Biology subjects

Hu, J.

Publications and source records attributed to Hu, J..

At least 487 records · Page 27Linked to original sources

bioRxiv2019

Genetic analysis of Aedes aegypti captured in two international airports serving the Greater Tokyo area during 2012-2015

Introduction of exotic diseases vectors into a new habitat can drastically change the local epidemiological situation. During 2012--2015, larvae and an adult of the yellow-fever mosquito, Aedes aegypti, were captured alive in two international airports serving to the Greater Tokyo Area, Japan. Because this species does not naturally distribute in this country, those mosquitoes were considered to be introduced from oversea via air-transportation. To infer the places of origin of those mosquitoes, we genotyped 12 microsatellite loci for which the most comprehensive population genetic reference is available. Although clustering by Bayesian and multivariate methods both suggested all those airport mosquitoes belong to Asia/Pacific population, they were not clustered into a single population. Also, there was variation in mitochondrial Cox1 haplotypes among mosquitoes collected in different incidents of discovery which indicated the existence of multiple maternal origins. Whereas we conclude there is little evidence to support overwintering of Ae. aegypti in the airports in this study, special attention is still desired to prevent the invasion of this prominent arbovirus vector.

genetics↗

bioRxiv2019

DeepSeqPanII: an interpretable recurrent neural network model with attention mechanism for peptide-HLA class II binding prediction

Human leukocyte antigen (HLA) complex molecules play an essential role in immune interactions by presenting peptides on the cell surface to T cells. With significant progress in deep learning, a series of neural network based models have been proposed and demonstrated with their good performances for peptide-HLA class I binding prediction. However, there still lack effective binding prediction models for HLA class II protein binding with peptides due to its inherent challenges. In this work, we present a novel sequence-based pan-specific neural network structure, DeepSeaPanII, for peptide-HLA class II binding prediction. Compared with existing pan-specific models, our model is an end-to-end neural network model without the need for pre- or post-processing on input samples. Besides state-of-the-art peformance in binding affinity prediction, DeepSeqPanII can also extract biological insight on the binding mechanism over the peptide and HLA sequences by its attention mechanism based binding core prediction capability. The leave-one-allele-out cross validation and benchmark evaluation results show that our proposed network model achieved state-of-the-art performance in HLA-II peptide binding. The source code and trained models are freely available at https://github.com/pcpLiu/DeepSeqPanII.

bioinformatics↗

bioRxiv2019

A functional analysis of the Drosophila gene hindsight: evidence for positive regulation of EGFR signaling

We have investigated the relationship between the function of the gene hindsight (hnt), which is the Drosophila homolog of Ras Responsive Element Binding protein-1 (RREB-1), and the EGFR signaling pathway. We report that hnt mutant embryos are defective in EGFR signaling dependent processes, namely chordotonal organ recruitment and oenocyte specification. We also show the temperature sensitive hypomorphic allele hntpebbled is enhanced by the hypomorphic MAPK allele rolled (rl1). We find that hnt overexpression results in ectopic DPax2 expression within the embryonic peripheral nervous system, and we show that this effect is EGFR-dependent. Finally, we show that the canonical U-shaped embryonic lethal phenotype of hnt, which is associated with premature degeneration of the extraembyonic amnioserosa and a failure in germ band retraction, is rescued by expression of several components of the EGFR signaling pathway (sSpi, Ras85DV12, pntP1) as well as the caspase inhibitor p35. Based on this collection of corroborating evidence, we suggest that an overarching function of hnt involves the positive regulation of EGFR signaling.

developmental biology↗

bioRxiv2019

ASEP: gene-based detection of allele-specific expression in a population by RNA-seq

