Biology subjects

Yu, Y.

Publications and source records attributed to Yu, Y..

At least 541 records · Page 30Linked to original sources

bioRxiv2019

Nutritional Immunity and Antibiotic Drug Treatments Influence Microbial Composition but Fail to Eliminate Urethral Catheter Biofilms in Recurrently Catheterized Patients

Polymicrobial biofilms that form on indwelling urethral catheters used by neurogenic bladder patients are known to recur following catheter replacements. Uropathogens dominate in catheter biofilms (CBs), grow and disperse as multi-cellular aggregates. Their microbial complexity, the characteristics of host immune responses and the molecular crosstalk in this ecosystem are incompletely understood. By surveying eight patients over up to six months with meta-omics analysis methods, we shed new light on the longitudinal microbial dynamics in CBs and the microbial-host crosstalk. There was evidence of chronic innate immune responses in all patients. Pathogens dominated the microbial contents. Proteus mirabilis often out-competed other species in cases of salt encrustation of catheters. The examination of proteomes in CBs and associated urinary pellets revealed many abundant bacterial systems for transition metal ion (TMI) acquisition. TMIs are sequestered by effector proteins released by activated neutrophils and urothelial cells, such as lactotransferrin and calgranulins, which were abundant in the host proteomes. We identified positive quantitative correlations among systems responsible for siderophore biosynthesis, TMI/siderophore uptake and TMI cellular import in bacterial species, suggesting competition for TMIs to support their metabolism and growth in CBs. Enterococcus faecalis was prevalent as a cohabitant of CBs and expressed three lipoproteins with apparent TMI acquisition functions. Fastidious anaerobic bacteria such as Veillonella, Actinobaculum, and Bifidobacterium grew in CB communities that appeared to be oxygen starved. Finally, antibiotic drug treatments were shown to influence microbial composition of CBs but failed to prevent re-colonization of urethral catheters with persisting and/or drug-resistant newly emerging pathogens.

microbiology↗

bioRxiv2019

Establishing reference samples for detection of somatic mutations and germline variants with NGS technologies

We characterized two reference samples for NGS technologies: a human triple-negative breast cancer cell line and a matched normal cell line. Leveraging several whole-genome sequencing (WGS) platforms, multiple sequencing replicates, and orthogonal mutation detection bioinformatics pipelines, we minimized the potential biases from sequencing technologies, assays, and informatics. Thus, our \"truth sets\" were defined using evidence from 21 repeats of WGS runs with coverages ranging from 50X to 100X (a total of 140 billion reads). These \"truth sets\" present many relevant variants/mutations including 193 COSMIC mutations and 9,016 germline variants from the ClinVar database, nonsense mutations in BRCA1/2 and missense mutations in TP53 and FGFR1. Independent validation in three orthogonal experiments demonstrated a successful stress test of the truth set. We expect these reference materials and \"truth sets\" to facilitate assay development, qualification, validation, and proficiency testing. In addition, our methods can be extended to establish new fully characterized reference samples for the community.

bioinformatics↗

bioRxiv2019

Leveraging Endogenous ADAR for Programmable Editing on RNA

Nucleic acid editing carries enormous potential for biological research and the development of therapeutics. Current tools for DNA or RNA editing rely on introducing exogenous proteins into living organisms, which is subject to potential risks or technical barriers due to possible aberrant effector activity, delivery limits and immunogenicity. Here, we report a programmable approach that employs a short RNA to leverage endogenous ADAR (Adenosine Deaminase Acting on RNA) proteins for targeted RNA editing. We engineered an RNA that is partially complementary to the target transcript to recruit native ADAR1 or ADAR2 to change adenosine to inosine at a specific site. We designated this new method as LEAPER (Leveraging Endogenous ADAR for Programmable Editing on RNA) and the ADAR-recruiting RNA as arRNA. arRNA, either expressed from plasmid or viral vector, or synthesized as an oligonucleotide, could achieve desirable editing. LEAPER has a manageable off-target rate on the targeted transcripts and rare global off-targets. We demonstrated that LEAPER could restore p53 function by repairing a specific cancer-relevant point mutation. Moreover, LEAPER could apply to a broad spectrum of cell types including multiple human primary cells, and it restored the -L-iduronidase catalytic activity in Hurler syndrome patient-derived primary fibroblasts without evoking innate immune responses. As a single molecule system akin to RNAi, LEAPER enables precise and efficient RNA editing, offering the transformative potential for basic research and therapeutics.

