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Zhang, Q.

Publications and source records attributed to Zhang, Q..

At least 379 records · Page 21Linked to original sources

Decoupling of the Onset of Anharmonicity between a Protein and Its Surface Water around 200 K

The protein dynamical transition at [~] 200 K, where the biomolecule transforms from a harmonic, non-functional form to an anharmonic, functional state, has been thought to be slaved to the thermal activation of dynamics in its surface hydration water. Here, by selectively probing the dynamics of protein and hydration water using elastic neutron scattering and isotopic labelling, we found that the onset of anharmonicity in the two components around 200 K are decoupled. The one in protein is an intrinsic transition, whose characteristic temperature is independent of the instrumental resolution time, but varies with the biomolecular structure and the amount of hydration, while the one of water is merely a resolution effect.

biophysics↗

Sibling chimerism among microglia in marmosets

Chimerism happens rarely among most mammals but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which in utero connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12-80%) throughout life. The presence of Y-chromosome DNA sequences in organs of female marmosets has long suggested that chimerism might also affect these organs. However, a longstanding question is whether this chimerism is driven by blood-derived cells or involves contributions from other cell types. To address this question, we analyzed single-cell RNA-seq data from blood, liver, kidney and many brain regions across a number of marmosets, using transcribed single nucleotide polymorphisms (SNPs) to identify cells with the siblings genome in various cell types within these tissues. Sibling-derived chimerism in all tissues arose entirely from cells of hematopoietic origin (i.e., myeloid and lymphoid lineages). In brain tissue this was reflected as sibling-derived chimerism among microglia (20-52%) and macrophages (18-64%) but not among other resident cell types (neurons, glia or ependymal cells). The percentage of microglia that were sibling-derived showed significant variation across brain regions, even within individual animals, likely reflecting distinct responses by genetic-sibling microglia to local recruitment or proliferation cues or, potentially, distinct clonal expansion histories in different brain areas. In the animals and tissues we analyzed, microglial gene expression profiles bore a much stronger relationship to local/host context than to sibling genetic differences. Naturally occurring marmoset chimerism will provide new ways to recognize the effects of genes, mutations and brain contexts on microglial biology and to distinguish between effects of microglia and other cell types on brain phenotypes.

neuroscience↗

Amur grape genome sequence

To date, there is no high-quality sequence for genomes of the East Asian grape species, hindering biological and breeding research efforts to improve grape cultivars. This study presents a [~]522 Mb of the Vitis amurensis (Va) genome sequence containing 27,635 coding genes. Phylogenetic analysis indicated that V. riparia (Vr) may firstly split from the other two species, Va, V. Vinifera (Vv; Pinot Noir: PN40024 and Cabernet Sauvignon). Much divergent gene reservation among three grape duplicated gene sets suggests that the core eudicot common hexaploidy (ECH), 130 million years ago (Mya), has still played a non-negligible role in grape species divergence and biological innovation. Prominent accumulation of sequence variants might have improved cold resistance in Va, resulting in a more robust cold resistance gene regulatory network than those in Vv and Vr. In contrast, Va preserved much fewer NBS disease resistance genes than the other grapes. Notably, multi-omics analysis identified one trans-cinnamate 4-monooxygenase gene positively correlated to the resveratrol accumulated during Va berry development. A selective sweep analysis revealed a hypothetical Va sex-determination region (SDR). Besides, a PPR-containing protein-coding gene in the hypothetical SDR may be related with sex determination in Va. The content and arrangement order of genes in the putative SDR of female Va were similar to the SDR of female Vv. However, the putative SDR of female Va lost one Flavin-containing monooxygenases (FMO) and contained one extra uncharacterized protein-coding gene. These findings will improve the understanding of Vitis biology and contribute to the improvement of grape breeding.

genomics↗

ModelSEED v2: High-throughput genome-scale metabolic model reconstruction with enhanced energy biosynthesis pathway prediction

Since the release of ModelSEED in 2010, the systems biology research community has used the ModelSEED genome-scale metabolic model reconstruction pipeline to build over 200,000 draft metabolic reconstructions that support hundreds of publications. Here we describe the first comprehensive update to this reconstruction tool, with new features such as (i) a dramatically improved representation of energy metabolism, which ensures that models produce accurate amounts of ATP per mol of nutrient consumed; (ii) a new template for Archaea model reconstruction; and (iii) a significantly improved curation of all metabolic pathways with mappings to RAST subsystems annotations. We applied the improved pipeline to build and analyze core and genome-scale models for Archaea and Bacteria genomes in KEGG. The new ModelSEED pipeline generates larger models that possess more reactions and genes and require fewer gap-filled reactions. In addition, we see conserved patterns in the ATP biosynthesis mechanism across phylogeny, and identify clades where our understanding of energy biosynthesis is still poor. ModelSEED v2 is available through KBase and the ModelSEED website (https://modelseed.org/), which supports reconstruction, gap-filling, flux balance analysis and model export through a modern web interface.