Allele-specific expression (ASE) analysis, which quantifies the relative expression of two alleles in a diploid individual, is a powerful tool for identifying cis-regulated gene expression variations that underlie phenotypic differences among individuals. Existing methods for gene-level ASE detection analyze one individual at a time, therefore wasting shared information across individuals. Failure to accommodate such shared information not only loses power, but also makes it difficult to interpret results across individuals. However, ASE detection across individuals is challenging because the data often include individuals that are either heterozygous or homozygous for the unobserved cis-regulatory SNP, leading to heterogeneity in ASE as only those heterozygous individuals are informative for ASE, whereas those homozygous individuals have balanced expression. To simultaneously model multi-individual information and account for such heterogeneity, we developed ASEP, a mixture model with subject-specific random effect accounting for multi-SNP correlations within the same gene. ASEP is able to detect gene-level ASE under one condition and differential ASE between two conditions (e.g., pre-versus post-treatment). Extensive simulations have demonstrated the convincing performance of ASEP under a wide range of scenarios. We further applied ASEP to RNA-seq data of human macrophages, and identified genes showing evidence of differential ASE pre-versus post-stimulation, which were extended through findings in cardiometabolic trait-relevant genome-wide association studies. To the best of our knowledge, ASEP is the first method for gene-level ASE detection at the population level. With the growing adoption of RNA-seq, we believe ASEP will be well-suited for various ASE studies for human diseases.

genomics↗

bioRxiv2019

Controlled Self-Assembly of {lambda}-DNA Networks with the Synergistic Effect of DC Electric Field

Large-scale and morphologically controlled self-assembled {lambda}-DNA networks were successfully constructed by the synergistic effect of DC electric field. The effect of DNA concentration, direction and intensity of the electric field, even the modification of the mica surface using Mg2+ on the characteristics of the as-prepared DNA networks were investigated in detail by atomic force microscopy (AFM). It was found that the horizontal electric field was more advantageous to the formation of DNA networks with more regular structures. At the same concentration, the height of DNA network was not affected significantly by the intensity change of the horizontal electric field. The modification of Mg2+ on mica surface increased the aggregation of DNA molecules, which contributed to the morphological change of the DNA networks. Furthermore, DNA molecules were obviously stretched in both horizontal and vertical electric fields at low DNA concentrations.\n\nStatement of significanceThrough the synergistic effect of DC electric field, a series of large-scale and morphologically controlled self-assembled {lambda}-DNA networks were successfully fabricated. We found that the horizontal electric field was more advantageous to the formation of DNA networks with more regular structures. At the same concentration of DNA solution, the height of DNA network was not affected significantly by the intensity change of the horizontal electric field. The modification of Mg2+ on mica surface increased the aggregation of DNA molecules, which contributed to the morphological change of the DNA networks. We suggest this study will promote the understanding on the preparation of controllable self-assembled {lambda}-DNA networks and the application of DNA networks.

biophysics↗

bioRxiv2019

An integrated Asian human SNV and indel benchmark combining multiple sequencing methods

Precision medicine of human requires an accurate and complete reference variant benchmark for different populations. A human standard cell line of NA12878 provides a good reference for part of the human populations, but it is still lack of a fine reference standard sample and variant benchmark for the Asians. Here, we constructed a stabilized cell line of a Chinese Han volunteer. We received about 4.16T clean data of the sample using eight sequencing strategies in different laboratories, including two BGI regular NGS platforms, three Illumina regular NGS platforms, two linked-read libraries, and PacBio CCS model. The sequencing depth and reference coverage of eight sequencing strategies have reached the saturation. We detected small variants of SNPs and Indels using the eight data sets and obtained eight variant sets by performing a series of strictly quality control. Finally, we got 3.35M SNPs and 349K indels supported by all of sequencing data, which could be considered as a high confidence standard small variant sets for the studies. Besides, we also detected 5,913 high quality SNPs located in the high homologous regions supported by both linked-reads and CCS data benefited by their long-range information, while these regions are recalcitrant to regular NGS data due to the limited mappability and read length. We compared the later SNPs against the public databases and 969 sites of them were novel SNPs, indicating these SNPs provide a vital complement for the variant database. Moreover, we also phased more than 99% heterozygous SNPs also supported by linked-reads and CCS data. This work provided an integrated Asians SNV and indel benchmark for the further basic studies and precision medicine.

genomics↗

bioRxiv2019

GATA2 Expression by Intima-Infiltrating Macrophages Drives Early Atheroma Formation