genomics↗

bioRxiv2019

Epidemiology of drug-resistant tuberculosis in Chongqing, China: a retrospective observational study from 2010 to 2017

China is one of the top 30 countries with high multidrug-resistant tuberculosis (MDR-TB) and rifampin-resistant tuberculosis (RR-TB) burden. Chongqing is a southwest city of China with a large rural population. A retrospective observational study has been performed based on routine tuberculosis (TB) surveillance data in Chongqing from 2010 to 2017. The MDR/RR-TB notification rate increased from 0.03 cases per 100,000 population in 2010 to 2.09 cases per 100,000 population in 2017. The extensively drug-resistant TB (XDR-TB) notification rate has increased to 0.09 cases per 100,000 population in 2017. There was a decreasing detection gap between the number of notified MDR/RR-TB cases and the estimate number of MDR/RR-TB cases among all notified TB cases. The treatment success rate of MDR/RR-TB was 50.66% in this period. The rate of MDR/RR-TB in new TB cases was 6.23%, and this rate in previously treated TB cases was 32.7%. Despite the progress achieved, the prevalence of MDR/RR-TB was still high facing challenges including detection gaps, the regional disparity, and the high risk for MDR/RR-TB in elderly people and farmers. Sustained government financing and policy support should be guaranteed in the future.

epidemiology↗

bioRxiv2019

A Pandas complex adapted for piRNA-guided transposon silencing

The repression of transposons by the Piwi-interacting RNA (piRNA) pathway is essential to protect animal germ cells. In Drosophila ovaries, Panoramix (Panx) enforces transcriptional silencing by binding to the target-engaged Piwi-piRNA complex, although the precise mechanisms by which this occurs remain elusive. Here, we show that Panx functions together with a germline specific paralogue of a nuclear export factor, dNxf2, and its cofactor dNxt1 (p15), as a ternary complex to suppress transposon expression. Structural and functional analyses demonstrate that dNxf2 binds Panx via its UBA domain, which plays an important role in transposon silencing. Unexpectedly, dNxf2 interacts directly with dNxf1 (TAP), a general nuclear export factor. As a result, dNxf2 prevents dNxf1 from binding to the FG repeats of the nuclear pore complex, a process required for proper RNA export. Transient tethering of dNxf2 to nascent transcripts leads to their nuclear retention. Therefore, we propose that dNxf2 may function as a Pandas (Panoramix-dNxf2 dependent TAP/p15 silencing) complex, which counteracts the canonical RNA exporting machinery and restricts transposons to the nuclear peripheries. Our findings may have broader implications for understanding how RNA metabolism modulates epigenetic gene silencing and heterochromatin formation.

molecular biology↗

bioRxiv2019

Tissue-specific changes in the RNA structurome mediate salinity response in Arabidopsis

RNA structures are influenced by their physico-chemical environment. Few studies have assessed genome-wide impacts of abiotic stresses on in vivo RNA structure, however, and none have investigated tissue-specificity. We applied our Structure-seq method to assess in vivo mRNA secondary structure in Arabidopsis shoots and roots under control and salt stress conditions. Structure-seq utilizes dimethyl sulfate (DMS) for in vivo transcriptome-wide covalent modification of accessible As and Cs, i.e. those lacking base pairing and protection. Tissue type was a strong determinant of DMS reactivity, indicating tissue-specificity of RNA structuromes. Both tissues exhibited a significant inverse correlation between salt stress-induced changes in transcript reactivity and changes in transcript abundance, implicating changes in RNA structure and accessibility in transcriptome regulation. In mRNAs wherein the 5UTR, CDS and 3UTR concertedly increased or decreased in mean reactivity under salinity, this inverse correlation was more pronounced, suggesting that concordant structural changes across the mRNA have the greatest impact on abundance. Transcripts with the greatest and least salt stress-induced changes in DMS reactivity were enriched in genes encoding stress-related functions and included housekeeping functions, respectively. We conclude that secondary structure regulates mRNA abundance, thereby contributing to tissue specificity of the transcriptome and its dynamic adjustment under stress.\n\nOne Sentence Summary: Transcriptome-wide methods reveal dynamic tissue-specific and salt stress-dependent modulation of mRNA accessibility and structure, and correlated mRNA abundance changes.

