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Zhang, S.

Publications and source records attributed to Zhang, S..

At least 1,099 records · Page 61Linked to original sources
bioRxiv2020

A synergistic action of sirtuins directly recognizes DNA breaks and potentiates DNA damage response and repair

The DNA damage response (DDR) is a highly orchestrated process but how double-strand DNA breaks (DSBs) are initially recognized is unclear. Here, we show that polymerized SIRT6 deacetylase recognizes DSBs and potentiates the DDR. First, SIRT1 deacetylates SIRT6 at residue K33, which is important for SIRT6 polymerization and mobilization toward DSBs. Then, K33-deacetylated SIRT6 anchors to {gamma}H2AX, allowing its retention on and subsequent remodeling of local chromatin. We show that a K33R mutation that mimics hypoacetylated SIRT6 can rescue defective DNA repair as a result of SIRT1 deficiency in cultured cells. These data highlight the synergistic action between SIRTs in the spatiotemporal regulation of the DDR and DNA repair.

biochemistry↗
bioRxiv2020

Gut lymph purification regulates monocyte activity in rats with ischemia-reperfusion injury-induced sepsis

ObjectiveTo confirm that gut lymph purification (GLP) based on oXiris regulates monocyte activity by targeting the removal of ischemia-reperfusion injury (IRI)-induced intestinal toxic substances (ITSs) in rats. MethodsSepsis was induced by intestinal IRI in 24 adult male Sprague-Dawley rats that were randomly divided into the control, intestinal IRI, and IRI+GLP groups. The gut lymph fluid (GLF) was drained for 180 minutes. The ITSs levels and the proliferation, apoptosis and positive expression rates of MHC-II molecules of monocytes coincubated with the GLF were detected. ResultsEndotoxin, TNF-, IL-4, IL-6 and IL-10 levels in the lymph and plasma of the IRI group were significantly higher than those of the control group (p < 0.01). Compared with the IRI group, GLP treatment significantly decreased the ITS levels (p < 0.05). Monocyte proliferation and the positive expression rate of MHC-{square} molecules were significantly reduced after co-culturing with GLF upon IRI (p < 0.01), and the apoptotic rate was significantly increased (p < 0.01). However, culturing monocytes with GLP significantly enhanced the monocyte proliferation, increased the positive expression rate of MHC-{square} monocytes (p < 0.01), and reduced the apoptotic rate (p < 0.01). ConclusionsGLP therapy based on oXiris effectively removed ITSs from the GLF after IRI, thereby blocking the main process of multiple organ dysfunction syndrome by regulating monocyte activity.

molecular biology↗
bioRxiv2020

BRAWNIN: A sORF-encoded Peptide Essential for Vertebrate Mitochondrial Complex III Assembly

The emergence of small open reading frame (sORF)-encoded peptides (SEPs) is rapidly expanding the known proteome at the lower end of the size distribution1,2. Here, we show that the mitochondria proteome is enriched for proteins smaller than 100 a.a. (defined as SEPs). Using a mitochondrial prediction and validation pipeline for small open-reading-frame (sORF)-encoded peptides (SEPs), we report the discovery of 16 endogenous mitochondrial SEPs (mito-SEPs) associated with oxidative phosphorylation (OXPHOS). Through functional prediction, proteomics, metabolomics and metabolic flux modeling, we demonstrate that BRAWNIN (BR), a 71 amino acid peptide encoded by the C12orf73 gene, is essential for respiratory chain complex III (CIII) assembly. In human cells, BR is induced by the energy-sensing AMPK pathway, and its depletion impairs mitochondrial ATP production. In vivo, BR is enriched in muscle tissues and its maternal zygotic deletion in zebrafish causes complete CIII loss, resulting in severe growth retardation, lactic acidosis and early death. Our findings demonstrate that BR is essential for oxidative phosphorylation across vertebrate species. We propose that mito-SEPs are an untapped resource for essential regulators of oxidative metabolism.

