Biology subjects

Chen, Q.

Publications and source records attributed to Chen, Q..

At least 469 records · Page 26Linked to original sources

bioRxiv2018

FT/FD-GRF5 repression loop directs growth to increase soybean yield

Major advances in crop yield are eternally needed to cope with population growth. To balance vegetative and reproductive growth plays an important role in agricultural yield. To extend vegetative phase can increase crop yield, however, this strategy risks loss of yield in the field as crops may not mature in time before winter come. Here, we identified a repression feedback loop between GmFTL/GmFDL and GmGRF5-1 (Glycine-max-Flowering-Locus-T/Glycine-max-FDL and Glycine-max-GROWTH-REGULATING-FACTOR5-1), which functions as a pivotal regulator in balancing vegetative and reproductive phases in soybean. GmFTL/GmFDL and GmGRF5-1 directly repress gene expression each other. Additionally, GmGRF5-1 enhances vegetative growth by directly enhancing expression of photosynthesis- and auxin synthesis-related genes. To modulate the loop, such as fine-tuning GmFTL expression to trade-off vegetative and reproductive growth, increases substantially soybean yield in the field. Our findings not only uncover the mechanism balancing vegetative and reproductive growth, but open a new window to improve crop yield.

plant biology↗

bioRxiv2018

Combination of Dynamic Turbidimetry and Tube Agglutination to Identify Procoagulant Genes by Transposon Mutagenesis in Staphylococcus aureus

Agglutinating function is responsible for an important pathogenic pattern in S.aureus. Although the mechanism of aggregation has been widely studied since S.aureus has been found, the agglutinating detailed process remains largely unknown. Here, we screened a transposon mutant library of Newman strain using tube agglutination and dynamic turbidmetry test and identified 8 genes whose insertion mutations lead to a decrease in plasma agglomerate ability. These partial candidate genes were further confirmed by gene knockout and gene complement as well as RT-PCR techniques. these insertion mutants, including NWMN_0166, NWMN_0674, NWMN_0756, NWMN_0952, NWMN_1282, NWMN_1228, NWMN_1345 and NWMN_1319, which mapped into coagulase, clumping factor A, oxidative phosphorylation, energy metabolism, protein synthesis and regulatory system, suggesting that these genes may play an important role in aggregating ability. The newly constructed knockout strains of coa, cydA and their complemented strains were also tested aggregating ability. The result of plasma agglutination was consistent between coa knockout strain and coa mutant strain, meanwhile, cydA complement strain didnt restored its function. Further studies need to confirm these results. These findings provide novel insights into the mechanisms of aggregating ability and offer new targets for development of drugs in S.aureus.

microbiology↗

bioRxiv2018

Skepticism toward adaptive signals in DNA sequence comparisons - Is the neutral theory dead yet?

A recent study suggests that the evidence of adaptive DNA sequence evolution accumulated in the last 20 years may be suspect1. The suspicion thus calls for a re-examination of the reported evidence. The two main lines of evidence are from the McDonald-Kreitman (MK) test, which compares divergence and polymorphism data, and the PAML test, which analyzes multi-species divergence data. Here, we apply these two tests concurrently on the genomic data of Drosophila and Arabidopsis. To our surprise, the >100 genes identified by the two tests do not overlap beyond random expectations. The results could mean i) high false positives by either test or ii) high false-negatives by both tests due to low powers. To rule out the latter, we merge every 20 - 30 genes into a "supergene". At the supergene level, the power of detection is high, with 8% - 56% yielding adaptive signals. Nevertheless, the calls still do not overlap. Since it is unlikely that one test is largely correct and the other is mostly wrong (see Discussion), the total evidence of adaptive DNA sequence evolution should be deemed unreliable. As suggested by Chen et al.1, the reported evidence for positive selection may in fact be signals of fluctuating negative selection, which are handled differently by the two tests. Possible paths forward on this central evolutionary issue are discussed.