plant biology↗

bioRxiv2019

An Array of 60,000 Antibodies for Proteome-Scale Antibody Generation and Target Discovery

Antibodies are essential for elucidating the roles of genes decoded by genome sequencing. However, affordable technology for proteome-scale antibody generation does not exist. To address this, we developed the Proteome Epitope Tag Antibody Library (PETAL) and its array. PETAL consists of 62,208 mAbs against 15,199 peptides from diverse proteomes. PETAL harbors binders for a great multitude of proteins in nature due to antibody multispecificity, an intrinsic feature of an antibody. Distinctive combinations of 10,000-20,000 mAbs were found to target specific proteomes by array screening. Phenotype-specific mAb-target pairs were discovered for maize and zebrafish samples. Immunofluorescence and flow cytometry mAbs for human membrane proteins and ChIP-seq mAbs for transcription factors were identified from respective proteome-binding PETAL mAbs. Differential screening of cell surface proteomes of tumor and normal tissues discovered internalizing tumor antigens for antibody-drug conjugates. By discovering high affinity mAbs at a fraction of current time and cost, PETAL enables proteome-scale antibody generation and target discovery.

systems biology↗

bioRxiv2019

Scalable and Accurate Drug-target Prediction Based on Heterogeneous Bio-linked Network Mining

MotivationDespite the existing classification- and inference-based machine learning methods that show promising results in drug-target prediction, these methods possess inevitable limitations, where: 1) results are often biased as it lacks negative samples in the classification-based methods, and 2) novel drug-target associations with new (or isolated) drugs/targets cannot be explored by inference-based methods. As big data continues to boom, there is a need to study a scalable, robust, and accurate solution that can process large heterogeneous datasets and yield valuable predictions. ResultsWe introduce a drug-target prediction method that improved our previously proposed method from the three aspects: 1) we constructed a heterogeneous network which incorporates 12 repositories and includes 7 types of biomedical entities (#20,119 entities, # 194,296 associations), 2) we enhanced the feature learning method with Node2Vec, a scalable state-of-art feature learning method, 3) we integrate the originally proposed inference-based model with a classification model, which is further fine-tuned by a negative sample selection algorithm. The proposed method shows a better result for drug-target association prediction: 95.3% AUC ROC score compared to the existing methods in the 10-fold cross-validation tests. We studied the biased learning/testing in the network-based pairwise prediction, and conclude a best training strategy. Finally, we conducted a disease specific prediction task based on 20 diseases. New drug-target associations were successfully predicted with AUC ROC in average, 97.2% (validated based on the DrugBank 5.1.0). The experiments showed the reliability of the proposed method in predicting novel drug-target associations for the disease treatment.

bioinformatics↗

bioRxiv2019

IMCC: Quantitative Analysis of the Inter-module Connectivity for Bio-network

Inter-module connectivity, which tend to connect different communities and maintain network architectural integrity, is contributing to functional coordination and information flow between modules in perturbations. Detecting the strength of inter-module connection is essential to characterize the reactive bio-systematical variation. A quantitative evaluation method for inter-module connections is needed. Here, based on the high-throughput microarray data from mouse, an evaluation approach (named as IMCC) for inter-module connectivity was developed. The IMCC model, which is an integration of direct and indirect inter-module connections, successfully excluded inter-module connections without statistical significance or below the cutoff value, and provided a more comprehensive landscape of inter-module relationships. We showed that the IMCC method reflected a more precise functional coordination between modules according to KEGG database, were validated by topological parameter. Application of IMCC in genome-scale stroke networks deciphered characteristic pathological \"core-periphery\" structure of modular map and functional coordination module pair.\n\nAuthor summeryInter-module connectivity, which tend to connect different communities and maintain network architectural integrity, is contributing to functional coordination and information flow between modules in perturbations. Moreover, modular rearrangements provide more efficient ways for phenotype alteration, inter-module connections have been considered to be evolutionary interaction switches\". Such modular map rewiring can be used as a network biomarker to characterize the dynamics of drug responses. Detecting the strength of inter-module connection is essential to characterize the reactive bio-systematical variation response to disease or drug. We aim to construct a quantitative evaluation method for inter-module connections. Thus, this study has implications in systematical exploration detailed variation of inter-module pharmacological action mode of drugs.