cell biology↗
bioRxiv2020

Analysis of metagenome-assembled genomes from the mouse gut microbiota reveals distinctive strain-level characteristics

The laboratorial mouse harbors a unique gut microbiota with potential value for human microbiota-associated studies. Mouse gut microbiota has been explored at the genus and species levels, but features rarely been showed at the strain level. The identification of 833,051 and 658,438 nonredundant genes of faeces and gut content samples from the laboratorial C57/BL mice showed over half of these genes were newly found compared to the previous mouse gut microbial gene catalogue. Metagenome-assembled genomes (MAGs) was used to reconstruct 46 nonredundant MAGs belonging to uncultured specieses. These MAGs included members across all phyla in mouse gut (i.e. Firmicutes, Bacteroidetes, Proteobacteria, Deferribacteres, Verrucomicrobia, and Tenericutes) and allowed a strain-level delineating of the mouse gut microbiota. Comparison of MAGs with human gut colonies revealed distinctive genomic and functional characteristics of mouses Bacteroidetes and Firmicutes strains. Genomic characteristics of rare phyla in mouse gut microbiota were demonstrated by MAG approach, including strains of Mucispirillum schaedleri, Parasutterella excrementihominis, Helicobacter typhlonius, and Akkermansia muciniphila. ImportanceThe identification of nonredundant genes suggested the existence of unknown microbes in the mouse gut samples. The metagenome-assembled genomes (MAGs) instantiated the specificity of mouse gut species and revealed an intestinal microbial correlation between mouse and human. The cultivation of faeces and gut contents sample validated the existence of MAGs and estimate their accuracy. Full-length 16S ribosomal RNA gene sequencing enabled taxonomic characterization. This study highlighted a unique ecosystem in the gut of laboratorial mice that obviously differed with the human gut flora at the strain level. The outcomes may be beneficial to researches based on laboratorial mouse models.

microbiology↗
bioRxiv2020

Removing mains power artefacts from EEG - a novel template-based method

EEG signals are often contaminated with artefacts, particularly with mains power from electrical equipment. Low-pass filtering and notch filtering can lose valuable data. Here we describe a novel mains power noise removal method based on the fact that mains power noise is a sine wave component with an essentially fixed frequency and the same phase across all channels. This removes the blink component, leaving uncontaminated EEG largely unchanged. Blink removal had a success rate of >99.9% recovered variance of the original EEG when removing synthesised mains power components. We compared this method with two other popular mains power noise removal methods. Our method was better than Cleanline which is an ICA based method and multiple PLI which is an adaptive notch filter based method. With the higher recovery, our method shows clear advantages over Cleanline and multiple PLI for removing mains power noise. From the aspect of data loss, it is obviously better than low-pass filter and normal notch filter.

bioengineering↗
bioRxiv2020

Extracellular ATP released from Candida albicans activates non-peptidergic neurons to augment host defense

