Biology subjects

Liang, H.

Publications and source records attributed to Liang, H..

At least 145 records · Page 8Linked to original sources

bioRxiv2019

A Hox code defines spinocerebellar neuron subtype regionalisation

Coordinated body movement requires the integration of many sensory inputs. This includes proprioception, the sense of relative body position and force associated with movement. Proprioceptive information is relayed to the cerebellum via spinocerebellar neurons, located in the spinal cord within a number of major neuronal columns or as various scattered cell populations. Despite the importance of proprioception to fluid movement, a molecular understanding of spinocerebellar relay interneurons is only beginning to be explored, with limited knowledge of molecular heterogeneity within and between columns. Using fluorescent reporter knock-in mice, neuronal tracing and in situ hybridisation, we identify widespread expression of Hox cluster genes, including both protein-coding genes and microRNAs, within spinocerebellar neurons. We reveal a \"Hox code\" based on axial level and individual spinocerebellar column, which, at cervico-thoracic levels, is essential for subtype regionalisation. Specifically, we show that Hoxc9 function is required in most, but not all, cells of the major thoracic spinocerebellar column, Clarkes column, revealing heterogeneity reliant on Hox signatures.

developmental biology↗

bioRxiv2019

A microfabricated, 3D-sharpened silicon shuttle for insertion of flexible electrode arrays through dura mater into brain

Electrode arrays for chronic implantation in the brain are a critical technology in both neuroscience and medicine. Recently, flexible, thin-film polymer electrode arrays have shown promise in facilitating stable, single-unit recordings spanning months in rats. While array flexibility enhances integration with neural tissue, it also requires removal of the dura mater, the tough membrane surrounding the brain, and temporary bracing to penetrate the brain parenchyma. Durotomy increases brain swelling, vascular damage, and surgical time. Insertion using a bracing shuttle results in additional vascular damage and brain compression, which increase with device diameter; while a higher-diameter shuttle will have a higher critical load and more likely penetrate dura, it will damage more brain parenchyma and vasculature. One way to penetrate the intact dura and limit tissue compression without increasing shuttle diameter is to reduce the force required for insertion by sharpening the shuttle tip. We describe a novel design and fabrication process to create silicon insertion shuttles that are sharp in three dimensions and can penetrate rat dura, for faster, easier, and less damaging implantation of polymer arrays. Sharpened profiles are obtained by reflowing patterned photoresist, then transferring its sloped profile to silicon with dry etches. We demonstrate that sharpened shuttles can reliably implant polymer probes through dura to yield high quality single unit and local field potential recordings for at least 95 days. On insertion directly through dura, tissue compression is minimal. This is the first demonstration of a rat dural-penetrating array for chronic recording. This device obviates the need for a durotomy, reducing surgical time and risk of damage to the blood-brain barrier. This is an improvement to state-of-the-art flexible polymer electrode arrays that facilitates their implantation, particularly in multi-site recording experiments. This sharpening process can also be integrated into silicon electrode array fabrication.

neuroscience↗

bioRxiv2019

The Complete Chloroplast Genome of Tetraselmis desikacharyi (Chlorodendrophyceae) and Phylogenetic Analysis

Tetraselmis desikacharyi is a marine alga, known as an important plankton for aquaculture as a feed organism. However, the genomic study on this class is rare. Here, we present a complete Chlorodendrophyceae chloroplast genome of T. desikacharyi, belonging to Chlorodendrophyceae with a full length of 149,934bp, characterized by a very small single-copy (SSC) region without any genes and a large inverted repeat (IR) region. A maximum-likelihood (ML) phylogenetic analysis was performed using three kinds of data comprising 50 protein-coding genes, which placed the Chlorodendrophyceae as a deep-diverging lineage of the core Chlorophyta.\n\nT. desikacharyi, characterized by their intense green colored chloroplast, is important for aquaculture as a feed organism, and for studying plankton growth cycles due to their fast growth rate (Arora et al., 2013; Norris et al., 1980). However, only two chloroplast genomes have been published in ...