Aberrant macrophage polarization is a major contributor to the onset and progression of atherosclerosis. Despite this, macrophage polarization during in early stages of human atherosclerotic disease is poorly understood. Using transcriptomic analysis of macrophages recovered from early-stage human atherosclerotic lesions, we have identified a unique gene expression profile dissimilar to that observed in later stages of disease that is characterized by upregulation of the hematopoietic transcription factor GATA2. GATA2 overexpression in vitro recapitulated defects observed in patient macrophages, including deficiencies in the uptake and processing of apoptotic cells, and in the catalysis of atherogenic protein modifications, with GATA2 knockdown abrogating these defects. Our data describe a previously unreported macrophage differentiation state present in early atheroma formation and identifies GATA2 as a driver of macrophage functional defects during the early stages of atherosclerosis in humans.

immunology↗

bioRxiv2019

Estimating and testing the microbial causal mediation effect with high-dimensional and compositional microbiome data

MotivationRecent microbiome association studies have revealed important associations between microbiome and disease/health status. Such findings encourage scientists to dive deeper to uncover the causal role of microbiome in the underlying biological mechanism, and have led to applying statistical models to quantify causal microbiome effects and to identify the specific microbial agents. However, there are no existing causal mediation methods specifically designed to handle high dimensional and compositional microbiome data.\n\nResultsWe propose a rigorous Sparse Microbial Causal Mediation Model (SparseMCMM) specifically designed for the high dimensional and compositional microbiome data in a typical three-factor (treatment, microbiome and outcome) causal study design. In particular, linear log-contrast regression model and Dirichlet regression model are proposed to estimate the causal direct effect of treatment and the causal mediation effects of microbiome at both the community and individual taxon levels. Regularization techniques are used to perform the variable selection in the proposed model framework to identify signature causal microbes. Two hypothesis tests on the overall mediation effect are proposed and their statistical significance is estimated by permutation procedures. Extensive simulated scenarios show that SparseMCMM has excellent performance in estimation and hypothesis testing. Finally, we showcase the utility of the proposed SparseMCMM method in a study which the murine microbiome has been manipulated by providing a clear and sensible causal path among antibiotic treatment, microbiome composition and mouse weight.

bioinformatics↗

bioRxiv2019

Super-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis

Aberrant chromatin structure is a hallmark in cancer cells and has long been used for clinical diagnosis of cancer. However, underlying higher-order chromatin folding during malignant transformation remains elusive, due to the lack of molecular scale resolution. Using optimized stochastic optical reconstruction microscopy (STORM) for pathological tissue (PathSTORM), we uncovered a gradual decompaction and fragmented higher-order chromatin folding throughout all stages of carcinogenesis in multiple tumor types, even prior to the tumor formation. Our integrated imaging, genomic, and transcriptomic analyses reveal the functional consequences in enhanced formation of transcription factories, spatial juxtaposition with relaxed nanosized chromatin domains and impaired genomic stability. We also demonstrate the potential of imaging higher-order chromatin decompaction to detect high-risk precursors that cannot be distinguished by conventional pathology. Taken together, our findings reveal the gradual decompaction and fragmentation of higher-order chromatin structure as an enabling characteristic in early carcinogenesis to facilitate malignant transformation, which may improve cancer diagnosis, risk stratification, and prevention.\n\nSIGNIFICANCEGenomic DNA is folded into a higher-order structure that regulates transcription and maintains genomic stability. Although much progress has been made on understanding biochemical characteristics of epigenetic modifications in cancer, the higher-order folding of chromatin structure remains largely unknown. Using optimized super-resolution microscopy, we uncover de-compacted and fragmented chromatin folding in tumor initiation and stepwise progression in multiple tumor types, even prior to the presence of tumor cells. This study underlines the significance of unfolding higher-order chromatin structure as an enabling characteristic to promote tumorigenesis, which may facilitate the development and evaluation of new preventive strategies. The potential of imaging higher-order chromatin folding to improve cancer detection and risk stratification is demonstrated by detecting high-risk precursors that cannot be distinguished by conventional pathology.

