Biology subjects

Wu, H.

Publications and source records attributed to Wu, H..

At least 541 records · Page 30Linked to original sources

bioRxiv2018

Trans-ethnic genome-wide association study provides insight into effector genes and molecular mechanisms for kidney function and highlights a causal effect on kidney-specific disease aetiologies

Chronic kidney disease (CKD) affects [~]10% of the global population, with considerable ethnic differences in prevalence and aetiology. We assembled genome-wide association studies (GWAS)1-3 of estimated glomerular filtration rate (eGFR), a measure of kidney function that defines CKD, in 312,468 individuals from four ancestry groups. We identified 93 loci (20 novel), which were delineated to 127 distinct association signals. These signals were homogenous across ancestries, and were enriched for protein-coding exons, kidney-specific histone modifications, and transcription factor binding sites for HDAC2 and EZH2. Fine-mapping revealed 40 high-confidence variants driving eGFR associations and highlighted potential causal genes with cell-type specific expression in glomerulus, and proximal and distal nephron. Mendelian randomisation (MR) supported causal effects of eGFR on overall and cause-specific CKD, kidney stone formation, diastolic blood pressure (DBP) and hypertension. These results define novel molecular mechanisms and effector genes for eGFR, offering insight into clinical outcomes and routes to CKD treatment development.

genetics↗

bioRxiv2018

Dissecting differential signals in high-throughput data from complex tissues

Samples from clinical practices are often mixtures of different cell types. The high-throughput data obtained from these samples are thus mixed signals. The cell mixture brings complications to data analysis, and will lead to biased results if not properly accounted for. We develop a method to model the high-throughput data from mixed, heterogeneous samples, and to detect differential signals. Our method allows flexible statistical inference for detecting a variety of cell-type specific changes. Extensive simulation studies and analyses of two real datasets demonstrate the favorable performance of our proposed method compared with existing ones serving similar purpose.

bioinformatics↗

bioRxiv2018

Lactate dehydrogenases amplify reactive oxygen species in cancer cells in response to oxidative stimuli

Previous studies have revealed that lactate dehydrogenase A (LDHA) exhibited an indirect antioxidative activity, which played a crucial role in preventing cancer cells from oxidative stress. Here we demonstrated that, apart from antioxidative activities, LDHA and LDHB displayed prooxidative activity in cancer cells. In aqueous phase, LDHA and B both exhibited ROS-generating activity and LDHB was more active than LDHA. In cancer cells, the dominant antioxidative activity of LDH can be switched to dominant prooxidative activity or vice versa, depending on the strength of oxidative stimuli, indicating that LDH were bifunctional. Moreover, we demonstrated that mitochondrial superoxide served as an initiator to trigger LDH-catalyzed amplification of ROS. The oxidative stimuli, such as modulators of electron transfer chain and anticancer agents that kill cancer cells via ROS induction, induced a ROS generation involving 2 phases, induction of mitochondrial superoxide and amplification of ROS by LDH.

cancer biology↗

bioRxiv2018

Identifying Lineage-specific Targets of Darwinian Selection by a Bayesian Analysis of Genomic Polymorphisms and Divergence from Multiple Species

We present a method that jointly analyzes the polymorphism and divergence sites in genomic sequences of multiple species to identify the genes under positive or negative selection and pinpoints the occurrence time of selection to a specific lineage of the species phylogeny. This method integrates population genetics models using the Bayesian Poisson random field framework and combines information over all gene loci to boost the power to detect selection. The method provides posterior distributions of the fitness effects of each gene along with parameters associated with the evolutionary history, including the species divergence times and effective population sizes of external species. A simulation is performed, and the results demonstrate that our method provides accurate estimates of these population genetic parameters.\n\nThe proposed method is applied to genomic sequences of humans, chimpanzees, gorillas and orangutans, and a spatial and temporal map is constructed of the natural selection that occurred during the evolutionary history of the four Hominidae species. In addition to FOXP2 and other known genes, we identify a new list of lineage-specific targets of Darwinian selection. The positively selected genes in the human lineage are enriched in pathways of gene expression regulation, immune system, metabolism etc. Interestingly, some pathways, such as gene expression, are significantly enriched with positively selected genes, whereas other pathways, such as metabolism, are enriched with both positively and negatively selected genes. Our analysis provides insights into Darwinian evolution in the coding regions of humans and great apes and thus serves as a basis for further molecular and functional studies.

