillin-NLRP3 complex. Functionally, Paxillin is essential for ATP-induced NLRP3 inflammasome activation in mouse BMDMs and BMDCs as we as in human PBMCs and THP-1-differentiated macrophages. Thus, Paxillin plays key roles in ATP-induced activation of P2X7 receptor and NLRP3 inflammasome by facilitating the formation of the P2X7-Paxillin-NLRP3 complex.

immunology↗

bioRxiv2020

The ModelSEED Database for the integration of metabolic annotations and the reconstruction, comparison, and analysis of metabolic models for plants, fungi, and microbes

For over ten years, ModelSEED has been a primary resource for the construction of draft genome-scale metabolic models based on annotated microbial or plant genomes. Now being released, the biochemistry database serves as the foundation of biochemical data underlying ModelSEED and KBase. The biochemistry database embodies several properties that, taken together, distinguish it from other published biochemistry resources by: (i) including compartmentalization, transport reactions, charged molecules and proton balancing on reactions;; (ii) being extensible by the user community, with all data stored in GitHub; and (iii) design as a biochemical "Rosetta Stone" to facilitate comparison and integration of annotations from many different tools and databases. The database was constructed by combining chemical data from many resources, applying standard transformations, identifying redundancies, and computing thermodynamic properties. The ModelSEED biochemistry is continually tested using flux balance analysis to ensure the biochemical network is modeling-ready and capable of simulating diverse phenotypes. Ontologies can be designed to aid in comparing and reconciling metabolic reconstructions that differ in how they represent various metabolic pathways. ModelSEED now includes 33,978 compounds and 36,645 reactions, available as a set of extensible files on GitHub, and available to search at https://modelseed.org and KBase.

systems biology↗

bioRxiv2020

Resolving fate and transcriptome of hematopoietic stem cell clones

Adult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developed PolyloxExpress - a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiation-inactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.

immunology↗

bioRxiv2020

Potent human neutralizing antibodies elicited by SARS-CoV-2 infection

The pandemic caused by emerging coronavirus SARS-CoV-2 presents a serious global public health emergency in urgent need of prophylactic and therapeutic interventions. SARS-CoV-2 cellular entry depends on binding between the viral Spike protein receptor-binding domain (RBD) and the angiotensin converting enzyme 2 (ACE2) target cell receptor. Here, we report on the isolation and characterization of 206 RBD-specific monoclonal antibodies (mAbs) derived from single B cells of eight SARS-CoV-2 infected individuals. These mAbs come from diverse families of antibody heavy and light chains without apparent enrichment for particular families in the repertoire. In samples from one patient selected for further analyses, we found coexistence of germline and germline divergent clones. Both clone types demonstrated impressive binding and neutralizing activity against pseudovirus and live SARS-CoV-2. However, the antibody neutralizing potency is determined by competition with ACE2 receptor for RBD binding. Surprisingly, none of the SARS-CoV-2 antibodies nor the infected plasma cross-reacted with RBDs from either SARS-CoV or MERS-CoV although substantial plasma cross-reactivity to the trimeric Spike proteins from SARS-CoV and MERS-CoV was found. These results suggest that antibody response to RBDs is viral species-specific while that cross-recognition target regions outside the RBD. The specificity and neutralizing characteristics of this plasma cross-reactivity requires further investigation. Nevertheless, the diverse and potent neutralizing antibodies identified here are promising candidates for prophylactic and therapeutic SARS-CoV-2 interventions.

immunology↗

bioRxiv2020

Molecular Typing of Human Respiratory Adenoviruses with Universal PCR and Sequencing Primers for Three Major Capsid Genes: Penton base, Hexon, and Fiber