cancer biology↗

bioRxiv2019

MHC genotyping from rhesus macaque exome sequences

Indian rhesus macaque major histocompatibility complex (MHC) variation can influence the outcomes of transplantation and infectious disease studies. Frequently, rhesus macaques are MHC genotyped to identify variants that could account for unexpected results. Since the MHC is only one region in the genome where variation could impact experimental outcomes, strategies for simultaneously profiling variation in the macaque MHC and the remainder of the protein coding genome would be useful. Here we introduce macaque exome sequence (MES) genotyping, in which MHC class I and class II genotypes are determined with high confidence using target-enrichment probes that are enriched for MHC sequences. For a cohort of 27 Indian rhesus macaques, we describe two methods for obtaining MHC genotypes from MES data and demonstrate that the MHC class I and class II genotyping results obtained with these methods are 98.1% and 98.7% concordant, respectively, with expected MHC genotypes. In contrast, conventional MHC genotyping results obtained by deep sequencing of short multiplex PCR amplicons were only 92.6% concordant with expectations for this cohort.

immunology↗

bioRxiv2019

Isoform specificity of PKMs during long-term facilitation in Aplysia is mediated through stabilization by KIBRA

Persistent activity of protein kinase M (PKM), the truncated form of protein kinase C (PKC), can maintain long-term changes in synaptic strength in many systems including the hermaphrodite marine mollusk, Aplysia californica. Moreover, different types of long-term facilitation (LTF) in cultured Aplysia sensorimotor synapses rely on the activities of different PKM isoforms in the presynaptic sensory neuron and postsynaptic motor neuron. When the atypical PKM isoform was required, the kidney and brain expressed adaptor protein (KIBRA) was also required. Here, we explore how this isoform specificity is established. We find that PKM overexpression in the motor neuron, but not the sensory neuron, is sufficient to increase synaptic strength and that this activity is not isoform specific. KIBRA is not the rate-limiting step in facilitation since overexpression of KIBRA is neither sufficient to increase synaptic strength, nor to prolong a form of PKM-dependent intermediate synaptic facilitation. However, the isoform specificity of dominant negative (DN)-PKMs to erase LTF is correlated with isoform specific competition for stabilization by KIBRA. We identify a new conserved region of KIBRA. Different splice isoforms in this region stabilize different PKMs based on the isoform-specific sequence of an alpha-helix handle in the PKMs. Thus, specific stabilization of distinct PKMs by different isoforms of KIBRA can explain the isoform specificity of PKMs during LTF in Aplysia.\n\nSignificance StatementLong lasting changes in synaptic plasticity associated with memory formation are maintained by persistent protein kinases. We have previously shown in the Aplysia sensorimotor model that distinct isoforms of persistently active protein kinase Cs (PKMs) maintain distinct forms of long-lasting synaptic changes, even when both forms are expressed in the same motor neuron. Here, we show that, while the effects of overexpression of PKMs in not isoform specific, isoform specificity is defined by a handle helix in PKMs that confers stabilization by distinct splice forms in a previously undefined domain of the adaptor protein KIBRA. Thus, we define new regions in both KIBRA and PKMs that define the isoform specificity for maintaining synaptic strength in distinct facilitation paradigms.

neuroscience↗

bioRxiv2019

The fungal gene cluster for biosynthesis of the antibacterial agent viriditoxin

BackgroundViriditoxin is one of the classical secondary metabolites produced by fungi and that has antibacterial and other activities; however, the mechanism of its biosynthesis has remained unknown.\n\nResultsHere, a gene cluster responsible for its synthesis was identified, using bioinformatic approaches from two species that produce viriditoxin and then through gene disruption and metabolite profiling. All eight genes in the cluster in Paecilomyces variotii were mutated, revealing their roles in the synthesis of this molecule and establishing its biosynthetic pathway which includes an interesting Baeyer-Villiger monooxygenase catalyzed reaction. Additionally, a candidate catalytically-inactive hydrolase was identified as being required for the stereoselective biosynthesis of (M)-viriditoxin. The localization of two proteins were assessed by fusing these proteins to green fluorescent protein, revealing that at least two intracellular structures are involved in the compartmentalization of the synthesis steps of this metabolite.\n\nConclusionsThe full pathway for synthesis of viriditoxin was established by a combination of genomics, bioinformatics, gene disruption and chemical analysis processes. Hence, this work reveals the basis for the synthesis of an understudied class of fungal secondary metabolites and provides a new model species for understanding the synthesis of biaryl compounds with a chiral axis.