genomics↗

bioRxiv2019

Fertility intentions and influential factors in Dalian urban city ---A cross-sectional study based on Universal Two-child policy in China

BackgroundIn October, 2015, Chinese government announced that one-child policy had finally been replaced by a universal two-child policy. However, the effects of new policy may be far less than expected. So we conducted this research to explore potential influential factors of fertility intention.\n\nMethodsThis cross-sectional study was conducted and a self-administered questionnaire was designed for collecting socio-demographic information, future fertility intention and influential factors of individual reproductive behavior. The analyses were performed using the SPSS 19.0 statistical software package.\n\nResultsA total of 1370 respondents were interviewed. Our research indicated that the mean ideal number of children was only 1.73 and urban respondents sex preference was symmetrical preference. 79.1% (884) married people had the first child already, only 7.6% (71) respondents had two children. Among 1370 participants, 30.4% respondents stated that they would have a second child; while 69.6% respondents refused to have two children in future (just wanted only a child). Binary logistic regression analysis (model 1) showed that female, older age, lower education lever, birth place was Dalian, lower family income, the ideal number of children were associated with having 1 child in the future. Model 2 (only respondents with childbearing experience) showed that female, lower family income, couldnt get additional financial support from parents were more likely refused to have two children; in additional, the ideal number of children and childbearing experience were significantly influences on future fertility intention.\n\nConclusionFertility intention and reproductive behavior still below replacement in Dalian city. Our results suggest that several factors (including socioeconomic characteristics, economic factors, desired number of child, childbearing experience) have distinctive effects on fertility intention.

epidemiology↗

bioRxiv2019

Pair-wise Comparison Analysis for Multiple Pool-sep: an efficient method identified anthocyanin biosynthesis genes in rice pericarp

The complex traits are derived from multiple genes and exhibit a large variety of phenotypes. High-throughput sequencing technologies have become the new strategies for mapping the important traits of crops. However, these methods have their own disadvantages and limitations. Here we introduced Pair-wise Comparison Analysis for Multiple Pool-seq (PCAMP) for mapping the candidate genomic regions involved in anthocyanin biosynthesis in rice pericarp. In this protocol, the second filial generation (F2) populations obtained by crossing two parents with different target traits were divided into n (n>=3) subpopulations according to their phenotypes. Thirty phenotypically identical individuals were selected from each subpopulation and DNA samples were extracted to form a pool for sequencing. Finally, we compared the SNP-index between every two Pool-seqs to map the candidate genomic regions. We applied PCAMP to analyse F2 populations and successfully identified five known genes and five new candidate genomic regions for anthocyanin biosynthesis in rice pericarp. These results demonstrate that PCAMP is an efficient new method for dissecting the complex traits of crops.

molecular biology↗

bioRxiv2019

Molecular subtyping and prognostic assessment based on tumor mutation burden in patients with lung adenocarcinomas

Tumor mutation burden (TMB) is a potential biomarker for response to immunotherapy. The subset of patients with TMB has not been well characterized in lung adenocarcinomas. Here we performed molecular subtyping based on TMB and compared the features of different subtypes including clinical features, somatic driver genes and mutational signatures. We found that patients with lower tumor mutation burden had a longer disease-free survival, while higher tumor mutation burden is associated with smoking and aging. Analysis of somatic driver genes and mutational signatures demonstrates a significant association between somatic RYR2 mutations and the subtype with higher mutation burden. Overall, our study identified two molecular subtypes based on TMB and described the corresponding difference in their clinical and genomic levels.

genomics↗

bioRxiv2019

A novel blaSIM-1-carrying megaplasmid pSIM-1-BJ01 isolated from clinical Klebsiella pneumonia