systems biology↗

Staphyloccocus aureus biofilm, in the absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune-suppressive genes in human monocytes

Staphyloccocus aureus (S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI). S. aureus forms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic-resistant metabolic state. We developed an in vitro system to study S. aureus biofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data, S. aureus biofilm induced expression of inflammatory genes such as TNF and IL1B, and their anti-inflammatory counter-regulator IL-10. S. aureus biofilm also activated expression of PD-1 ligands that suppress T cell function, and of IL-1RA that suppresses differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm-encased bacteria that was heat resistant and > 3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita-PAMP. Induction of T cell suppressive genes by S. aureus biofilm provides insights into mechanisms that suppress T cell immunity in PJI, and suggest that anti-PD-1 therapy that is modeled on immune checkpoint blockade for tumors may be beneficial in PJI.

immunology↗

Inhibition of miR-199b-5p reduces pathological alterations in Osteoarthritis by targeting Fzd6 and Gcnt2

Osteoarthritis (OA) is a degenerative disease with a high prevalence in the elderly population, but our understanding of its mechanisms remains incomplete. Analysis of serum exosomal small RNA sequencing data from clinical patients and gene expression data from OA patient serum and cartilage obtained from the GEO database revealed a common dysregulated miRNA, miRNA-199b-5p. In vitro cell experiments demonstrated that miRNA-199b-5p inhibits chondrocyte vitality and promotes extracellular matrix degradation. Conversely, inhibition of miRNA-199b-5p under inflammatory conditions exhibited protective effects against damage. Local viral injection of miRNA-199b-5p into mice induced a decrease in pain threshold and OA-like changes. In an OA model, inhibition of miRNA-199b-5p alleviated the pathological progression of OA. Furthermore, bioinformatics analysis and experimental validation identified Gcnt2 and Fzd6 as potential target genes of miRNA-199b-5p. Thus, these results indicated that miRNA-199b-5p/Gcnt2 and Fzd6 axis might be a novel therapeutic target for the treatment of OA.

molecular biology↗

Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of two Faecalibacterium intestinalis isolates in alleviating constipation, the cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and the functional potential of isolates from the two new species belonging to the genera Parabacteroides and Lactobacillus in host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.

microbiology↗

Reconciling ASPP-p53 Binding Mode Discrepancies through an Ensemble Binding Framework that Bridges Crystallography and NMR Data

ASPP2 and iASPP bind to p53 through their conserved ANK-SH3 domains to respectively promote and inhibit p53-dependent cell apoptosis. While crystallography has indicated that these two proteins employ distinct surfaces of their ANK-SH3 domains to bind to p53, solution NMR data has suggested similar surfaces. In this study, we employed multi-scale molecular dynamics (MD) combined with free energy calculations to reconcile the discrepancy in the binding modes. We demonstrated that the binding mode based solely on a single crystal structure does not enable iASPPs RT loop to engage with p53s C-terminal linker--a verified interaction. Instead, an ensemble of simulated iASPP-p53 complexes facilitates this interaction. We showed that the ensemble-average inter-protein contacting residues and NMR-detected interfacial residues align well with ASPP proteins, and the ensemble-average binding free energies better match experimental Kd values compared to single crystallgarphy-determined binding mode. For iASPP, the sampled ensemble complexes can be grouped into two classes, resembling the binding modes determined by crystallography and solution NMR. We thus propose that crystal packing shifts the equilibrium of binding modes towards the crystallographydetermined one. Lastly, we show that the ensemble binding complexes are sensitive to p53s intrinsically disordered regions (IDRs), attesting to experimental observations that these IDRs contribute to biological functions. Our results provide a dynamic and ensemble perspective for scrutinizing these important cancer-related protein-protein interactions (PPIs).