microbiology↗

bioRxiv2019

Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage

Folate contributes to the accumulation of DNA strand breaks (DSBs) in the genome. Kdm6a plays a critical role in early embryogenesis but it is unknown whether Kdm6a is involved in the DNA damage response under folate deficiency. Here, we established a low folate environment for mouse embryonic cells using a folate antagonist (methotrexate, MTX). We found increased enrichment of DSBs in Kdm6a in MTX-treated cells, resulting in reduced Kdm6a expression. MTX treatment enriched KDM6A in the nonhomologous end-joining (NHEJ) repair pathway and controlled the expression of the Ku heterodimer (Ku70/80) and XRCC4. The activation of NHEJ repair pathway-associated genes under folate deficiency relied on the specific interaction between KDM6A and p53. p53 silencing increased Ku heterodimer expression. In addition, in a neural tube defect (NTD) mouse model and low folate neural tube defect human brain samples, KDM6A levels were also decreased and accompanied by over-expression of Ku80. Our findings highlight how alterations in folate levels affect KDM6A with respect to DNA breakage and DNA repair, offering a new insight into the molecular function of KDM6A.\n\nSummary statementOur study demonstrates for the first time that in mammals, Kdm6a and p53 have synergistic effects during DNA fragmentation repair.

bioinformatics↗

bioRxiv2019

Clinical pattern of antibiotic overuse and misuse in primary healthcare hospitals in the southwest of China

PurposeOveruse and misuse of antibiotics are the primary risk factors for antibiotics resistance. Inadequate professional competence of primary care physicians might exacerbate these problems in China. This retrospective study aims to document the clinical pattern of antibiotics use and its overuse and misuse rates in rural primary care institutions, and to evaluate the association between antibiotics use and characteristics of the physicians and their patients.\n\nMethodsMedical records from 16 primary care hospitals in rural areas of Guizhou province, China were obtained from the Health Information System in 2018. Classification of incorrect and/or unnecessary use, escalated use and combined antibiotics use was based on the Guiding Principle of Clinical Use of Antibiotics (2015, China) and the standard of USA Centers for Disease Control and Prevention. Generalized Estimating Equations were employed to determine predictive factors for inappropriate antibiotics use.\n\nResultsA total of 74,648 antibiotics prescriptions were retrieved. Uncomplicated respiratory infection was the most common disease accounting for 58.6% of all prescriptions. The main antibiotic group used was penicillins (51.5%) followed by cephalosporins and macrolides (14% each). Of 57,009 patient visits, only 8.7% of the antibiotic prescriptions were appropriate. Combined, escalated, and incorrect and/or unnecessary antibiotics use was found in 7.8%, 6.2% and 77.3% of patient visits, respectively, of which 28.7% were given intravenously. Antibiotics misuse was significantly more likely among newly employed physicians with lower levels of professional education. Adult patients and those who had public insurance had a higher risk of being prescribed incorrect and/or unnecessary antibiotics.\n\nConclusionOveruse of antibiotics for uncomplicated respiratory infection and use of cephalosporins, macrolides and injection antibiotics in primary care are the major problems of clinical practice in rural areas of Guizhou.

epidemiology↗

bioRxiv2019

Specific inhibition of DPY30 activity by ASH2L-derived peptides suppresses blood cancer cell growth

DPY30 facilitates H3K4 methylation by directly binding to ASH2L in the SET1/MLL complexes and plays an important role in hematologic malignancies. However, the domain on DPY30 that regulates cancer growth is not evident, and the potential of pharmacologically targeting this chromatin modulator to inhibit cancer has not been explored. Here we have developed a peptide-based strategy to specifically target DPY30 activity. We have designed cell-penetrating peptides derived from ASH2L that can either bind to DPY30 or show defective or enhanced binding to DPY30. The DPY30-binding peptides specifically inhibit its activity in interacting with ASH2L and enhancing H3K4 methylation. Treatment with the DPY30-binding peptides significantly inhibited the growth of MLL-rearranged leukemia and other MYC-dependent hematologic cancer cells. We also revealed subsets of genes that may mediate the effect of the peptides on cancer cell growth, and showed that the DPY30-binding peptide sensitized leukemia to other types of epigenetic inhibitors. These results strongly support a critical role of the ASH2L-binding groove of DPY30 in promoting blood cancers, and demonstrate a proof-of-principle for the feasibility of pharmacologically targeting the ASH2L-binding groove of DPY30 for potential cancer inhibition.