evolutionary biology↗

bioRxiv2018

Identification of a Distinct Metabolomic Subtype of Sporadic ALS Patients

Sporadic amyotrophic lateral sclerosis (sALS) is a progressive motor neuron disease resulting in paralysis and death. Genes responsible for familial ALS have been identified, however the molecular basis for sALS is unknown. To discover metabotypic biomarkers that inform on disease etiology, untargeted metabolite profiling was performed on 77 patient-derived dermal fibroblast lines and 45 age/sex-matched controls. Surprisingly, 25% of sALS lines showed upregulated methionine-derived homocysteine, channeled to cysteine and glutathione (GSH). Stable isotope tracing of [U-13C]-glucose showed activation of the trans-sulfuration pathway, associated with accelerated glucose flux into the TCA cycle, glutamate, GSH, alanine, aspartate, acylcarnitines and nucleotide phosphates. A four-molecule support vector machine model distinguished the sALS subtype from controls with 97.5% accuracy. Plasma metabolite profiling identified increased taurine as a hallmark metabolite for this sALS subset, suggesting systemic perturbation of cysteine metabolism. Furthermore, integrated multiomics (mRNAs/microRNAs/metabolites) identified the super-trans-sulfuration pathway as a top hit for the sALS subtype. We conclude that sALS can be stratified into distinct metabotypes, providing for future development of personalized therapies that offer new hope to sufferers.

neuroscience↗

bioRxiv2018

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet we know little about the specific genetic loci influencing human cortical structure. To identify genetic variants, including structural variants, impacting cortical structure, we conducted a genome-wide association meta-analysis of brain MRI data from 51,662 individuals. We analysed the surface area and average thickness of the whole cortex and 34 regions with known functional specialisations. We identified 255 nominally significant loci (P [≤] 5 x 10-8); 199 survived multiple testing correction (P [≤] 8.3 x 10-10; 187 surface area; 12 thickness). We found significant enrichment for loci influencing total surface area within regulatory elements active during prenatal cortical development, supporting the radial unit hypothesis. Loci impacting regional surface area cluster near genes in Wnt signalling pathways, known to influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinsons disease, insomnia, depression and ADHD.\n\nOne Sentence SummaryCommon genetic variation is associated with inter-individual variation in the structure of the human cortex, both globally and within specific regions, and is shared with genetic risk factors for some neuropsychiatric disorders.

genetics↗

bioRxiv2018

Population based hospitalization burden of laboratory-confirmed hand, foot and mouth disease caused by multiple enterovirus serotypes in southern China

BackgroundHand, foot and mouth disease (HFMD) is spread widely across Asia, and the hospitalization burden is as yet not well understood. Here, we estimated serotype-specific and age-specific hospitalization rates of HFMD in Southern China.\n\nMethodsWe enrolled pediatric patients admitted to 3/3 county-level hospitals and 3/23 township level hospitals in Anhua county, Hunan (CN) with HFMD, and collected samples to identify enterovirus serotypes by RT-PCRs between October 2013 and September 2016. The information of other eligible but un-enrolled patients were retrospectively collected from the same six hospitals. Monthly number of hospitalizations for all causes was collected from each of 23 township level hospitals to extrapolate hospitalizations associated with HFMD among these.\n\nResultsDuring the three years, an estimated 3,236 pediatric patients were hospitalized with lab-confirmed HFMD, and among these only one patient was severe. The mean hospitalization rates were 660 (95% CI: 638-684) per 100,000 person-years for lab-confirmed HFMD, with higher rates among CV-A16 and CV-A6 associated HFMD (213 vs 209 per 100,000 person-years), and lower among EV-A71, CV-A10 and other enteroviruses associated HFMD (134, 39 and 66 per 100,000 person-years, p<0.001). Children aged 12-23 months had the highest hospitalization rates (3,594/100,000 person-years), followed by those aged 24-35 months (1,828/100,000 person-years) and 6-11 months (1,572/100,000 person-years). Compared with other serotypes, CV-A6-associated hospitalizations were evident at younger ages.\n\nConclusionsOur study indicates a substantial hospitalization burden associated with non-severe HFMD in a rural county in southern China. Future mitigation policies should take into account the disease burden identified, and optimize interventions for HFMD.

epidemiology↗

bioRxiv2018

Perceptual inference employs intrinsic alpha frequency to resolve perceptual ambiguity