genomics↗

bioRxiv2018

Identification of pyroptosis inhibitors that target a reactive cysteine in gasdermin D

Inflammasomes are multi-protein signalling scaffolds that assemble in response to invasive pathogens and sterile danger signals to activate inflammatory caspases (1/4/5/11), which trigger inflammatory death (pyroptosis) and processing and release of pro-inflammatory cytokines1,2. Inflammasome activation contributes to many human diseases, including inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimers disease, and sepsis, the often fatal response to systemic infection3-6. The recent identification of the pore-forming protein gasdermin D (GSDMD) as the final pyroptosis executioner downstream of inflammasome activation presents an attractive drug target for these diseases7-11. Here we show that disulfiram, a drug used to treat alcohol addiction12, and Bay 11-7082, a previously identified NF-{kappa}B inhibitor13, potently inhibit GSDMD pore formation in liposomes and inflammasome-mediated pyroptosis and IL-1{beta} secretion in human and mouse cells. Moreover, disulfiram, administered at a clinically well-tolerated dose, inhibits LPS-induced septic death and IL-1{beta} secretion in mice. Both compounds covalently modify a conserved Cys (Cys191 in human and Cys192 in mouse GSDMD) that is critical for pore formation8,14. Inflammatory caspases employ Cys active sites, and many previously identified inhibitors of inflammatory mediators, including those against NLRP3 and NF-{kappa}B, covalently modify reactive cysteine residues15. Since NLRP3 and noncanonical inflammasome activation are amplified by cellular oxidative stress16-22, these redox-sensitive reactive cysteine residues may regulate inflammation endogenously, and compounds that covalently modify reactive cysteines may inhibit inflammation by acting at multiple steps. Indeed, both disulfiram and Bay 11-7082 also directly inhibit inflammatory caspases and pleiotropically suppress multiple processes in inflammation triggered by both canonical and noncanonical inflammasomes, including priming, puncta formation and caspase activation. Hence, cysteine-reactive compounds, despite their lack of specificity, may be attractive agents for reducing inflammation.

immunology↗

bioRxiv2018

A Novel AuNPs-based Glucose Oxidase Mimic with Enhanced Activity and Selectivity Constructed by Molecular Imprinting and O2-Containing Nanoemulsion Embedding

In spite of the competitive advantages, inorganic nanoparticle mimic enzymes exhibit inherent disadvantages of limited catalytic efficiency and lacking selectivity. Here a AuNPs based mimic enzyme with significantly enhanced glucose selectivity and catalytic activity was constructed and demonstrated for the first time. Aminophenylboronic acid was employed to increase the affinity to glucose, as well as build molecular imprinted polymer shells to realize the selectivity for template molecules of glucose. Besides that, heptadecafluoro-n-octyl bromide nanoemulsion with the function of providing oxygen was introduced to gain a further improvement in catalytic activity, which successfully enhanced the catalytic efficiency (kcat/Km) up to about 270-fold. Based on the demonstrated catalytic properties, AuNPs based glucose oxidase mimics have been successfully applied in practical glucose detection of drinks and blood glucose.

biochemistry↗

bioRxiv2018

Variation and diversification of the microbiome of Schlechtendalia chinensis on two alternate host plants