systems biology↗

bioRxiv2019

The antimicrobial peptide Defensin cooperates with Tumour Necrosis Factor to drive tumour cell death in Drosophila

Antimicrobial peptides (AMPs) are small cationic molecules best known as mediators of the innate defence against microbial infection. While in vitro and ex vivo evidence suggest AMPs capacity to kill cancer cells, in vivo demonstration of an anti-tumour role of endogenous AMPs is lacking. Using a Drosophila model of tumourigenesis, we demonstrate a role for the AMP Defensin in the control of tumour progression. Our results reveal that Tumour Necrosis Factor mediates exposure of phosphatidylserine (PS), which makes tumour cells selectively sensitive to the action of Defensin remotely secreted from tracheal and fat tissues. Defensin binds tumour cells in PS-enriched areas, provoking cell death and tumour regression. Altogether, our results provide the first in vivo demonstration for a role of an endogenous AMP as an anti-cancer agent, as well as a mechanism that explains tumour cell sensitivity to the action of AMPs.

cancer biology↗

bioRxiv2018

Decreased metabolism and increased tolerability to extreme environment in Staphylococcus warneri with long-term space flight

BackgroundMany studies have shown that space environment can affect bacteria to cause a range of mutations. However, so far, there are less studies on the effects of long-term space flight (>1 month) on bacteria. In this study, a Staphylococcus warneri strain, which was isolated from the Shenzhou-10 spacecraft that had experienced a space flight (15-day), was carried into space again. After 64-day flight, the combined phenotypic, genomic, transcriptomic and proteomic analyses were performed to compare the influence of the two space flights on this bacteria.\n\nResultsCompared with short-term space flight, long-term space flight increased the biofilm formation ability of S. warneri and the cell wall resistance to external environment stress, but reduced the sensitivity to chemical stimulation. Further analysis showed that these changes might be related to the significantly up-regulated gene expression of phosphotransferase system, which regulated glucose metabolism pathway, including glucose, mannose, fructose and cellobiose. The mutation of S. warneri caused by 15-day space flight was limited at phenotype and gene level after ground culture.\n\nConclusionAfter a 79-day space flight, the changes of S. warneri are meaningful. Phosphotransferase system of S. warneri was up-regulated by long-term space stimulation, which resulted in a series of changes in cell wall, biofilm and chemical sensitivity, thus enhancing the resistance and adaptability of bacteria to the external environment.\n\nImportanceTaking S. warneri as an example, we found that the mutation of bacteria in long-term space flight mainly focused on the adaptation and tolerance like environmental adaptation, physical resistance and cell repair to various pressures and these changes should be more obvious or even become stable mutations. But the clinical changes, for example drug resistance and virulence should not be significant because there is no threat of antibiotics.

microbiology↗

bioRxiv2018

LARP1 is a major phosphorylation substrate of mTORC1

The mammalian target of rapamycin complex 1 (mTORC1) controls critical cellular functions such as protein synthesis, lipid metabolism, protein turnover and ribosome biogenesis through the phosphorylation of multiple substrates. In this study, we examined the phosphorylation of a recently identified target of mTORC1: La-related protein 1 (LARP1), a member of the LARP superfamily. Previously, we and others have shown that LARP1 plays an important role in repressing TOP mRNA translation downstream of mTORC1. LARP1 binds the 7-methylguanosine triphosphate (m7Gppp) cap moiety and the adjacent 5terminal oligopyrimidine (5TOP) motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 plays a critical role in the control of TOP mRNA translation via LARP1 but the precise mechanism by which this occurs is incompletely understood. The data described herein help to elucidate this process. Specifically, it show that: (i) mTORC1 interacts with LARP1, but not other LARP superfamily members, via the C-terminal region that comprises the DM15 domain, (ii) mTORC1 pathway controls the phosphorylation of multiple (up to 26) serine and threonine residues on LARP1 in vivo, (iii) mTORC1 regulates the binding of LARP1 to TOP mRNAs and (iv) phosphorylation of S689 by mTORC1 is particularly important for the association of the DM15 domain of LARP1 with the 5UTR of RPS6 TOP mRNA. These data reveal LARP1 as a major substrate of mTORC1.