biophysics↗

Evolutionary prediction for new echolocators

It was suggested over 60 years ago that echolocation is widespread in animals. Although echolocation has been found to evolve independently in several mammalian lineages, this hypothesis remains largely untested due to the difficulty of determining the presence of echolocation. To address this issue, we combined molecular convergence analyses from 190 high-quality mammalian genomes with machine learning to predict potential new mammalian echolocators. Our model predicted three promising lineages of echolocating mammals. Behavioral experiments confirmed that the gracile shrew mole (Uropsilus gracilis), the highest- ranking species among predicted echolocators, as well as almost all shrew moles (Uropsilinae), are capable of echolocation through the use of ultrasonic pulses. In contrast to most bats that use laryngeal echolocation, the characteristics of calls, the morphology of the stylohyal bone, and the results of tongue ligation experiments all suggest that shrew moles produce ultrasonic clicks with their tongues for echolocation. Finally, we estimated at least 20% of all living mammalian orders with echolocation ability, thus empirically supporting Griffins hypothesis that echolocation is widespread among animals. Our findings not only provide evidence that three novel lineages of echolocating mammals, but also demonstrate that phylogenetically replicated phenotypes can be predicted through genetic convergence. One sentence summaryShrew moles are capable of echolocation.

evolutionary biology↗

Decoding the Influence of Central LEAP2 on Hedonic Food Intake and its association with Dopaminergic Reward Pathways

The gut-brain peptide ghrelin and its receptor (GHSR) are established as a regulator of hunger and reward-processing. However, the recently recognized GHSR inverse agonist, liver-expressed antimicrobial peptide 2 (LEAP2), is less characterized. Given the role of GHSR in many central processes, and in particular reward, understanding the central effects of LEAP2 is of high interest to understand reward-related behaviors and disorders, including hedonic feeding in eating disorders. The present study aimed to elucidate LEAP2s central effect on reward-related behaviors through hedonic feeding and its mechanism. LEAP2 was administrated centrally in male mice and effectively reduced hedonic feeding but had no or little effect on homeostatic chow intake when a more palatable option was available. Strikingly, the effect on hedonic feeding was correlated to the preference of the palatable food option, where peanut butter showed the highest preference and the greatest reduction by LEAP2. Further, LEAP2 reduced the rewarding memory of high-preference foods, as well as attenuated the accumbal dopamine release associated with peanut butter exposure and eating. Interestingly, LEAP2 was widely expressed in the brain, and in particular in reward-related brain areas such as the laterodorsal tegmental area (LDTg). The expression in this area was also markedly altered when given free access to peanut butter. Accordingly, infusion of LEAP2 into the LDTg was sufficient to attenuate acute peanut butter eating. Taken together, the present results show that central LEAP2 has a profound effect on central dopaminergic reward signaling and affects several aspects of hedonic eating. The present study highlights LEAP2s effect on reward, which may have application not only for hedonic feeding, but for other reward-related psychiatric disorders as well.

neuroscience↗

Plant immunity activated and suppressed by a conserved effector protein family in mirid bug Riptortus pedestris

Riptortus pedestris (Fabricius) a major soybean pest migrates into soybean fields during pod filling stage resulting in a leaf and stem staygreen while pods without beans syndrome. Given the agricultural importance of this species and the lack of characterized HAMP from piercing-sucking insects we performed a large scale of screening by expression of 87 R. pedestris salivary proteins with signal peptides in Nicotiana benthamiana obtaining a candidate HAMP RPH1. RPH1 activated a series of PTI responses including ROS burst upregulation of defense marker genes such as PR1 WRKY7 WRKY8 Acre31 and CYP71D20 MAPK activation and biosynthesis of phytohormones in plants. RPH1 significantly enhances soybean resistance against R. pedestris feeding. PRR coreceptors BAK1 and SOBIR1 were required for RPH1-induced PTI responses. Remarkably RPH1 homologs were widely distributed in herbivorous insects and majority of homologs from selected species induced cell death or ROS. Thus our results demonstrated that RPH1 is a conserved HAMP within chewing and piercing-sucking insects. We also discovered that R. pedestris evolved four paralogs to overcome the plant immunity triggered by RPH1. This study filled a major gap of HAMP identification from piercing-sucking insect and also deciphered a novel evasion strategy of plant immunity exploited by herbivorous insects. One sentence summaryRiptortus pedestris RPH1, a conserved HAMP in herbivores, activates a variety of PTI responses in plants. To couterdefense, R. pedestris evolved four paralogs to suppress RPH1-induced PTI responses. The author(s) responsible for distribution of materials integral to the findings presented in this article in accordance with the policy described in the Instructions for Authors (https://academic.oup.com/plcell/pages/General-Instructions) is: Ai Xia (xia@njau.edu.edu).