Schlechtendalia chinensis, a gall-inducing aphid, has two host plants in its life cycle. Its wintering host is a moss (typically Plagiomnium maximoviczii) and its main host is Rhus chinensis (Sumac), on which it forms galls during the summer.. This study investigated bacteria associated with S. chinensis living on the two different host plants by sequencing 16S rRNAs. A total of 183 Operational Taxonomic Units (OTUs) from 50 genera were identified from aphids living on moss, whereas 182 OTUs from 49 genera were found from aphids living in Sumac galls. The most abundant bacterial genus among identified OTUs from aphids feeding on both hosts was Buchnera. Despite similar numbers of OTUs, the composition of bacterial taxa showed significant differences between aphids living on moss and those living on R. chinensis. Specifically, there were 12 OTUs from 5 genera (family) unique to aphids living on moss, and 11 OTUs from 4 genera (family) unique to aphids feeding in galls on R. Chinensis. Principal Coordinate Analysis (PCoA) also revealed that bacteria from moss-residing aphids clustered differently from aphids collected from galls. Our results provid a foundation for future analyses on the roles of symbiotic bacteria in plant - aphid interactions in general, and how gall-specific symbionts differ in this respect.

microbiology↗

bioRxiv2018

Next-Generation Sequencing Could be a Promising Diagnostic Approach for Pathogen Detection: Pathogenic Analysis of Pediatric Bacterial Meningitis by Next-Generation Sequencing Technology Directly from Cerebrospinal Fluid Specimens

BackgroundBacterial meningitis remains one of the major challenges in infectious diseases, leading to sequel in many cases. A prompt diagnosis of the causative microorganism is critical to significantly improve outcome of bacterial meningitis. Although various targeted tests for cerebrospinal fluid (CSF) samples are available, it is a big problem for the identification of etiology of bacterial meningitis.\n\nMethodsHere we describe the use of unbiased sequence analyses by next-generation sequencing (NGS) technology for the identification of infectious microorganisms from CSF samples of pediatric bacterial meningitis patients in the Department of Infectious Diseases from Beijing Childrens Hospital.\n\nResultsIn total, we had 99 bacterial meningitis patients in our study, 55 (55.6%) of these were etiologically confirmed by clinical microbiology methods. Combined with NGS, 68 cases (68.7%) were etiologically confirmed. The main pathogens identified in this study were Streptococcus pneumoniae (n=29), group B streptococcus (n=15), Staphylococcus aureus (n=7), Escherichia coli (n=7). In addition, two cases with cytomegalovirus infection and one with Taenia saginata asiatica were confirmed by NGS.\n\nConclusionsNGS could be a promising alternative diagnostic approach for critically ill patients suffering from bacterial meningitis in pediatric population.\n\nSummaryWe conducted the study for the identification of microorganisms by next-generation sequencing directly from CSF samples of pediatric bacterial meningitis patients. And the study showed that NGS could be a promising alternative diagnostic approach for bacterial meningitis in pediatric population.

microbiology↗

bioRxiv2018

MLL1 minimal catalytic complex is a dynamic conformational ensemble susceptible to pharmacological allosteric disruption

Histone H3K4 methylation is an epigenetic mark associated with actively transcribed genes. This modification is catalyzed by the mixed lineage leukaemia (MLL) family of histone methyltransferases including MLL1, MLL2, MLL3, MLL4, SET1A and SET1B. Catalytic activity of MLL proteins is dependent on interactions with additional conserved proteins but the structural basis for subunit assembly and the mechanism of regulation is not well understood. We used a hybrid methods approach to study the assembly and biochemical function of the minimally active MLL1 complex (MLL1, WDR5 and RbBP5). A combination of small angle X-ray scattering (SAXS), cross-linking mass spectrometry (XL-MS), NMR spectroscopy, and computational modeling were used to generate a dynamic ensemble model in which subunits are assembled via multiple weak interaction sites. We identified a new interaction site between the MLL1 SET domain and the WD40 repeat domain of RbBP5, and demonstrate the susceptibility of the catalytic function of the complex to disruption of individual interaction sites.

biophysics↗

bioRxiv2018

Tuning site-specific dynamics to drive allosteric activation in a pneumococcal zinc uptake regulator