Intestinal microbes release ATP to modulate local immune responses. Herein we demonstrates that Candida albicans, an opportunistic commensal fungus, also modulates immune responses via secretion of ATP. We found that ATP secretion from C. albicans varied between standard laboratory strains. A survey of eighty-nine clinical isolates revealed heterogeneity in ATP secretion, independent of growth kinetics and intracellular ATP levels. Isolates from blood released less ATP than commensals, suggesting that ATP secretion assists with commensalism. To confirm this, cohorts of mice were infected with strains matched for origin, and intracellular ATP concentration, but high or low extracellular ATP. In all cases fungal burden was inversely correlated with ATP secretion. Mice lacking P2RX7, the key ATP receptor expressed by immune cells in the skin, showed no alteration in fungal burden. Rather, treatments with a P2RX2/3 antagonist result in increased fungal burden. P2RX2/3 is expressed by non-peptidergic neurons that terminate in the epidermis. Cultured sensory neurons flux Ca2+ when exposed to supernatant from heat-killed C. albicans (HKCA), and these non-peptidergic fibers are the dominant subset that respond to HKCA. Ca2+ flux, but not CGRP-release, can be abrogated by pretreatment of HKCA supernatant with apyrase. To determine whether non-peptidergic neurons participate in host defense, we generated MRGPRD-DTR mice. Infection in these mice resulted in increased CFU only for those C. albicans strains with high ATP secretion. Taken together, our findings indicate that C. albicans releases ATP, which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses. Author SummaryBacterial release of ATP has been shown to modulate immune responses. Candida albicans displays heterogeneity in ATP release among laboratory strains and commensal clinical isolates release more ATP than invasive isolates. C. albicans strains with high ATP secretion show lower fungal burden following epicutaneous infection. Mice lacking P2RX7, the key ATP receptor expressed by immune cells, showed no alteration in fungal burden. In contrast, treatment with P2RX2/3 antagonists resulted in increased fungal burden. P2RX3 is expressed by a subset of non-peptidergic neurons that terminate in the epidermis. These non-peptidergic fibers are the predominant responders when cultured sensory neurons are exposed to heat-killed C. albicans in vitro. Mice lacking non-peptidergic neurons have increased infection when exposed to high but not low ATP-secreting isolates of C. albicans. Taken together, our findings indicate that C. albicans releases ATP which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses. Bullet pointsO_LIATP released from heat killed C. albicans activates non-peptidergic sensory neurons C_LIO_LILive C. albicans clinical isolates release variable amounts of ATP C_LIO_LIElevated levels of ATP released by C. albicans correlates with reduced infectivity in vivo C_LIO_LIMRGPRD-expressing cutaneous neurons are required for defense against ATP-secreting C. albicans C_LI

immunology↗
bioRxiv2020

d-PBWT: dynamic positional Burrows-Wheeler transform

Durbins PBWT, a scalable data structure for haplotype matching, has been successfully applied to identical by descent (IBD) segment identification and genotype imputation. Once the PBWT of a haplotype panel is constructed, it supports efficient retrieval of all shared long segments among all individuals (long matches) and efficient query between an external haplotype and the panel. However, the standard PBWT is an array-based static data structure and does not support dynamic updates of the panel. Here, we generalize the static PBWT to a dynamic data structure, d-PBWT, where the reverse prefix sorting at each position is represented by linked lists. We developed efficient algorithms for insertion and deletion of individual haplotypes. In addition, we verified that d-PBWT can support all algorithms of PBWT. In doing so, we systematically investigated variations of set maximal match and long match query algorithms: while they all have average case time complexity independent of database size, they have different worst case complexities, linear time complexity with the size of the genome, and dependency on additional data structures.

bioinformatics↗
bioRxiv2020

Genomic analyses provide insights into peach local adaptation and responses to climate change

The environment has constantly shaped plant genomes, but the genetic bases underlying how plants adapt to environmental influences remain largely unknown. We constructed a high-density genomic variation map by re-sequencing genomes of 263 geographically representative peach landraces and wild relatives. A combination of whole-genome selection scans and genome-wide environmental association studies (GWEAS) was performed to reveal the genomic bases of peach local adaptation to diverse climates comprehensively. A total of 2,092 selective sweeps that underlie local adaptation to both mild and extreme climates were identified, including 339 sweeps conferring genomic pattern of adaptation to high altitudes. Using GWEAS, a total of 3,496 genomic loci strongly associated with 51 specific environmental variables were detected. The molecular mechanism underlying adaptive evolution of high drought, strong UV-B, cold hardiness, sugar content, flesh color, and bloom date were revealed. Finally, based on 30 years of observation, a candidate gene associated with bloom date advance, representing peach responses to global warming, was identified. Collectively, our study provides insights into molecular bases of how environments have shaped peach genomes by natural selection and adds valuable genome resources and candidate genes for future studies on evolutionary genetics, adaptation to climate changes, and future breeding.

