Biology subjects

Ma, B.

Publications and source records attributed to Ma, B..

107 records · Page 6Linked to original sources

bioRxiv2021

Chitinase 3-like-1 is a Therapeutic Target That Mediates the Effects of Aging in COVID-19

COVID-19 is caused by the SARS-CoV-2 (SC2) virus and is more prevalent and severe in the elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor ACE2 and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging and that anti-CHI3L1, kasugamycin and inhibitors of phosphorylation, abrogate these ACE2- and SPP-inductive events. Human studies also demonstrated that the levels of circulating CHI3L1 are increased in the elderly and patients with CM where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP; that this induction is a major mechanism contributing to the effects of aging during SC2 infection and that CHI3L1 coopts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.

immunology↗

bioRxiv2020

Simeprevir suppresses SARS-CoV-2 replication and synergizes with remdesivir

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp). Our results thus reveal the viral protein targets of simeprevir, and provide preclinical rationale for the combination of simeprevir and remdesivir for the pharmacological management of COVID-19 patients. One Sentence SummaryDiscovery of simeprevir as a potent suppressor of SARS-CoV-2 viral replication that synergizes with remdesivir.

microbiology↗

bioRxiv2020

Binding of the SARS-CoV-2 Spike Protein to Glycans

The pandemic of SARS-CoV-2 has caused a high number of deaths in the world. To combat it, it is necessary to develop a better understanding of how the virus infects host cells. Infection normally starts with the attachment of the virus to cell-surface glycans like heparan sulfate (HS) and sialic acid-containing oligosaccharides. In this study, we examined and compared the binding of the subunits and spike (S) proteins of SARS-CoV-2 and SARS-CoV, MERS-CoV to these glycans. Our results revealed that the S proteins and subunits can bind to HS in a sulfation-dependent manner, the length of HS is not a critical factor for the binding, and no binding with sialic acid residues was detected. Overall, this work suggests that HS binding may be a general mechanism for the attachment of these coronaviruses to host cells, and supports the potential importance of HS in infection and in the development of antiviral agents against these viruses.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗

bioRxiv2020

Remdesivir potently inhibits SARS-CoV-2 in human lung cells and chimeric SARS-CoV expressing the SARS-CoV-2 RNA polymerase in mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of the novel pandemic viral disease COVID-19. With no approved therapies, this pandemic illustrates the urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug of an adenosine analog, potently inhibits SARS-CoV-2 replication in human lung cells and primary human airway epithelial cultures (EC50 = 0.01 M). Weaker activity was observed in Vero E6 cells (EC50 = 1.65 M) due to their low capacity to metabolize RDV. To rapidly evaluate in vivo efficacy, we engineered a chimeric SARS-CoV encoding the viral target of RDV, the RNA-dependent RNA polymerase, of SARS-CoV-2. In mice infected with chimeric virus, therapeutic RDV administration diminished lung viral load and improved pulmonary function as compared to vehicle treated animals. These data provide evidence that RDV is potently active against SARS-CoV-2 in vitro and in vivo, supporting its further clinical testing for treatment of COVID-19.

microbiology↗

bioRxiv2020

Assessment of whether published non-Cochrane systematic reviews of nursing follow the review protocols registered in the International Prospective Register of Systematic Reviews (PROSPERO): A comparative study

Purpose We compare published non-Cochrane reviews of nursing with their pre-registered protocols on PROSPERO to quantify the prevalence of differences and the extent to which the differences were explained.Methods We searched for protocols and their corresponding reviews in PROSPERO’s nursing group that were “completed and published” from inception to September 8th, 2019. Two authors independently identified differences and classified the difference as none, partial, or complete, and determined if the existed differences had been explained. Frequency (n), percentage (%), median, and inter-quartile ranges were used to analyze the extent of differences and explanations.Results We identified 22 pre-registered protocols and their reviews. All 22 pairs (100%) exhibited differences. Eighteen pairs (82%) showed differences in at least six methodological sections, while 21 pairs (95%) involved completed difference in at least one section. The median number of differences per review was 8.00 (upper quartile = 6.00, lower quartile = 9.75). The differences involved all 13 compared methodology-related sections. Only 5 (3%) of all differences were explained in the systematic reviews.Conclusions We observed widespread differences between non-Cochrane reviews of nursing and their protocols recorded in PROSPERO, with relatively few explanations for the changes. Measures including establishing a new item in the reporting guideline of systematic reviews to guide reporting and explaining the reasons for differences between protocols and systematic reviews or even requiring authors to do so at the Journal’s author guideline are recommended to improve transparency.View Full Text

scientific communication and education↗

bioRxiv2020

Internally quenched fluorogenic probe provides selective and rapid detection of cathepsin L activity