MarR (multiple antibiotic resistance repressor) family proteins are bacterial repressors that regulate transcription in response to a wide range of chemical signals. Although specific features of MarR family function have been described, the role of atomic motions in MarRs remains unexplored thus limiting insights into the evolution of allostery in this ubiquitous family of repressors. Here, we provide the first experimental evidence that internal dynamics play a crucial functional role in MarR proteins. Streptococcus pneumoniae AdcR (adhesin-competence repressor) regulates ZnII homeostasis and ZnII functions as an allosteric activator of DNA binding. ZnII coordination triggers a transition from independent domains to a more compact structure. We identify residues that impact allosteric activation on the basis of ZnII-induced perturbations of atomic motions over a wide range of timescales. These findings reconcile the distinct allosteric mechanisms proposed for other MarRs and highlight the importance of conformational dynamics in biological regulation.

biochemistry↗

bioRxiv2018

Trypanosomes have divergent kinesin-2 proteins that function differentially in IFT, cell division, and motility

Trypanosoma brucei, the causative agent of African sleeping sickness, has a flagellum that is crucial for motility, pathogenicity, and viability. In most eukaryotes, the intraflagellar transport (IFT) machinery drives flagellum biogenesis, and anterograde IFT requires kinesin-2 motor proteins. In this study, we investigated the function of the two T. brucei kinesin-2 proteins, TbKin2a and TbKin2b, in bloodstream form trypanosomes. We found that compared to other kinesin-2 proteins, TbKin2a and TbKin2b show greater variation in neck, stalk, and tail domain sequences. Both kinesins contributed additively to flagellar lengthening. Surprisingly, silencing TbKin2a inhibited cell proliferation, cytokinesis and motility, whereas silencing TbKin2b did not. TbKin2a was localized on the flagellum and colocalized with IFT components near the basal body, consistent with it performing a role in IFT. TbKin2a was also detected on the flagellar attachment zone, a specialized structure in trypanosome cells that connects the flagellum to the cell body. Our results indicate that kinesin-2 proteins in trypanosomes play conserved roles in IFT and exhibit a specialized localization, emphasizing the evolutionary flexibility of motor protein function in an organism with a large complement of kinesins.

cell biology↗

bioRxiv2018

Genetic control of transition from juvenile to mature wood with respect to microfibril angle (MFA) in Norway spruce (Picea abies) and lodgepole pine (Pinus contorta)

Genetic control of microfibril angle (MFA) transition from juvenile to mature was evaluated in Norway spruce and lodgepole pine. Increment cores were collected at breast height from 5,618 trees in two 21-year-old Norway spruce progeny trials in southern Sweden, and from 823 trees in two 34-35 - year-old lodgepole pine progeny trials in northern Sweden. Radial variations in MFA from pith to bark were measured for each core using SilviScan. To estimate MFA transition from juvenile to mature, a threshold level of MFA 20{degrees} was considered and six different regression functions were fitted to the MFA profile of each tree after exclusion of outliers, following three steps. The narrow-sense heritability estimates (h2) obtained for MFA transition were highest based on the slope function, ranging from 0.21 to 0.23 for Norway spruce and from 0.34 to 0.53 for lodgepole pine, while h2 were mostly non-significant based on the logistic function, under all exclusion methods. Results of this study indicate that it is possible to select for an earlier MFA transition from juvenile to mature in Norway spruce and lodgepole pine selective breeding programs, as the genetic gains ({triangleup}G) obtained in direct selection of this trait were very high in both species.

genomics↗

bioRxiv2018

Association mapping identified novel candidate loci affecting wood formation in Norway spruce