A rare carbapenem-resistant gene blaSIM-1 was found in a 316-kb megaplasmid designated pSIM-1-BJ01 isolated from a clinical strain Klebsiella pneumonia 13624. The plasmid pSIM-1-BJ01 was fully sequenced and analyzed. Its length is 316,557 bp and it has 342 putative open reading frames with two multidrug-resistant regions and a total of 19 resistant genes. Its backbone was highly homologous to the newly reported plasmid pRJA166a, which was isolated from a clinical third-generation cephalosporin-resistant hypervirulen strain K. pneumonia ST23. The plasmid pSIM-1-BJ01 was verified to be able to transfer to Escherichia coli. The emergency of the transferable blaSIM-1-carrying multidrug-resistant plasmid pSIM-1-BJ01 suggests the spread of blaSIM among Enterobacteriaceae is possible. Therefore, the data presented herein provided insights into the genomic diversity and evolution of blaSIM-carrying plasmids, as well as the dissemination and epidemiology of blaSIM among Enterobacteriaceae in public health system.

epidemiology↗

bioRxiv2019

A 3-hydroxy-3-methylglutaryl-CoA synthase-based probe for the discovery of the acyltransferase-less type I polyketide synthases

Acyltransferase (AT)-less type I polyketide synthases (PKSs) produce complex natural products due to the presence of many unique tailoring enzymes. The 3-hydroxy-3-methylglutaryl coenzyme A synthases (HCSs) are responsible for {beta}-alkylation of the growing polyketide intermediates in AT-less type I PKSs. In this study, we discovered a large group of HCSs, closely associated with the characterized and orphan AT-less type I PKSs through in silico genome mining, sequence and genome neighborhood network analysis. Using HCS-based probes, the survey of 1207 inhouse strains and 18 soil samples from different geological locations revealed the vast diversity of HCS-containing AT-less type I PKSs. The presence of HCSs in many AT-less type I PKSs suggests their co-evolutionary relationship. Our study should inspire future efforts to discover new polyketide natural products from AT-less type I PKSs.

microbiology↗

bioRxiv2018

Membrane curvature sensing of the lipid-anchored K-Ras small GTPases

Cell morphologies, defined by plasma membrane (PM) local curvature, change during mitogen-dependent function and pathology, such as growth, division and proliferation. The lipid-anchored Ras small GTPases are essential upstream regulators of the mitogen-activated protein kinases (MAPKs) cascades and play key roles in many pathological conditions, especially cancer. Ras signaling is mostly compartmentalized to the cell PM through the formation of nanometer-sized domains, termed as nanoclusters, and undergo selective lipid sorting for efficient effector recruitment and activation. Thus, Ras function might be sensitive to changing PM curvature, potentially regulating mechanosensing of mitogen signaling. We employed nanofabrication and super-resolution imaging and found that Ras functions respond to PM curvature modulations in an isoform specific manner: nanoclustering and signaling of the most oncogenically prevalent isoform K-Ras favor less curved PM, while those of another isoform H-Ras favor more curved PM. We then examined whether Ras membrane curvature sensing is mediated by lipid sorting. We found that anionic phospholipids sense changing PM curvature in distinct manners: phosphatidylserine (PS) localization shows preference for less curved membrane but phosphoinositol 4,5-bisphosphate (PIP2) localization favors more curved PM. Depletion of endogenous PS abolishes K-Ras PM curvature sensing. Exogenous PS addback and synthetic bilayer binding assays further show that only mixed-chain PS species, but not other PS species, mediate K-Ras curvature sensing. Taken together, the Ras proteolipid nano-assemblies on the PM act as relay stations to convert mechanical stimulations to mitogenic signaling circuits, thus a novel mechanism for cancer cell mechanotransduction

biochemistry↗

bioRxiv2018

Discovery of allosteric non-covalent KRAS inhibitors that bind with sub micromolar affinity and disrupt effector binding