The brain uses its intrinsic dynamics to actively predict observed sensory inputs, especially under perceptual ambiguity. However, it remains unclear how this inference process is neurally implemented in biasing perception of ambiguous inputs towards the predicted percepts. Using electroencephalography and intracranial recordings, we first show that the alpha-band frequency defines a unified time window for perceptual grouping across both space and time: information segments, either spatially or temporally segregated, will be integrated if they fall within the same alpha cycle. Moreover, predictions employ this prior knowledge on intrinsic alpha frequency to shift perceptual inference towards the most possibly observed percepts. Multivariate decoding analysis showed that perceptual inference, based on variance in prestimulus alpha frequency (PAF), biases post-stimulus neural representations by inducing preactivation of the predicted percepts. fMRI results additionally showed that prestimulus activity and intrinsic organization status in the frontoparietal attentional network predict perceptual outcomes, probably by modulating occipitoparietal PAFs.

neuroscience↗

bioRxiv2018

Mother centrioles are dispensable for deuterosome formation and function during basal body amplification

Mammalian epithelial cells use a pair of mother centrioles (MCs) and numerous deuterosomes as platforms for efficient basal body assembly during multiciliogenesis. How deuterosomes form and function, however, remain controversial. They are proposed to either arise spontaneously followed by maturation into larger ones with increased procentriole-producing capacity or be assembled solely on the young MC, nucleate procentrioles under the MCs guidance, and released as procentriole-occupied \"halos\". Here we show that both MCs are dispensable for deuterosome formation in multiciliate cells. In both mouse tracheal epithelial and ependymal cells (mTECs and mEPCs), discrete deuterosomes in the cytoplasm were initially procentriole-free and then grew into halos. More importantly, eliminating the young MC or both MCs in proliferating precursor cells through shRNA-mediated depletion of Plk4, a kinase essential to procentriole assembly, did not abolish deuterosome formation when these cells were induced to differentiate into mEPCs. The average deuterosome numbers per cell only reduced by 21% as compared to control mEPCs. Therefore, MC is not essential to the assembly of both deuterosomes and deuterosome-mediated procentrioles.

cell biology↗

bioRxiv2018

BodyMap transcriptomes reveal unique circular RNA features across tissue types and developmental stages

Circular RNAs (circRNAs) are a novel class of regulatory RNAs. Here, we present a comprehensive investigation of circRNA expression profiles across 11 tissues and 4 developmental stages in rats, along with cross-species analyses in humans and mice. Although positively correlated, circRNAs exhibit higher tissue specificity than cognate mRNAs. Also, genes with higher expression levels exhibit a larger fraction of spliced circular transcripts than their linear counterparts. Intriguingly, while we observed a monotonic increase of circRNA abundance with age in the rat brain, we further discovered a dynamic, age-dependent pattern of circRNA expression in the testes that is characterized by a dramatic increase with advancing stages of sexual maturity and a decrease with aging. The age-sensitive testicular circRNAs are highly associated with spermatogenesis, independent of cognate mRNA expression. The tissue/age implications of circRNAs suggest that they present unique physiological functions rather than simply occurring as occasional by-products of gene transcription.

bioinformatics↗

bioRxiv2018

CRISPR/Cas9 gene editing for the creation of an MGAT1 deficient CHO cell line to control HIV-1 vaccine glycosylation