[tpltrtarr] Norway spruce (Picea abies) is an important boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics controlling important wood quality traits in the species.\n[tpltrtarr]We performed a functional genome-wide association mapping of 17 wood traits in Norway spruce using 178101 single-nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood traits were defined using functional modelling of wood properties across annual growth rings.\n[tpltrtarr]Association mapping was performed using a multilocus LASSO penalized regression method and we detected a total of 51 significant SNPs from 39 candidate genes that are involved in wood formation.\n[tpltrtarr]Our study represents the first functional multi-locus genome-wide association mapping (AM) in Norway spruce. The results advance our understanding of the genetics influencing wood traits, identify novel candidate genes for further functional studies and support current Norway spruce breeding efforts.

genetics↗

bioRxiv2018

All-optical electrophysiology reveals brain-state dependent changes in hippocampal subthreshold dynamics and excitability

A technology to record membrane potential from multiple neurons, simultaneously, in behaving animals will have a transformative impact on neuroscience research1. Parallel recordings could reveal the subthreshold potentials and intercellular correlations that underlie network behavior2. Paired stimulation and recording can further reveal the input-output properties of individual cells or networks in the context of different brain states3. Genetically encoded voltage indicators are a promising tool for these purposes, but were so far limited to single-cell recordings with marginal signal to noise ratio (SNR) in vivo4-6. We developed improved near infrared voltage indicators, high speed microscopes and targeted gene expression schemes which enabled recordings of supra- and subthreshold voltage dynamics from multiple neurons simultaneously in mouse hippocampus, in vivo. The reporters revealed sub-cellular details of back-propagating action potentials, correlations in sub-threshold voltage between multiple cells, and changes in dynamics associated with transitions from resting to locomotion. In combination with optogenetic stimulation, the reporters revealed brain state-dependent changes in neuronal excitability, reflecting the interplay of excitatory and inhibitory synaptic inputs. These tools open the possibility for detailed explorations of network dynamics in the context of behavior.

neuroscience↗

bioRxiv2018

Loss of SDHB reprograms energy metabolisms and inhibits high fat diet induced metabolic syndromes

Mitochondrial respiratory complex II utilizes succinate, key substrate of the Krebs cycle, for oxidative phosphorylation, which is essential for glucose metabolism. Mutations of complex II cause cancers and mitochondrial diseases, raising a critical question of the (patho-)physiological functions. To address the fundamental role of complex II in systemic energy metabolism, we specifically knockout SDHB in mice liver, a key complex II subunit that tethers the catalytic SDHA subunit and transfers the electrons to ubiquinone, and found that SHDB deficiency abolishes the assembly of complex II without affecting other respiration complexes while largely retaining SDHA stability. SHDB ablation reprograms energy metabolism and hyperactivates the glycolysis, Krebs cycle and {beta}-oxidation pathways, leading to catastrophic energy deficit and early death. Strikingly, sucrose supplementation or high fat diet resumes both glucose and lipid metabolism and prevent early death. Also, SDHB deficient mice are completely resistant to high fat diet induced obesity. Our findings reveal that the unanticipated role of complex II orchestrating both lipid and glucose metabolisms, and suggest that SDHB is an ideal therapeutic target for combating obesity.

molecular biology↗

bioRxiv2018

Local Delivery of Stromal Cell-Derived Factor-1α Improves the Pregnancy Rate of Injured Uterus through the Promotion of Endometrial and Vascular Regeneration

Severe infection and mechanical injury of the uterus may lead to infertility and miscarriage. Currently, there is a lack of effective treatment modality for functional repair of uterine injury. To address this clinical challenge, this study aimed to develop a chemotactic composite scaffold by incorporating recombinant human stromal cell-derived factor-1 (rhSDF-1) into a silk fibroin-bacterial cellulose (SF-BC) membrane carrier. A rat model of uterine injury was utilized for this study, which was composed of three groups: blank control, implantation with SF-BC only or SF-BC loaded with rhSDF-1. The tissue regeneration efficacy of the three groups were analyzed and compared. The results showed that SF-BC loaded with rhSDF-1 significantly enhanced endometrial regeneration and arteriogenesis of the injured rat uterus, which led to improved pregnancy outcomes, thus indicating much promise for functional uterine repair and regeneration.