genomics↗
bioRxiv2019

Personalized genealogical history inferred from biobank-scale IBD segments

When modern biobanks collect genotype information for a significant fraction of a population, dense genetic connections of a person can be traced using identity by descent (IBD) segments. These connections offer opportunities to characterize individuals in the context of the underlying populations. Here, we conducted an individual-centric analysis of IBDs among the UK Biobank participants that represent 0.7% of the UK population. On average, one UK individual shares IBDs over 5 cM with 14,000 UK Biobank participants, which we refer to as "cousins". Using these segments, approximately 80% of a persons genome can be reconstructed. Also, using changes of cousin counts sharing IBDs at different lengths, we identified a group, potentially British Jews, who has a distinct pattern of familial expansion history. Finally, using the enrichment of cousins in ones neighborhood, we identified regional variations of personal preference favoring living closer to ones extended families. In summary, our analysis revealed genetic makeup, personal genealogical history, and social behaviors at population scale, opening possibilities for further studies of individuals genetic connections in biobank data.

genetics↗
bioRxiv2019

Dorsal Premotor Cortex Involved in Hand Gesture Preparation in Macaques

Reaching to grasp movement is thought to rely upon two independent brain pathways. The dorsomedial one is involved in reaching while the dorsolateral one is dealing with grasping. However, some recent evidences suggested that the dorsomedial pathway might participate in grasp movement. Therefore, it is important to investigate whether PMd is involved in grasp planning, and if participating, what kind of role PMd played in grasp planning. In this study, two macaques monkeys were trained to grasp same object by instructing or freely choosing one of two grips, power grip or hook grip. A 96-channel microelectrode array was implanted to collect the population activity of PMd in each subject. Both single unit activity and population activity were analyzed. We found that nearly 21.0% and 26.8% units in PMd of two monkeys displayed grip selectivity during gesture planning in both instructing or freely choosing conditions. These units exhibit selectivity for different gestures when facing the identical visual stimuli (freely choosing condition). At the same time, similar activity patterns are displayed for the same gesture when faced with different selection strategies (freely choosing condition vs. instructing condition). These results show that some neurons of PMd are mainly involved in the hand shape preparation and have no obvious relationship with external visual stimuli and selection strategies.

animal behavior and cognition↗
bioRxiv2019

Genome-wide analysis of chalcone synthase (CHS) family from eggplant (Solanum melongena L.) in flavonoid biosynthetic pathway and expression pattern in response to heat stress

Enzymes of chalcone synthase (CHS) family participate in the synthesis of a series of secondary metabolites in plants, fungi and bacteria. CHS showed significant correlation to the accumulation patterns of anthocyanin. The peel color mainly determined by the content of anthocyanin, is a majority economic trait for eggplant affected by heat stress. A total of 7 CHS(SmCHS1-7) putative genes were identified in genome-wide of eggplant (S. melongena L.). The SmCHS genes distribute on 7 scaffolds and were classified into 3 clusters. Phylogenetic relationships analysis showed that 73 CHS genes from 7 Solanaceae species were classified into 10 groups. SmCHS5, SmCHS6 and SmCHS7 were continuously down-regulated under 38{degrees}C and 45{degrees}C treatment, while SmCHS4 was up-regulated under 38{degrees}C but little change at 45{degrees}C in peel. Expression profiles of anthocyanin biosynthesis key genes families showed that the PAL, 4CL and AN11 genes were mainly expressed in all five tissues. CHI, F3H, F35H, DFR, 3GT and bHLH1 genes were expressed in flower and peel. Under heat stress, 52 key genes expression level were reduced under heat stress. By contrast, expression patterns of eight key genes similar to SmCHS4 up-regulated at the 38{degrees}C-3h. Comparative analysis of putative CHS protein biochemical characteristics, cis-regulatory elements, regulatory network revealed that SmCHS genes family have conservation gene structure and functional diversification. SmCHS showed two or more expression patterns and execute multiple functions to regulate anthocyanin content. Combined with regulatory networks, it is possible to further understand the regulation mechanism of peel color in eggplant.