plant biology↗

A chromosome-scale assembly for dAnjou pear

Cultivated pear consists of several Pyrus species with P. communis (European pear) representing a large fraction of worldwide production. As a relatively recently domesticated crop and perennial tree, pear can benefit from genome-assisted breeding. Additionally, comparative genomics within Rosaceae promises greater understanding of evolution within this economically important family. Here, we generate a fully-phased chromosome-scale genome assembly of P. communis cv. dAnjou. Using PacBio HiFi and Dovetail Omni-C reads, the genome is resolved into the expected 17 chromosomes, with each haplotype totalling nearly 540 Megabases and a contig N50 of nearly 14 Mb. Both haplotypes are highly syntenic to each other, and to the Malus domestica Honeycrisp apple genome. Nearly 45,000 genes were annotated in each haplotype, over 90% of which have direct RNA-seq expression evidence. We detect signatures of the known whole-genome duplication shared between apple and pear, and we estimate 57% of dAnjou genes are retained in duplicate derived from this event. This genome highlights the value of generating phased diploid assemblies for recovering the full allelic complement in highly heterozygous crop species.

genomics↗

Habitat fragmentation weakens the positive relationship between grassland plant richness and above-ground biomass

Habitat loss and fragmentation per se have been shown to be a major threat to global biodiversity and ecosystem function. However, little is known about how habitat loss and fragmentation per se alters the relationship between biodiversity and ecosystem function (BEF relationship) in the natural landscape context. Based on 130 landscapes identified by a stratified random sampling in the agro-pastoral ecotone of northern China, we investigated the effects of landscape context (habitat loss and fragmentation per se) on plant richness, above-ground biomass, and the relationship between them in grassland communities using a structural equation model. We found that habitat loss directly decreased plant richness and hence decreased above-ground biomass, while fragmentation per se directly increased plant richness and hence increased above-ground biomass. Fragmentation per se also directly decreased soil water content and hence decreased above-ground biomass. Meanwhile, habitat loss decreased the magnitude of the positive relationship between plant richness and above-ground biomass by reducing the percentage of grassland specialists in the community, while fragmentation per se had no significant modulating effect on this relationship. These results demonstrate that habitat loss and fragmentation per se have inconsistent effects on biodiversity and ecosystem function, with the BEF relationship being modulated by landscape context. Our findings emphasise that habitat loss rather than fragmentation per se can weaken the positive BEF relationship by decreasing the degree of habitat specialisation of the community. HighlightsO_LIBEF relationship is moderated by landscape context in fragmented landscapes. C_LIO_LIHabitat loss and fragmentation per se have inconsistent effects. C_LIO_LIHabitat loss can weaken the positive BEF relationship via reducing the percentage of grassland specialists in the community. C_LI

ecology↗

Predicting human microbe-drug associations via graph attention network with multiple kernel fusion

Microbial dysregulation may lead to the occurrence of diseases, and using microbe and drug data to infer the microbe-drug association has attracted extensive attention. There have been many studies to build association prediction models, but most of them are through biological experiments, which are time-consuming and expensive. Therefore, it is necessary to develop a computational method focusing on microbe-drug spatial information to predict the microbe-drug associations. In this work, we use the biological information to construct heterogeneous networks of drugs and microbes. We propose a new method based on Multiple Kernel fusion on Graph Attention Network (GAT) to predict human microbe-drug associations, called GATMDA. Our method extracts multi-layer features based on GAT which can learn the embedding of microbes and drugs on each layer and achieve the purpose of extracting multiple information. We further fuse multiple kernel matrices based on average weighting method. Finally, combined kernel in the microbe space and drug space are used to infer microbe-drug associations. Compared with eight state-of-the-art methods, our method receives the highest AUC and AUPR on MDAD and aBiofilm dataset. Case studies for Human immunodeficiency virus 1 (HIV-1) and adenovirus further confirm the effectiveness of GATMDA in identifying potential microbe-drug associations.