bioengineering↗

bioRxiv2017

Transcriptome dynamics describe and predict state transition from health to leukemia

Temporal dynamics of gene expression are informative of changes associated with disease development and evolution. Given the complexity of high-dimensional temporal datasets, an analytical framework guided by a robust theory is needed to interpret time-sequential changes and to predict system dynamics. Herein, we use acute myeloid leukemia as a proof-of-principle to model gene expression dynamics in a transcriptome state-space constructed based on time-sequential RNA-sequencing data. We describe the construction of a state-transition model to identify state-transition critical points which accurately predicts leukemia development. We show an analytical approach based on state-transition critical points identified step-wise transcriptomic perturbations driving leukemia progression. Furthermore, the gene(s) trajectory and geometry of the transcriptome state-space provides biologically-relevant gene expression signals that are not synchronized in time, and allows quantification of gene(s) contribution to leukemia development. Therefore, our state-transition model can synthesize information, identify critical points to guide interpretation of transcriptome trajectories and predict disease development.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC=\"FIGDIR/small/238923v2_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (55K):\norg.highwire.dtl.DTLVardef@12eeaccorg.highwire.dtl.DTLVardef@1392af9org.highwire.dtl.DTLVardef@34786dorg.highwire.dtl.DTLVardef@ce78bb_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefThe theory of state-transition is applied to acute myeloid leukemia (AML) to model transcriptome dynamics and trajectories in a state-space, and is used to identify critical points corresponding to critical transcriptomic perturbations that predict leukemia development.\n\nHighlightsO_LILeukemia transcriptome dynamics are modeled as movement in transcriptome state-space\nC_LIO_LIState-transition model and critical points accurately predicts leukemia development\nC_LIO_LICritical point-based approach identifies step-wise transcriptome events in leukemia\nC_LIO_LIState-based geometric analysis provides quantification of leukemogenic contribution\nC_LI

cancer biology↗

bioRxiv2017

SemEHR: A General-purpose Semantic Search System to Surface Semantic Data from Clinical Notes for Tailored Care, Trial Recruitment and Clinical Research

ObjectiveUnlocking the data contained within both structured and unstructured components of Electronic Health Records (EHRs) has the potential to provide a step change in data available forsecondary research use, generation of actionable medical insights, hospital management and trial recruitment. To achieve this, we implemented SemEHR - a semantic search and analytics, open source tool for EHRs.\n\nMethodsSemEHR implements a generic information extraction (IE) and retrieval infrastructure by identifying contextualised mentions of a wide range of biomedical concepts within EHRs. Natural Language Processing (NLP) annotations are further assembled at patient level and extended with EHR-specific knowledge to generate a timeline for each patient. The semantic data is serviced via ontology-based search and analytics interfaces.\n\nResultsSemEHR has been deployed to a number of UK hospitals including the Clinical Record Interactive Search (CRIS), an anonymised replica of the EHR of the UK South London and Maudsley (SLaM) NHS Foundation Trust, one of Europes largest providers of mental health services. In two CRIS-based studies, SemEHR achieved 93% (Hepatitis C case) and 99% (HIV case) F-Measure results in identifying true positive patients. At Kings College Hospital in London, as part of the CogStack programme (github.com/cogstack), SemEHR is being used to recruit patients into the UK Dept of Health 100k Genome Project (genomicsengland.co.uk). The validation study suggests that the tool can validate previously recruited cases and is very fast in searching phenotypes - time for recruitment criteria checking reduced from days to minutes. Validated on an open intensive care EHR data - MIMICIII, the vital signs extracted by SemEHR can achieve around 97% accuracy.\n\nConclusionResults from the multiple case studies demonstrate SemEHRs efficiency - weeks or months of work can be done within hours or minutes in some cases. SemEHR provides a more comprehensive view of a patient, bringing in more and unexpected insight compared to study-oriented bespoke information extraction systems.\n\nSemEHR is open source available at https://github.com/CogStack/SemEHR.

bioinformatics↗