Human adenoviruses (HAdVs) within species B, C, and E include the predominant types responsible for highly contagious and potentially severe respiratory infections. The traditional method to type these pathogens was based on virus neutralization and hemagglutination assays using antisera, which is both time-consuming and difficult, particularly due to the non-availability of reagents. Molecular typing based on partial characterization of HAdV hexon, as well as the restriction enzyme analysis (REA) of the genomics DNA, is difficult to identify recombinants. Here, a rapid, simple, and cost-effective molecular typing of respiratory HAdVs is presented. This incorporates three pairs of universal PCR primers that target the variable regions of the three major capsid genes, i.e. hexon, penton base and fiber genes. The protocol developed enables detection and typing of respiratory HAdVs within species B, C, and E, as well as of some strains within species D and F. Using this method, we surveyed a total of 100 children with acute respiratory infection caused by HAdVs in Hong Kong, Summer 2014 (July to October). 100 Throat swab specimens were collected. The samples were analyzed by PCR and the sequences were characterized by BLAST. HAdVs were detected in 98 out of 100 (98%) samples. The predominant HAdV type was species B type 3. Among the patients, 74 were of HAdV-B3 (74%), 10 were of HAdV-E4 (10%), 6 were of HAdV-C2 (21.7%), 2 were of HAdV-C6 (2%), 1 were of HAdV-B7 (2%), 1 were of HAdV-C1 (74%), and 2 were of recombinant types. The developed method allows the rapid identification of HAdVs with recombinant genomes, and bypasses the need for whole genome data, for the real-time surveillance of circulating adenovirus strains in immediate outbreaks and populations by clinical microbiologists, public health officers, and epidemiologists.

microbiology↗

bioRxiv2020

RBD mutations from circulating SARS-CoV-2 strains enhance the structure stability and infectivity of the spike protein

The current global pandemic of COVID-19 is caused by a novel coronavirus SARS-CoV-2. The SARS-CoV-2 spike protein receptor-binding domain (RBD) is the critical determinant of viral tropism and infectivity. To investigate whether naturally occurring mutations in the RBD during the early transmission phase have altered the receptor binding affinity and infectivity, firstly we analyzed in silico the binding dynamics between mutated SARS-CoV-2 RBDs and the human ACE2 receptor. Among 32,123 genomes of SARS-CoV-2 isolates (January through March, 2020), 302 non-synonymous RBD mutants were identified and clustered into 96 mutant types. The six dominant mutations were analyzed applying molecular dynamics simulations. The mutant type V367F continuously circulating worldwide displayed higher binding affinity to human ACE2 due to the enhanced structural stabilization of the RBD beta-sheet scaffold. The increased infectivity of V367 mutants was further validated by performing receptor-ligand binding ELISA, surface plasmon resonance, and pseudotyped virus assays. Genome phylogenetic analysis of V367F mutants showed that during the early transmission phase, most V367F mutants clustered more closely with the SARS-CoV-2 prototype strain than the dual-mutation variants (V367F + D614G) which emerged later and formed a distinct sub-cluster. The analysis of critical RBD mutations provides further insights into the evolutionary trajectory of SARS-CoV-2 under negative selection pressure and supports the continuing surveillance of spike mutations to aid in the development of new COVID-19 drugs and vaccines. ImportanceA novel coronavirus SARS-CoV-2 has caused the pandemic of COVID-19. The origin of SARS-CoV-2 was associated with zoonotic infections. The spike protein receptor-binding domain (RBD) is identified as the critical determinant of viral tropism and infectivity. Thus, whether the mutations in the RBD of the circulating SARS-CoV-2 isolates have altered the receptor binding affinity and caused them more infectious, should be paid more attentions to. Given that SARS-CoV-2 is a novel coronavirus, the significance of our research is in identifying and validating the RBD mutant types emerging during the early transmission phase that have increased human ACE2 receptor binding affinity and infectivity. The RBD mutation analysis provides insights into SARS-CoV-2 evolution. The continuous surveillance of RBD mutations with increased human ACE2 affinity in human or other animals is important and necessary, particularly when the direct correlation between the virus variations and vaccine effectiveness is underdetermined during the sustained COVID-19 pandemic.

microbiology↗

bioRxiv2020

Recapitulation of SARS-CoV-2 Infection and Cholangiocyte Damage with Human Liver Organoids

The newly emerged pandemic coronavirus, SARS-CoV-2, has posed a significant public health threat worldwide. However, the mode of virus transmission and tissue tropism is not well established yet. Recent findings of substantial liver damage in patients and ACE2+ cholangiocytes in healthy liver tissues prompted us to hypothesize that human liver ductal organoids could serve as a model to determine the susceptibility and mechanisms underlining the liver damage upon SARS-CoV-2 infection. By single-cell RNA sequencing, we found that long-term liver ductal organoid culture preserved the human specific ACE2+ population of cholangiocytes. Moreover, human liver ductal organoids were permissive to SARS-CoV-2 infection and support robust replication. Notably, virus infection impaired the barrier and bile acid transporting functions of cholangiocytes through dysregulation of genes involved in tight junction formation and bile acid transportation, which could explain the bile acid accumulation and consequent liver damage in patients. These results indicate that control of liver damage caused directly by viral infection should be valued in treating COVID-19 patients. Our findings also provide an application of human organoids in investigating the tropism and pathogenesis of SARS-CoV-2, which would facilitate novel drug discovery.