Cathepsin L (CTL) is a cysteine protease that demonstrates upregulated activity and/or altered trafficking during disease states such as cancer. The overlapping substrate specificity of cathepsin family members makes selective detection of activity from a single cathepsin difficult, and CTL activity is particularly difficult to parse from its close homologue CTV and the ubiquitous CTB. Despite this, screening campaigns have explored the extended chemical space in the cathepsin binding sites and identified unique substrate structures that offer selectivity for one enzyme over others. In this vein, we present CTLAP, a fluorogenic probe that is rapidly activated by CTL and displays good selectivity over CTB and CTV, the closest competing analytes for CTL activity probes. CTLAP exhibits intrinsically low background fluorescence, which we attribute to possible self-quenching mechanisms. CTLAP demonstrates markedly higher turn-on ratios (24-fold) and moderately improved enzyme selectivity compared to Z-FR-AMC (10-fold turn-on ratio), a commercially available CTL-selective probe commonly used to detect CTL activity in mixed samples. Optimum selectivity for CTL is achieved within 10 min of incubation with the enzyme, suggesting that CTLAP is amenable for rapid detection of CTL, even in the presence of competing cathepsins.

biochemistry↗

bioRxiv2019

DDIA: data dependent-independent acquisition proteomics - DDA and DIA in a single LC-MS/MS run

Data dependent acquisition (DDA) and data independent acquisition (DIA) are traditionally separate experimental paradigms in bottom-up proteomics. In this work, we developed a strategy combining the two experimental methods into a single LC-MS/MS run. We call the novel strategy, data dependent-independent acquisition proteomics, or DDIA for short. Peptides identified by conventional and robust DDA identification workflow provide useful information for interrogation of DIA scans. Deep learning based LC-MS/MS property prediction tools, developed previously can be used repeatedly to produce spectral libraries facilitating DIA scan extraction. A complete DDIA data processing pipeline, including modules for iRT vs RT calibration curve generation, DIA extraction classifier training, FDR control has been developed. A key advantage of the DDIA method is that it requires minimal information for processing its data.\n\nGRAPHIC ABSTRACT\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC=\"FIGDIR/small/802231v1_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (16K):\norg.highwire.dtl.DTLVardef@a631c6org.highwire.dtl.DTLVardef@10dc3a0org.highwire.dtl.DTLVardef@a65061org.highwire.dtl.DTLVardef@e72627_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2019

The methodological quality of animal studies: A cross-sectional study based on the SYRCLEs risk of bias tool

ObjectiveTo assess the methodological quality of animal studies published in China and abroad using the SYRCLEs risk of bias tool, and to provide references to improve the methodological quality of animal studies to encourage high quality preclinical studies.\n\nMethodsAn electronic search was performed in the Chinese Scientific Citation Database (CSCD) and Web of Science from 2014 to October 2018. Document screening and data extraction were performed independently by four researchers. The methodological quality of the included studies was assessed using the SYRCLEs risk of bias tool. Statistical analysis was performed using SPSS23.\n\nResultsA total of 2764 animal studies were included. Of the studies, 984 were published in English and 1780 were in Chinese. The citation frequency of more than 90% of the included studies was less than 5. The results of methodological quality assessment showed that 36.36% (8/22) of the sub-items were rated as \"low risk\" in more than 50% of the included studies, of which 75% (6/8) were rated as \"low risk\" in more than 80% of the included studies. A total of 59.09% (13/22) of the sub-items were rated as \"low risk\" in less than 30% of the included studies, of which 92.31% (12/13) were rated as \"low risk\" in less than 10% of the included studies. The incidence of \"low risk\" Chinese studies regarding performance bias, detection bias and reporting bias were lower than English studies. For foreign studies, more attention should be paid to selection bias, attrition bias, and reporting bias.\n\nConclusionWe identified limitations in the methodological quality of animal experiment studies published in China and abroad. We therefore suggest that it is necessary to take targeted measures to popularize the SYRCLEs risk of bias tool to effectively improve the design and implementation of animal experiments, and guide study development.

scientific communication and education↗

bioRxiv2019

VIRGO, a comprehensive non-redundant gene catalog, reveals extensive within community intraspecies diversity in the human vagina