Approximately 15% of all human tumors harbor mutant KRAS, a membrane-associated small GTPase and a notorious oncogene. Somatic mutations that render KRAS constitutively active lead to uncontrolled cell growth, survival, proliferation, and eventually cancer. KRAS is thus a critical anticancer drug target. However, despite aggressive efforts in recent years, there is no drug on the market that directly targets KRAS. In the current work, we combined molecular simulation and high-throughput virtual screening with a battery of cell-based and biophysical assays to discover a novel, pyrazolopyrimidine-based allosteric KRAS inhibitor that exhibits promising biochemical properties. The compound selectively binds to active KRAS with sub-micromolar affinity, slightly modulates exchange factor activity, disrupts effector Raf binding, significantly reduces signal transduction through mutant KRAS and inhibits cancer cell growth. Moreover, by studying two of its analogues, we identified key chemical features of the compound that are critical for affinity, effect on effector binding and mode of action. We propose a set of specific interactions with key residues at the switch regions of KRAS as critical for abrogating effector binding and reducing the rate of nucleotide exchange. Together, these findings not only demonstrate the viability of direct KRAS inhibition and offer guidance for future optimization efforts, but also show that pyrazolopyrimidine-based compounds may represent a first-in-class lead toward a clinically relevant targeting of KRAS by allosteric non-covalent inhibitors.

biochemistry↗

bioRxiv2018

Diagnostic Whole Exome Sequencing in Patients with Short Stature

Short stature is among the most common reasons for children being referred to the pediatric endocrinology clinics. The cause of short stature is broad, in which genetic factors play a substantial role, especially in primary growth disorders. However, identifying the molecular causes for short stature remains as a challenge because of the high heterogeneity of the phenotypes. Here, whole exome sequencing (WES) was used to identify the genetic causes of short stature with unknown etiology for 20 patients aged from 1 to 16 years old. The genetic causes of short stature were identified in 9 of the 20 patients, corresponding to a molecular diagnostic rate of 45%. Notably, in 2 of the 9 patients identified with genetic causes, the diagnosed diseases based on WES are different from the original clinical diagnosis. Our results highlight the clinical utility of WES in the diagnosis of rare, high heterogeneity disorders.

genetics↗

bioRxiv2018

Sequencing of the MHC region defines HLA-DQA1 as the major independent risk for anti-citrullinated protein antibodies (ACPA)-positive rheumatoid arthritis in Han population

The strong genetic contribution of the major histocompatibility complex (MHC) to rheumatoid arthritis (RA) susceptibility has been generally attributed to HLA-DRB1. However, due to the high linkage disequilibrium in the MHC region, it is difficult to define the real or/and additional independent genetic risks using the conventional HLA genotyping or chip-based microarray technology. By the capture sequencing of entire MHC region for discovery and HLA-typing for validation in 2,773 subjects of Han ancestry, we identified HLA-DQ1:160D as the strongest independent genetic risk for anti-citrullinated protein antibodies (ACPA)-positive RA in Han population (P = 6.16 x 10-36, OR=2.29). Further stepwise conditional analysis revealed that DR{beta}1:37N has an independent protective effect on ACPA-positive RA (P = 5.81 x 10-16, OR=0.49). The DQ1:160 coding allele DQA1*0303 displayed high impact on joint radiographic severity, especially in patients with early disease and smoking (P = 3.02 x 10-5). Interaction analysis by comparative molecular modeling revealed that the negative charge of DQ1:160D stabilizes the dimer of dimers, leading to an increased T cell activation. The electrostatic potential surface analysis indicated that the negative charged DR{beta}1:37N encoding alleles could bind with epitope P9 arginine, thus may result in a decreased RA susceptibility.\n\nIn this study, we provide the first evidence that HLA-DQA1, instead of HLA-DRB1, is the strongest and independent genetic risk for ACPA-positive RA in Chinese Han population. Our study also illustrates the value of MHC deep sequencing for fine mapping disease risk variants in the MHC region.

genetics↗

bioRxiv2018

Bacteria-to-human protein networks reveal origins of endogenous DNA damage

DNA damage provokes mutations and cancer, and results from external carcinogens or endogenous cellular processes. Yet, the intrinsic instigators of DNA damage are poorly understood. Here we identify proteins that promote endogenous DNA damage when overproduced: the DNA-damaging proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six DNA-damage-causing function clusters, demonstrating DDP mechanisms in three: reactive-oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their expression in tumors predicts heavy mutagenesis and poor prognosis. Half of tested human homologs, when overproduced in human cells, promote DNA damage and mutation, with DNA-damaging mechanisms like those in E. coli. Together, our work reveals DDP networks that provoke endogenous DNA damage and may indicate functions of many human known and newly implicated cancer-promoting proteins.