bioinformatics↗

The apparent loss of PRC2 chromatin occupancy as an artefact of RNA depletion

RNA has been implicated in the recruitment of chromatin modifiers, and previous studies have provided evidence in favour and against this idea. RNase treatment of chromatin is a prevalent tool for the study of RNA-mediated regulation of chromatin modifiers, but the limitations of this approach remain unclear. RNase A treatment during chromatin immunoprecipitation (RNase-ChIP or rChIP) reduces chromatin occupancy of the H3K27me3 methyltransferase PRC2. This led to suggestions of an "RNA bridge" between PRC2 and chromatin. Here we show that RNase A treatment during chromatin immunoprecipitation leads to the apparent loss of all facultative heterochromatin, including both PRC2 and H3K27me3 genome wide. This phenomenon persists in mouse embryonic stem cells, human cancer cells and human-induced pluripotent stem cells. We track this observation to a gain of DNA from non-targeted chromatin, sequenced at the expense of DNA from facultative heterochromatin, which reduces ChIP signals. Our results point to substantial limitations in using RNase A treatment for mapping RNA-dependent chromatin occupancy and invalidate conclusions that were previously established for PRC2 based on this assay. HighlightsO_LIRNA degradation during ChIP-seq is insufficient to displace PRC2 from chromatin. C_LIO_LIRNA degradation led to the artificial depletion of ChIP-seq signals in multiple cell lines. C_LIO_LIArtificially reduced ChIP-seq signals are explained by a gain of non-targeted DNA. C_LIO_LIRNA is critical in maintaining the solubility of chromatin during experimentation. C_LI

molecular biology↗

Long-term combination therapy with Metformin and Oxymetholone in a Fanconi Anemia mouse model

Fanconi Anemia (FA) is a disease caused by defective DNA repair which manifests as bone marrow failure, cancer predisposition, and developmental defects. Mice containing inactivating mutations in one or more genes in the FA pathway partially mimic the human disease. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow (BM) hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wild-type controls with either MET alone, OXM alone, MET+OXM or placebo diet. Both male and female mice were treated from age 3 weeks to 18 months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=0.01) and hemoglobin levels (p<0.05). In addition, the percentage of quiescent HSC (LSK) was significantly increased (p=0.001) by long-term treatment with MET alone. However, the absolute number of progenitors, measured by LSK frequency or CFU-S, was not significantly altered by MET therapy. The combination of metformin and oxymetholone did not result in a significant synergistic effect on any parameter. Male animals on MET+OXM or MET alone were significantly leaner than controls at 18 months, regardless of genotype. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. Highlights- Long-term coadministration of metformin in combination oxymetholone is well tolerated by Fancd2-/- mice. - HSC quiescence in mutant mice was enhanced by treatment with metformin alone. - Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

genetics↗

Machine Learning-Driven Phenotype Predictions based on Genome Annotations

Over the past two decades, there has been a remarkable and exponential expansion in the availability of genome sequences, encompassing a vast number of isolate genomes, amounting to hundreds of thousands, and now extending to millions of metagenome-assembled genomes. The rapid and accurate interpretation of this data, along with the profiling of diverse phenotypes such as respiration type, antimicrobial resistance, or carbon utilization, is essential for a wide range of medical and research applications. Here, we leverage sequenced-based functional annotations obtained from the RAST annotation algorithm as predictors and employ six machine learning algorithms (K-Nearest Neighbors, Gaussian Naive Bayes, Support Vector Machines, Neural Networks, Logistic Regression, and Decision Trees) to generate classifiers that can accurately predict phenotypes of unclassified bacterial organisms. We apply this approach in two case studies focused on respiration types (aerobic, anaerobic, and facultative anaerobic) and Gram-stain types (Gram negative and Gram positive). We demonstrate that all six classifiers accurately classify the phenotypes of Gram stain and respiration type, and discuss the biological significance of the predicted outcomes. We also present four new applications that have been deployed in The Department of Energy Systems Biology Knowledgebase (KBase) that enable users to: (i) Upload high-quality data to train classifiers; (ii) Annotate genomes in the training set with the RAST annotation algorithm; (iii) Build six different genome classifiers; and (iv) Predict the phenotype of unclassified genomes. (https://narrative.kbase.us/#catalog/modules/kb_genomeclassification)

systems biology↗

IBAS: Interaction-bridged association studies discovering novel genes underlying complex traits

The contribution of genetic variants to a complex phenotype may be mediated by various forms of complicated interactions. Currently, the discovery of genetic variants underlying interaction is limited, partly due to that the real interaction patterns are diverse and unknown, whereas exhaustively examining all potential combinations confers the risk of overfitting and instability. We propose IBAS, Interaction-Bridged Association Study, a new model using statistical learning techniques to extract representations of interaction patterns in transcriptome data, which act as a mediator for the next genotype-phenotype association test. Using simulated perturbation experiments, it is demonstrated that IBAS is more robust to noise than similar mediation-based protocols replying on single-genes, i.e., transcriptome-wide association studies (TWAS). By applying IBAS to real genotype-phenotype and expression data, we reported additional genes underlying complex traits as well as their biological annotations. IBAS unlocks the power of integrating gene-gene interactions in association mapping without concerning overfitting and instability.

bioinformatics↗