genomics↗
bioRxiv2019

An optimized acetylcholine sensor for monitoring in vivo cholinergic activity

The ability to directly measure acetylcholine (ACh) release is an essential first step towards understanding its physiological function. Here we optimized the GRABACh (GPCR-Activation-Based-ACh) sensor with significantly improved sensitivity and minimal downstream coupling. Using this sensor, we measured in-vivo cholinergic activity in both Drosophila and mice, revealing compartmental ACh signals in fly olfactory center and single-trial ACh dynamics in multiple regions of the mice brain under a variety of different behaviors

neuroscience↗
bioRxiv2019

Big data reveals deep associations in physical examination indicators and can help predict overall underlying health status

Because of lacking of the systematic investigation of correlations between the physical examination indicators (PEIs), currently most of them are independently used for disease warning. This results in very limited diagnostic values of general physical examination. Here, we first systematically analyzed the correlations between 221 PEIs in healthy and in 34 unhealthy states in 803,614 peoples in China. We revealed rich relevant between PEIs in healthy physical status (7,662 significant correlations, 31.5% of all). However, in disease conditions, the PEI correlations changed. We further focused on the difference of these PEIs between healthy and 35 unhealthy physical status, 1,239 significant PEI difference were discovered suggesting as candidate disease markers. Finally, we established machine learning algorithms to predict the health status by using 15%-16% PEIs by feature extraction, which reached 66%-99% precision predictions depending on the physical state. This new encyclopedia of PEI correlation provides rich information to chronic disease diagnosis. Our developed machine learning algorithms will have fundamental impact in practice of general physical examination.

pathology↗
bioRxiv2019

Wnt Regulation: Exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex

Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis, and is altered in human cancer. Signaling is turned on and off by regulating stability of the effector {beta}-catenin. The multiprotein destruction complex binds and phosphorylates {beta}-catenin, and transfers it to the SCF-TrCP E3-ubiquitin ligase, for ubiquitination and destruction. Wnt signals act though Dishevelled to turn down the destruction complex, stabilizing {beta}-catenin. Recent work clarified underlying mechanisms, but important questions remain. We explore {beta}-catenin transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin. We find that Slimb/TrCP is a dynamic component of the destruction complex biomolecular condensate, while other E3 proteins are not. Recruitment requires Axin and not APC, and Axins RGS domain plays an important role. We find that elevating Dishevelled levels in Drosophila embryos has paradoxical effects, promoting the ability of limiting levels of Axin to turn off Wnt signaling. When we elevate Dishevelled levels, it forms its own cytoplasmic puncta, but these do not recruit Axin. SIM imaging in mammalian cells suggests that this may result by promoting Dishevelled: Dishevelled interactions at the expense of Dishevelled:Axin interactions when Dishevelled levels are high.

cell biology↗
bioRxiv2019

Abnormal nitration and S-sulfhydration of Sp1-CSE-H2S pathway contribute to the progress of HHcy