cancer biology↗

bioRxiv2019

Genetic basis of plasticity for forage quality traits in response to water deficit in a diverse germplasm panel of alfalfa

Plant phenotypic plasticity is the ability of plants to express different phenotypes in response to environmental variations. Genetic bases by which phenotypic plasticity affects plant adaptation to environmental change remain largely unknown. In the present study, we characterized 26 forage quality traits in a panel of alfalfa 198 accessions in a field trial under water deficit gradient. The regression analysis revealed that the values of fiber-related traits decreased, while those among energy-related traits increased, as water deficit increased. Genetic loci for forage quality traits were investigated by Genome-wide association studies (GWAS) under different levels of water deficit. Genetic loci associated with forage quality traits were identified and compared. Similar regions were found between energy-related traits when grand means were used for GWAS. Most of the associated markers were identified under water deficit, suggesting genetic mechanisms for forage quality traits were differ between well-watered and water stressed plants. Although GWAS on forage quality have been reported, we are the first to address the genetic factors for forage quality traits under water deficit in autotetraploid alfalfa. The information gained from the present study will be useful for the genetic improvement of alfalfa with enhanced drought/salt tolerance while maintaining forage quality.

genetics↗

bioRxiv2019

Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models

Human papillomavirus (HPV) infections are commonly thought to be strictly sexually transmitted. However, studies have demonstrated the presence of HPV in cancers of many non-sexual internal organs, raising the question as to how the viruses gain access to these sites. A possible connection between blood transfusion and HPV-associated disease has not received much attention. We show, in two animal models, that blood infected with papillomavirus yields infections at permissive sites. Furthermore, we demonstrate that blood from actively infected mice can transmit the infection to naive animals. Finally, we report papillomavirus infections in the stomach tissues of animals infected via the blood. Stomach tissues are not known to be permissive for papillomavirus infection, although the literature suggests that HPVs may be associated with a subset of gastric cancers. These results indicate that the human blood supply, which is not screened for papillomaviruses, could be a potential source of HPV infection and subsequent cancers. SUMMARYHuman papillomaviruses cause 5% of human cancers. Currently, blood banks do not screen for these viruses. We demonstrate that blood transfused from papillomavirus-infected animals produces infections in recipients. Public health implications are significant if the same is true for humans. DefinitionsLocal papillomavirus infection: An infection initiated by the direct application of virus or viral DNA to the site of infection Intravenous (IV) papillomavirus infection: An infection resulting from blood-borne delivery of virus or viral DNA to the site of infection.

microbiology↗

bioRxiv2019

Protein Condensates with Appropriate Material Properties Regulate Tumorigenesis

It remains unknown if biophysical or material properties of biomolecular condensates regulate cancer. Here we show that AKAP95, a nuclear protein that regulates transcription and RNA splicing, plays an important role in tumorigenesis by supporting cancer cell growth and suppressing oncogene-induced senescence. AKAP95 forms phase-separated and liquid-like condensates in vitro and in nucleus. Mutations of key residues to different amino acids perturb AKAP95 condensation in opposite directions. Importantly, the activity of AKAP95 in splice regulation is abolished by disruption of condensation, significantly impaired by hardening of condensates, and regained by substituting its condensation-mediating region with other condensation-mediating regions from irrelevant proteins. Moreover, the abilities of AKAP95 in regulating gene expression and supporting tumorigenesis require AKAP95 to form condensates with proper liquidity and dynamicity. These results link phase separation to tumorigenesis and uncover an important role of appropriate biophysical properties of protein condensates in gene regulation and cancer.

biochemistry↗