cell biology↗

bioRxiv2020

Structural Basis for Ca2+-Dependent Activation of a Plant Metacaspase

Plants metacaspases mediate programmed cell death in development 1,2, biotic and abiotic stresses 3, damage-induced immune response 4, and resistance to pathogen attack 5. Most metacaspases require Ca2+ for their activation and substrate processing 6-8. However, the Ca2+-dependent activation mechanism remains elusive 9-11. Here we report the crystal structure of Metacaspase 4 from Arabidopsis thaliana (AtMC4) that modulates Ca2+-dependent, damage-induced plant immune defense. The AtMC4 structure exhibits an inhibitory conformation in which a large linker domain blocks activation and substrate access. In addition, the side chain of Lys225 in the linker domain blocks the active site by sitting directly between two catalytic residues. We show that the activation of AtMC4 and cleavage of its physiological substrate involve multiple cleavages in the linker domain upon activation by Ca2+. Our analysis provides insight into the Ca2+-dependent activation of AtMC4 and lays the basis for tuning its activity in response to stresses that may help engineer more sustainable crops for production of food and biofuel.

biochemistry↗

bioRxiv2020

DMLDA-LocLIFT: Identification of multi-label protein subcellular localization using DMLDA dimensionality reduction and LIFT classifier

BackgroundMulti-label proteins occur in two or more subcellular locations, which play a vital part in cell development and metabolism. Prediction and analysis of multi-label subcellular localization (SCL) can present new angle with drug target identification and new drug design. However, the prediction of multi-label protein SCL using biological experiments is expensive and labor-intensive. Therefore, predicting large-scale SCL with machine learning methods has turned into a hot study topic in bioinformatics. MethodsIn this study, a novel multi-label learning means for protein SCL prediction, called DMLDA-LocLIFT, is proposed. Firstly, the dipeptide composition, encoding based on grouped weight, pseudo amino acid composition, gene ontology and pseudo position specific scoring matrix are employed to encode subcellular protein sequences. Then, direct multi-label linear discriminant analysis (DMLDA) is used to reduce the dimension of the fused feature vector. Lastly, the optimal feature vectors are input into the multi-label learning with Label-specIfic FeaTures (LIFT) classifier to predict the location of multi-label proteins. ResultsThe jackknife test showed that the overall actual accuracy on Gram-negative bacteria, Gram-positive bacteria, and plant datasets are 98.60%, 99.60%, and 97.90% respectively, which are obviously better than other state-of-the-art prediction methods. ConclusionThe proposed model can effectively predict SCL of multi-label proteins and provide references for experimental identification of SCL. The source codes and data are publicly available at https://github.com/QUST-AIBBDRC/DMLDA-LocLIFT/.

bioinformatics↗

bioRxiv2020

Public broadly neutralizing antibodies against hepatitis B virus in individuals with elite serologic activity

SUMMARYAlthough there is no effective cure for chronic hepatitis B virus (HBV) infection, antibodies are protective and constitute clinical correlates of recovery from infection. To examine the human neutralizing antibody response to HBV in elite neutralizers we screened 144 individuals. The top individuals produced shared clones of broadly neutralizing antibodies (bNAbs) that targeted 3 non-overlapping epitopes on the HBV S antigen (HBsAg). Single bNAbs protected humanized mice against infection, but selected for resistance mutations in mice with established infection. In contrast, infection was controlled by a combination of bNAbs targeting non-overlapping epitopes with complementary sensitivity to mutations that commonly emerge during human infection. The co-crystal structure of one of the bNAbs with a peptide epitope containing residues frequently mutated in human immune escape variants revealed a loop anchored by oppositely charged residues. The structure provides a molecular explanation for why immunotherapy for HBV infection may require combinations of complementary bNAbs.

immunology↗