Over the last decade multiple broadly neutralizing monoclonal antibodies (bN-mAbs) to the HIV-1 envelope protein, gp120, have been described. Surprisingly many of these recognize epitopes consisting of both amino acid and glycan residues. Moreover, the glycans required for binding of these bN-mAbs are early intermediates in the N-linked glycosylation pathway. This type of glycosylation substantially alters the mass and net charge of HIV envelope (Env) proteins compared to molecules with the same amino acid sequence but possessing mature, complex (sialic acid containing) carbohydrates. Since cell lines suitable for biopharmaceutical production that limit N-linked glycosylation to mannose-5 (Man5) or earlier intermediates are not readily available, the production of vaccine immunogens displaying these glycan dependent epitopes has been challenging. Here we report the development of a stable suspension adapted CHO cell line that limits glycosylation to Man5 and earlier intermediates. This cell line was created using the CRISPR/Cas9 gene editing system and contains a mutation that inactivates the gene encoding Mannosyl (Alpha-1,3-)-Glycoprotein Beta-1,2-N-Acetylglucosaminyltransferase (MGAT1). Monomeric gp120s produced in the MGAT1- CHO cell line exhibit improved binding to prototypic glycan dependent bN-mAbs directed to the V1/V2 domain (e.g. PG9) and the V3 stem (e.g. PGT128 and 10-1074) while preserving the structure of the important glycan independent epitopes (e.g. VRC01). The ability of the MGAT1-CHO cell line to limit glycosylation to early intermediates in the N-linked glycosylation pathway, without impairing the doubling time or ability to grow at high cell densities, suggest that it will be a useful substrate for the biopharmaceutical production of HIV-1 vaccine immunogens.

bioengineering↗

bioRxiv2018

Corticospinal neuroplasticity and sensorimotor recovery in rats treated by infusion of neurotrophin-3 into disabled forelimb muscles started 24 h after stroke

Stroke often leads to arm disability and reduced responsiveness to stimuli on the other side of the body. Neurotrophin-3 (NT3) is made by skeletal muscle during infancy but levels drop postnatally and into adulthood. It is essential for the survival and wiring-up of sensory afferents from muscle. We have previously shown that gene therapy delivery of human NT3 into the affected triceps brachii forelimb muscle improves sensorimotor recovery after ischemic stroke in adult and elderly rats. Here, to move this therapy one step nearer to the clinic, we set out to test the hypothesis that intramuscular infusion of NT3 protein could improve sensorimotor recovery after ischemic cortical stroke in adult rats. To simulate a clinically-feasible time-to-treat, twenty-four hours later rats were randomized to receive NT3 or vehicle by infusion into triceps brachii for four weeks using implanted minipumps. NT3 increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. NT3 also reversed sensory deficits on the affected forearm. There was no evidence of forepaw sensitivity to cold stimuli after stroke or NT3 treatment. MRI confirmed that treatment did not induce neuroprotection. Functional MRI during low threshold electrical stimulation of the affected forearm showed an increase in peri-infarct BOLD signal with time in both stroke groups and indicated that neurotrophin-3 did not further increase peri-infarct BOLD signal. Rather, NT3 induced spinal neuroplasticity including sprouting of the spared corticospinal and serotonergic pathways. Neurophysiology showed that NT3 treatment increased functional connectivity between the corticospinal tracts and spinal circuits controlling muscles on the treated side. After intravenous injection, radiolabelled NT3 crossed from bloodstream into the brain and spinal cord in adult mice with or without strokes. Our results show that delayed, peripheral infusion of neurotrophin-3 can improve sensorimotor function after ischemic stroke. Phase I and II clinical trials of NT3 (for constipation and neuropathy) have shown that peripheral, high doses are safe and well tolerated, which paves the way for NT3 as a therapy for stroke.

neuroscience↗

bioRxiv2018

Identification of key genes related to dexamethasone-resistance in acute lymphoblastic leukemia

Drug resistance is the main cause of poor chemotherapy response in acute leukemia. Despite the extensive use of dexamethasone(DEX) in the treatment of acute lymphoblastic leukemia for many years, the mechanisms of dexamethasone - resistance has not been fully understood. We choose GSE94302 from GEO database aiming to identify key genes that contribute to the DEX resistance in acute lymphoblastic leukemia. Differentially expressed gene(DEGs) are selected by using GEO2R tools. A total of 837 DEGs were picked out, including 472 up-regulated and 365 down-regulated DEGs. All the DEGs were underwent gene ontology(GO) analysis and Kyoto Encyclopedia of Gene and Genome(KEGG) pathway analysis. In addition, the DEGs-encoded protein-protein interaction (PPI) was screened by using Cytoscape and Search Tool for the Retrieval of Interacting Genes(STRING). Total 20 genes were found as key genes related to DEX resistance with high degree of connectivity, including CDK1, PCNA, CCNB1, MYC, KPNA2, AURKA, NDC80, HSPA4, KIF11, UBE2C, PIK3CG, CD44, CD19, STAT1, DDX41, LYN, BCR, CD48, JAK1 and ITGB1. They could be used as biomarkers to identify the DEX-resistant acute lymphoblastic leukemia.