biochemistry↗

bioRxiv2018

Molecular mechanism of the Orai channel activation

The Orai channel is characterized by voltage independence, low conductance and high Ca2+ selectivity and plays an important role in Ca2+ influx through the plasma membrane. How the channel is activated and promotes Ca2+ permeation are not well understood. Here, we report the crystal structure and cryo-electron microscopy reconstruction of a Drosophila melanogaster Orai mutant (P288L) channel that is constitutively active according to electrophysiology. The open state of the Orai channel showed a hexameric assembly in which six TM1 helices in the center form the ion-conducting pore, and six TM4 helices in the periphery form extended long helices. Orai channel activation requires conformational transduction from TM4 to TM1 and eventually causes the basic section of TM1 to twist outward. The wider pore on the cytosolic side aggregates anions to increase the potential gradient across the membrane and thus facilitate Ca2+ permeation. The open-state structure of the Orai channel offers insights into channel assembly, channel activation and Ca2+ permeation.

biochemistry↗

bioRxiv2018

PTPN22 interacts with EB1 to regulate T cell receptor signaling

PTPN22 has been reported as an important negative regulator of T cell signaling. Here we identified EB1 as an associated protein of PTPN22 via 2-hybrid and mass spectrometry screening.\n\nRecently the phosphorylation of EB1 has been proved in the regulation of T cell receptor (TCR) mediated signaling pathway. Our results shown that PTPN22 interacted with EB1 through the P1 domain of PTPN22, and regulated the Y247 phosphorylation site of EB1. The subsequent results suggest that PTPN22 interacts with EB1 and regulate the phosphorylation of EB1, which results in the regulation of the expression of T cell activation markers of CD25 and CD69, and the phosphorylation levels of the T cell signaling molecules, such as ZAP-70, LAT and Erk, ultimately resulting in NFAT transcription factors entering the nucleus and regulating the secretion of cytokine IL-2. This newly identified interaction between PTPN22 and EB1 may play an important role in TCR signal pathways.

cell biology↗

bioRxiv2018

Mesoscale correlation structure with single cell resolution during visual coding

Among brain areas, axonal projections carry channels of information that can be mixed to varying degrees. Here, we assess the rules for the network consisting of the primary visual cortex and higher visual areas (V1-HVA) in mice. We use large field-of-view two-photon calcium imaging to measure correlated variability (i.e., noise correlations, NCs) among thousands of neurons, forming over a million unique pairs, distributed across multiple cortical areas simultaneously. The amplitude of NCs is proportional to functional connectivity in the network, and we find that they are robust, reproducible statistical measures, and are remarkably similar across stimuli, thus providing effective constraints to network models. We used these NCs to measure the statistics of functional connectivity among tuning classes of neurons in V1 and HVAs. Using a data-driven clustering approach, we identify approximately 60 distinct tuning classes found in V1 and HVAs. We find that NCs are higher between neurons from the same tuning class, both within and across cortical areas. Thus, in the V1-HVA network, mixing of channels is avoided. Instead, distinct channels of visual information are broadcast within and across cortical areas, at both the micron and millimeter length scales. This principle for the functional organization and correlation structure at the individual neuron level across multiple cortical areas can inform and constrain computational theories of neocortical networks.

neuroscience↗

bioRxiv2018

StPOPA, encoding an anionic peroxidase in Solanum tuberosum, enhances resistance against Phytophthora infestans