cancer biology↗

bioRxiv2018

Structure simulation of thrombopoietin receptor C-MPL with missense SNPs and its geographical distribution

Mpl is a key gene controlling the process of proliferation and differentiation of megakaryocyte and several studies reported that the mutation of mpl will even cause accurate megakaryocyte leukemia. By overlapping the missense mutation in NCBI and recorded SNP in 1000 genome database, we sorted out 4 SNPs(rs190983971, rs563996763, rs546510242, rs373621350) to find out its conformational changes. With Phyre v2.0, we simulated the secondary and tertiary structure change caused by the SNP and compared it with the original structure. The significant changes indicated its potential in leading to diseases associated with platelet reproduction. Finally, according to 1000 genome database, we constructed the geographically distribution of different populations and its SNPs carrying rate.

bioinformatics↗

bioRxiv2018

Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Bile acids are critical biological detergents in the gastrointestinal tract and also act as messengers to regulate a multitude of intracellular signaling events, including mitogenic signaling, lipid metabolism and endo/exocytosis. In particular, bile acids stimulate many receptors and ion channels on the cell surface, the mechanisms of which are still poorly understood. Membrane-associating proteins depend on the local spatial distribution of lipids in the plasma membrane (PM) for their function. Here, we report that the highly amphipathic secondary bile acid deoxycholic acid (DCA), a major constituent in the human bile, at doses <1M enhances the nanoclustering of phosphatidic acid (PA) but disrupts the local segregation of phosphoinositol 4,5-bisphosphate (PIP2) in the basolateral PM of the human colorectal adenocarcinoma Caco-2 cells. PA has been shown to be a key structural component of the signaling nano-domains of epidermal growth factor receptor (EGFR) on the cell surface. We show that DCA promotes the co-localization between PA and EGFR, the PA-driven EGFR dimerization/oligomerization and EGFR signaling. Depletion of PA abolishes the stimulatory effects of DCA on the EGFR oligomerization and signaling. This effect occurs in the cultured Caco-2 cells and the ex vivo human intestinal enteroids. We propose a novel mechanism, where the amphiphilic DCA monomers alter the nano-assemblies of anionic phospholipids and in turn change the dynamic structural integrity of the lipid-driven oligomerization of cell surface receptors and their signal transduction.

biophysics↗

bioRxiv2018

Combined use of procalcitonin and C-reactive protein levels can help clinically diagnose bacterial co-infections in children infected with H1N1 influenza

ObjectiveThis study evaluated the diagnostic value of measuring the levels of procalcitonin (PCT) and C-reactive protein (CRP) to differentiate children co-infected with H1N1 influenza and bacteria from children infected with H1N1 influenza alone and to provide a reliable clinical diagnostic support system with improved accuracy and precision control.\n\nMethodsConsecutive patients (children aged <5 years) with laboratory-confirmed H1N1 influenza who were hospitalized or received outpatient care from a tertiary-care hospital in Canton, China between 1 January 2012 and 1 September 2017 were included in the present study. Laboratory results, including serum PCT and CRP levels, white blood cell (WBC) counts, and blood and sputum cultures, were analyzed. The predictive value of the combination of biomarkers versus either biomarker alone for diagnosing bacterial co-infections was evaluated using logistic regression analyses.\n\nResultsOf 3180 children infected with H1N1 influenza, 226 (7.1%) met the bacterial co-infection criteria, with Staphylococcus pneumoniae being the most commonly identified bacteria (36.28%). Significantly higher PCT (1.46 vs 0.21 ng/ml, p<0.001) and CRP (19.20 vs 5.10 mg/dl, p<0.001) levels were detected in the bacterial co-infection group than in the H1N1 infection only group. Multivariate logistic regression analysis showed independent associations between PCT (odds ratio [OR]: 1.73, 95% confidence interval [CI],1.34-2.42, p<0.001) and CRP levels (OR:1.09, 95% CI, 1.06-1.13, p<0.001) with bacterial co-infections. Using PCT or CRP levels alone, the areas under the curves (AUCs) for predicting bacterial co-infections were 0.801 (95%CI, 0.772-0.855) and 0.762 (95%CI, 0.722-0.803), respectively. Using a combination of PCT and CRP, the logistic regression-based model, Logit(P)=-1.912+0.546 PCT+0.087 CRP, showed significantly greater accuracy (AUC: 0.893, 95%CI: 0.842-0.934) than did the other three biomarkers.\n\nConclusionsThe combination of PCT and CRP levels could provide a useful method of distinguishing bacterial co-infections from an H1N1 influenza infection alone in children during the early disease phase. After further validation, the flexible model derived here could assist clinicians in decision-making processes.