bioinformatics↗

bioRxiv2018

Quasi-neutral molecular evolution -- When positive and negative selection cancel out

In the absence of both positive and negative selection, DNA sequences evolve at the neutral rate, R = 1. Due to the prevalence of negative selection, R[~]1 is rarely achieved in organismal evolution. However, when R [~] 1 is observed, it does not necessarily indicate neutral evolution because positive and negative selection could be equally strong but in opposite directions - hereby referred to as quasi-neutrality. We now show that somatic-cell evolution could be the paradigm of quasi-neutral evolution for these reasons: 1) Quasi-neutrality is much more likely in small populations (size N < 50) than in large ones; 2) Stem cell population sizes in single niches of normal tissues, from which tumors likely emerges, have small Ns (usually < 50); 3) the genome-wide evolutionary rate across tissue types is close to R = 1; 4) Relative to the average of R [~] 1, many genes evolve at a much higher or lower rate, thus hinting both positive and negative selection; 5) When N < 50, selection efficacy decreases rapidly as N decreases even when the selection intensity stays constant; 6) Notably, N is smaller in the small intestine (SmI) than in the colon (CO); hence, the [~] 70 fold higher rate of phenotypic evolution (observed as cancer risk) in the latter can be explained by the greater efficacy of selection, which then leads to the fixation of more advantageous mutations and fewer deleterious ones in the CO. Under quasineutrality, positive and negative selection can be measured in the same system as the two forces are simultaneously present or absent.

evolutionary biology↗

bioRxiv2018

New interfaces on MiD51 for Drp1 recruitment and regulation

Mitochondrial fission is facilitated by dynamin-related protein Drp1 and a variety of its receptors. However, the molecular mechanism of how Drp1 is recruited to the mitochondrial surface by receptors MiD49 and MiD51 remains elusive. Here, we showed that the interaction between Drp1 and MiD51 is regulated by GTP binding and depends on the polymerization of Drp1. We identified two regions on MiD51 that directly bind to Drp1, and found that dimerization of MiD51 via an intermolecular disulfide bond between C452 residues is required for MiD51 to directly interact with Drp1. Our Results have suggested a multi-faceted regulatory mechanism for the interaction between Drp1 and MiD51 that illustrates the potentially complicated and tight regulation of mitochondrial fission.

biophysics↗

bioRxiv2018

Prefrontal co-expression of schizophrenia risk genes is associated with treatment response in patients

Gene co-expression networks are relevant to functional and clinical translation of schizophrenia (SCZ) risk genes. We hypothesized that SCZ risk genes may converge into coexpression pathways which may be associated with gene regulation mechanisms and with response to treatment in patients with SCZ. We identified gene co-expression networks in two prefrontal cortex post-mortem RNA sequencing datasets (total N=688) and replicated them in four more datasets (total N=227). We identified and replicated (all p-values<.001) a single module enriched for SCZ risk loci (13 risk genes in 10 loci). In silico screening of potential regulators of the SCZ risk module via bioinformatic analyses identified two transcription factors and three miRNAs associated with the risk module. To translate post-mortem information into clinical phenotypes, we identified polymorphisms predicting co-expression and combined them to obtain an index approximating module co-expression (Polygenic Co-expression Index: PCI). The PCI-co-expression association was successfully replicated in two independent brain transcriptome datasets (total N=131; all p-values<.05). Finally, we tested the association between the PCI and short-term treatment response in two independent samples of patients with SCZ treated with olanzapine (total N=167). The PCI was associated with treatment response in the positive symptom domain in both clinical cohorts (all p-values<.05).\n\nIn summary, our findings in a large sample of human post-mortem prefrontal cortex show that coexpression of a set of genes enriched for schizophrenia risk genes is relevant to treatment response. This co-expression pathway may be co-regulated by transcription factors and miRNA associated with it.

neuroscience↗

bioRxiv2018

Genetic Dissection of Haploid Male Fertility in Maize (Zea mays L.)