Potato late blight, caused by Phytophthora infestans, is one of the major threats affecting the quality and output of potato all over the world. Reactive oxygen species (ROS) acted as a signal molecule to transmit signals in plants at the early stage of disease infection, and it could induce disease resistance of the plant, including potato late blight. Anionic peroxidases in many plants were reported to be involved in defense to disease. However, limited information about anionic peroxidase genes is available for the potato. Here, we reported that the expression of the StPOPA, a gene encoding a suberization-associated anionic peroxidase, was associated with resistance in potato against P. infestans. The StPOPA gene was induced by P. infestans infection, mechanical damage, jasmonic acid and ethylene treatment. Overexpression of the StPOPA gene in potato enhanced the resistance against P. infestans via promoting the accumulation of callose in the cell wall and ROS in the cytoplasm, which restricted the infection and spreading of the disease possibly by purposeful programmed cell death. Taken together, our results suggested that the StPOPA gene contributed to potato immunity against P. infestans and this gene could be used for the genetic improvement of resistance against potato late blight.

pathology↗

bioRxiv2018

Gut Microbiota in male patients with chronic traumatic complete spinal cord injury

This study examined the diversity and structure of gut microbiota in healthy adults and chronic traumatic complete spinal cord injury (SCI) patients, documented neurogenic bowel management of SCI patients. The V3-V4 region of 16S rRNA gene from DNA of 91 fecal samples of 48 healthy and 43 diseased subjects was amplified and sequenced. There was difference in gut microbiota between healthy adult males and females. Neurogenic bowel dysfunction (NBD) was common in patients with chronic traumatic complete SCI, patients with quadriplegia have longer time to defecate than paraplegic patients, with higher NBD scores and heavier neurogenic bowel symptoms. Gut microbiota dysbiosis existed in SCI patients. The abundance of Veillonellaceae and Prevotellaceae increased while Bacteroidaceae and Bacteroides decreased in SCI group. The abundance of Bacteroidaceae, Bacteroides in quadriplegia group and Acidaminococcaceae, Blautia in paraplegia group were significant high than the health male group. Serum biomarkers GLU, HDL, CR and NBD symptoms defecation time, COURSE had significant correlation with microbial community structure. This study presents a comprehensive landscape of gut microbiota in adult male patients with chronic traumatic complete SCI and documents their neurogenic bowel management. The gut microbiota dysbiosis of SCI patients was correlation with serum biomarkers and NBD symptoms.\n\nIMPORTANCENeurogenic bowel dysfunction is a major physical and psychological problem in patients with spinal cord injury, which can seriously affect the quality life of them. Gut dysbiosis are highly likely to occur in spinal cord injury patients There are few studies on intestinal microecology after spinal cord injury, and the clinical studies are fewer. It is importance to document their neurogenic bowel management and present a landscape of gut microbiota in them. We found the gut microbiota dysbiosis of spinal cord injury patients was correlation with serum biomarkers and neurogenic bowel dysfunction symptoms. These results may have implications in the next study about metagenomics and precision treatment of neurogenic bowel dysfunction in spinal cord injury patients.

neuroscience↗

bioRxiv2018

Autophagy regulates hyaluronan synthase 2 levels in vascular endothelial cells

Hyaluronan is emerging as a key player regulating wound repair, inflammation, and angiogenesis. Of the three hyaluronan synthases (HAS1-3), HAS2 is the main driver of tumorigenicity by enhancing hyaluronan deposition. We discovered that HAS2 was degraded in vascular endothelial cells via autophagy, a catabolic process evoked by endorepellin and endostatin, two angiostatic and pro-autophagic effectors, and by Torin 1, a specific mTOR inhibitor. Protracted autophagy increased co-localization of HAS2 with three core components of the autophagosome, LC3, p62, and ATG9A, and binding of HAS2 to ATG9A. Importantly, autophagic induction led to an exclusive and marked suppression of secreted hyaluronan with no significant effects on either heparan or chondroitin sulfate levels. Thus, we have unveiled autophagy as a key catabolic mechanism regulating the production of hyaluronan in endothelial cells. Moreover, our study provides a biological link between autophagy and angiogenesis that could lead to potential targets for tumor neovascularization.\n\nSummaryHyaluronan is pro-angiogenic and pro-tumorigenic. We report a novel mechanism through which three autophagic inducers[-]endorepellin, endostatin, and Torin 1[-]regulate the levels of hyaluronan synthase-2. Protracted autophagy results in suppression of extracellular hyaluronan, thereby implicating autophagy in the regulation hyaluronan production.

cell biology↗