microbiology↗

bioRxiv2018

Immuno-genomic PanCancer Landscape Reveals Diverse Immune Escape Mechanisms and Immuno-Editing Histories

Immune reactions in the tumor micro-environment are one of the cancer hallmarks and emerging immune therapies have been proven effective in many types of cancer. To investigate cancer genome-immune interactions and the role of immuno-editing or immune escape mechanisms in cancer development, we analyzed 2,834 whole genomes and RNA-seq datasets across 31 distinct tumor types from the PanCancer Analysis of Whole Genomes (PCAWG) project with respect to key immuno-genomic aspects. We show that selective copy number changes in immune-related genes could contribute to immune escape. Furthermore, we developed an index of the immuno-editing history of each tumor sample based on the information of mutations in exonic regions and pseudogenes. Our immuno-genomic analyses of pan-cancer analyses have the potential to identify a subset of tumors with immunogenicity and diverse background or intrinsic pathways associated with their immune status and immuno-editing history.

genomics↗

bioRxiv2018

Identification of candidate genes for gelatinization temperature, gel consistency and pericarp color by GWAS in rice based on SLAF-sequencing

Rice is an important cereal in the world, uncovering the genetic basis of agronomic traits in rice landraces genes associated with agronomically important traits is indispensable for both understanding the genetic basis of phenotypic variation and efficient crop improvement. Gelatinization temperature, gel consistency and pericarp color are important indices of rice cooking and eating quality evaluation and potential nutritional importance, which attract wide attentions in the application of genetic and breeding. To dissect the genetic basis of gelatinization temperature (GT), gel consistency (GC) and pericarp color (PC), a total of 419 rice landraces core germplasm collections consisting of 330 indica lines, 78 japonica lines and 11 uncertain varieties were grown, collected, then GT, GC, PC were measured for two years, and sequenced using Specific Locus Amplified Fragment Sequencing (SLAF) technology. In this study, 261,385,070 clean reads and 56,768 polymorphic SLAF tags were obtained, which a total of 211,818 single nucleotide polymorphisms (SNPs) were discovered. With 208,993 SNPs meeting the criterion of minor allele frequency (MAF) > 0.05 and integrity> 0.5, the phylogenetic tree and population structure analysis were performed for all 419 rice landraces, and the whole panel mainly separated into six subpopulations based on population structure analysis. Genome-wide association study (GWAS) was carried out for the whole panel, indica subpanel and japonica subpanel with subset SNPs respectively. One quantitative trait locus (QTL) on chromosome 6 for GT was detected in the whole panel and indica subpanel, and one QTL associated with GC was located on chromosome 6 in the whole panel and indica subpanel. For the PC trait, 8 QTLs were detected in the whole panel on chromosome 1, 3, 4, 7, 8, 10 and 11, and 7 QTLs in the indica subpanel on chromosome 3, 4, 7, 8, 10 and 11. The loci on chromosome 3, 8, 10 and 11 have not been identified previously, and they may be the candidate genes of pericarp color. For the three traits, no QTL was detected in japonica subpanel probably because of the polymorphism repartition between the subpanel, or small population size of japonica subpanel. This paper provides new gene resources and insights into the molecular mechanisms of important agricultural trait of rice phenotypic variation and genetic improvement of rice quality variety breeding.

genomics↗