Haploid genome doubling is a key limiting step of haploid breeding in maize. Spontaneous restoration of haploid male fertility (HMF) provides a method by which costs can be saved and which does not require the use of toxic chemicals, in contrast to the artificial doubling process. To reveal the genetic basis of HMF, haploids were obtained from the offspring of 285 F2:3 families, derived from the cross Zheng58x K22. The F2:3 families were used as female donor and YHI-1 as the male inducer line. The rates of HMF from each family line were evaluated at two field sites over two planting seasons. Quantitative trait loci (QTL) for HMF were identified using a genetic linkage map containing 157 simple sequence repeat (SSR) markers. QTL for HMF displayed incomplete dominance. Transgressive segregation of haploids from F2:3 families was observed relative to haploids derived from the two parents of the mapping population. A total of nine QTL were detected, which were distributed on chromosomes 1, 3, 4, 7, and 8. Three QTL, qHMF3b, qHMF7a, and qHMF7b were detected in both locations, respectively. In our mapping population, HMF was controlled by three major QTL. These QTL could be useful to predict the ability of spontaneous haploid genome doubling in related breeding materials, and to accelerate the haploid breeding process by introgression or aggregation of those QTL.

genetics↗

bioRxiv2018

Fission yeast cytokinesis requires a putative mechanosensitive channel Pkd2p

Force plays a central role in separating daughter cells during cytokinesis, the last stage of cell division. However, the mechanism of force-sensing during cytokinesis remains unknown. Here we discovered that Pkd2p, a putative force-sensing TRP channel, localizes to the cleavage furrow during cytokinesis of the fission yeast, Schizosaccharomyces pombe. Pkd2p, whose human homologues are associated with Autosomal Polycystic Kidney Disease, is an essential protein whose localization depends on the contractile ring and the secretory pathway. We identified and characterized a novel pkd2 mutant pkd2-81KD. The pkd2 mutant cells show signs of osmotic stress, including temporary shrinking, paused turnover of the cytoskeletal structures and hyper-activated MAPK signaling. During cytokinesis, although the contractile ring constricts more rapidly in the pkd2 mutant than the wild-type cells (50% higher), the cell separation in the mutant is slower and often incomplete. These cytokinesis defects are also consistent with mis-regulated turgor pressure. Lastly, the pkd2 mutant exhibits strong genetic interactions with two mutants of the SIN pathway, a signaling cascade essential for cytokinesis. We propose that Pkd2p modulates osmotic homeostasis and is potentially a novel regulator of cytokinesis.\n\nHighlight summary for TOCFission yeast TRP channel Pkd2p is the homologue of human polycystins. The pkd2 mutant exhibits defects in the contractile ring closure and cell separation during cytokinesis. This essential protein localizes to the cleavage furrow where it likely regulates osmotic homeostasis during cytokinesis.

cell biology↗

bioRxiv2018

Super-resolution tracking of mitochondrial dynamics with a third-row transition metal complex dye

Combining luminescent transition metal complex (LTMC) with super-resolution microscopy is an excellent strategy for the long-term visualization of the dynamics of subcellular structures in living cells. However, it remains unclear whether iridium(III) complexes are applicable for a particular type of super-resolution technique, structured illumination microscopy (SIM), to image subcellular structures.\n\nAs described herein, we developed an iridium(III) dye, to track mitochondrial dynamics in living cells under SIM. The dye demonstrated excellent specificity and photostability and satisfactory cell permeability. While using SIM to image mitochondria, we achieved an approximately 80-nm resolution that allowed the clear observation of the structure of mitochondrial cristae. We used the dye to monitor and quantify mitochondrial dynamics relative to lysosomes, including fusion involved in mitophagy, and newly discovered mitochondria-lysosome contact (MLC) under different conditions. MLC remained intact and fusion vanished when five receptors, p62, NDP52, OPTN, NBR1, and TAX1BP1, were knocked out, suggesting that these two processes are independence.

biophysics↗