Sp1 (Specificity protein 1)-CSE (cystathionine-{gamma}-lyase)-H2S (hydrogen sulfide) pathway plays an important role in homocysteine-metabolism, whose disorder can result in hyperhomocysteinemia. The deficiency of plasma H2S in patients and animal models with hyperhomocysteinemia has been reported but it is unclear whether this deficiency plays a role in the progress of hyperhomocysteinemia. Furthermore, it remains unknown whether the post-translational modification of Sp1 or CSE mediated by hyperhomocysteinemia itself can in turn affect the development of hyperhomocysteinemia. By both in vivo and in vitro studies, we conducted immunoprecipitation and maleimide assays to detect the post-translational modification of Sp1-CSE-H2S pathway and revealed four major findings: (1) the accumulation of homocysteine augmented the nitration of CSE, thus blunted its bio-activity and caused H2S deficiency. (2) H2S deficiency lowered the S-sulfhydration of Sp1 and inhibited its transcriptional activity, resulted in lower expression of CSE. CSE deficiency decreased the H2S level further, which in turn lowered the S-sulfhydration level of CSE. (3) CSE was S-sulfhydrated at Cys84, Cys109, Cys172, Cys229, Cys252, Cys307 and Cys310 under physiological conditions, mutation of Cys84, Cys109, Cys229, Cys252 and Cys307 decreased its S-sulfhydration level and bio-activity. (4) H2S deficiency could trap hyperhomocysteinemia into a progressive vicious circle and trigger a rapid increase of homocysteine, while blocking nitration or restoring S-sulfhydration could break this circle. In conclusion, this study reveals a novel mechanism involved in the disorder of homocysteine-metabolism, which may provide a candidate therapeutic strategy for hyperhomocysteinemia.

pathology↗
bioRxiv2019

Transposon-mediated telomere destabilization: a driver of genome evolution in the blast fungus

Magnaporthe oryzae is a filamentous ascomycete fungus that causes devastating diseases of crops that include rice and wheat, and a variety of turf, forage and wild grasses. Strains from ryegrasses possess highly stable chromosome ends that undergo frequent rearrangements during vegetative growth in culture and in planta. Instability is associated with the presence of two related retrotransposons (Magnaporthe oryzae Telomeric Retrotransposons - MoTeRs) inserted within the telomere repeat tracts. The objective of the present study was to determine the mechanisms by which MoTeRs promote telomere instability. Targeted cloning, restriction mapping, and sequencing of both parental and novel telomeric restriction fragments, along with MinION sequencing of DNA from three single-spore cultures, allowed us to document the molecular alterations for 109 newly-formed telomeres. Rearrangement events included truncations of subterminal rDNA sequences; acquisition of MoTeR insertions by "plain" telomeres; insertion of the MAGGY retrotransposons into MoTeR arrays; expansion and contraction of subtelomeric tandem repeats; MoTeR truncations; duplication and terminalization of internal sequences; and breakage at long, interstitial telomeres generated during MoTeR insertion. Together, our data show that when MoTeRs invade the telomeres, they can dramatically perturb the integrity of chromosome ends, leading to the generation of unprotected DNA termini whose repair has the potential to generate chromosome alterations that extend well into the genome interior.

genomics↗
bioRxiv2019

The Genome of the Charophyte Alga Penium margaritaceum Bears Footprints of the Evolutionary Origins of Land Plants

The colonization of land by plants was a pivotal event in the history of the biosphere, and yet the underlying evolutionary features and innovations of the first land plant ancestors are not well understood. Here we present the genome sequence of the unicellular alga Penium margaritaceum, a member of the Zygnematophyceae, the sister lineage to land plants. The P. margaritaceum genome has a high proportion of repeat sequences, which are associated with massive segmental gene duplications, likely facilitating neofunctionalization. Compared with earlier diverging plant lineages, P. margaritaceum has uniquely expanded repertoires of gene families, signaling networks and adaptive responses, supporting its phylogenetic placement and highlighting the evolutionary trajectory towards terrestrialization. These encompass a broad range of physiological processes and cellular structures, such as large families of extracellular polymer biosynthetic and modifying enzymes involved in cell wall assembly and remodeling. Transcriptome profiling of cells exposed to conditions that are common in terrestrial habitats, namely high light and desiccation, further elucidated key adaptations to the semi-aquatic ecosystems that are home to the Zygnematophyceae. Such habitats, in which a simpler body plan would be advantageous, likely provided the evolutionary crucible in which selective pressures shaped the transition to land. Earlier diverging charophyte lineages that are characterized by more complex land plant-like anatomies have either remained exclusively aquatic, or developed alternative life styles that allow periods of desiccation.

plant biology↗