BackgroundAnalysis of metagenomic and metatranscriptomic data is complicated and typically requires extensive computational resources. Leveraging a curated reference database of genes encoded by members of the target microbiome can make these analyses more tractable. Unfortunately, there is no such reference database available for the vaginal microbiome.\n\nResultsIn this study, we assembled a comprehensive human vaginal non-redundant gene catalog (VIRGO) from 264 vaginal metagenomes and 416 genomes of urogenital bacterial isolates. VIRGO includes 0.95 million non-redundant genes compiled from a total of 5.5 million genes belonging to 318 unique bacterial species. We show that VIRGO covers more than 95% of the vaginal bacterial gene content in metagenomes from North American, African, and Chinese women. The gene catalog was extensively functionally annotated from 17 diverse protein databases, and importantly taxonomy was assigned through in silico binning of genes derived from metagenomic assemblies. To further enable focused analyses of individual genes and proteins, we also clustered the non-redundant genes into vaginal orthologous groups (VOG). The gene-centric design of VIRGO and VOG provides an easily accessible tool to comprehensively characterize the structure and function of vaginal metagenome and metatranscriptome datasets. To highlight the utility of VIRGO, we analyzed 1,507 additional vaginal metagenomes, uncovering an as of yet undetected high degree of intraspecies diversity within and across vaginal microbiota.\n\nConclusionsVIRGO offers a convenient reference database and toolkit that will facilitate a more in-depth understanding of the role of vaginal microorganisms in womens health and reproductive outcomes.

genomics↗

bioRxiv2019

Perinatal features of Prader-Willi syndrome: a Chinese cohort

BackgroundPrader-Willi syndrome (PWS) is a rare complex genetic disorder caused by an absence of expression of imprinted genes on the paternally derived chromosome 15q11-q13 region. This study aimed to characterize the perinatal features in a cohort of Chinese individuals with PWS.\n\nMethodsWe analyzed anonymous data of 134 patients from the PWS Registry in China. Perinatal and neonatal presentations were analyzed, and compared between the two PWS genetic subtypes. We also compared the perinatal features of PWS patients with the general population and other previous reported large cohorts from France, UK and USA.\n\nResultsThis study included 134 patients with PWS (115 patients with 15q11-q13 deletion and 19 with maternal UPD). High mean maternal age was found in this cohort (30.5 vs. 26.7) comparing with the general population. 88.6% of mothers reported a decrease of fetal movements. 42.5% and 18.7% of mothers had polyhydramnios and oligohydramnios during pregnancy, respectively. 82.8% of the patients were born by caesarean section. 32.1% of neonates had birth asphyxia, 98.5% had hypotonia and 97.8% had weak cry or even no cry at neonatal period. Feeding difficulty existed in 99.3% of the infants, and 94.8% of them had failure to thrive. 69.4% of the infants ever used feeding tube during hospitalization. However, 97.8% of them discontinued tube feeding after discharged home. Maternal age, maternal pre-pregnancy weight and BMI were significantly higher in the UPD group (all P<0.05).\n\nConclusionsPWS should be highlighted for differential diagnosis for infants with following perinatal factors including polyhydramnios, intrauterine decreased fetal movements, cesarean section, low birth weight, feeding difficulty, hypotonia, and failure to thrive. Higher maternal age may be a risk factor for PWS, especially for UPD, and further studies for the mechanism of PWS are required.\n\nAuthor SummaryEarly diagnosis and tailored multidisciplinary treatment are utmost important for better quality of life of the infants with Prader-willi syndrome. Genetic diagnosis for PWS is now easily available; and diagnosis can be made in most patients within the first months of life even prenatally if obstetricians or neonatologists can recognize the perinatal features of PWS well. However, most patients still had a late diagnosis because the early signs of PWS not recognized. Our study highlighted the perinatal features of a large cohort of Chinese patients with PWS, which will benefit for early diagnosis and treatment. We found high incidence of decreased fetal movements, polyhydramnios and delivery by cesarean section, and higher maternal age comparing with the general population. Neonatal features found in our cohort included low birth weight, birth asphyxia, failure to thrive, feeding difficulty, weak cry and hypotonia. We found mothers with UPD had higher maternal age, pre-pregnancy weight and BMI. Most patients required tube feeding during hospitalization, however tube feeding was discontinued by their parents after discharge at home. Nutrition deficiency was a serious problem in infants with PWS. Home tube-feeding instruction should be carried out for parents of PWS patients in China.

genetics↗

bioRxiv2018

Polycomb Cbx2 Condensates Assemble through Phase Separation

Polycomb group (PcG) proteins are master regulators of development and differentiation. Mutation and dysregulation of PcG genes cause developmental defects and cancer. PcG proteins form condensates in the nucleus of cells and these condensates are the physical sites of PcG-targeted gene silencing. However, the physiochemical principles underlying the PcG condensate formation remain unknown. Here we show that Polycomb repressive complex 1 (PRC1) protein Cbx2, one member of the Cbx family proteins, contains a long stretch of intrinsically disordered region (IDR). Cbx2 undergoes phase separation to form condensates. Cbx2 condensates exhibit liquid-like properties and can concentrate DNA and nucleosomes. We demonstrate that the conserved residues within the IDR promote the condensate formation in vitro and in vivo. We further indicate that H3K27me3 has minimal effects on the Cbx2 condensate formation while depletion of core PRC1 subunits facilitates the condensate formation. Thus, our results reveal that PcG condensates assemble through liquid-liquid phase separation (LLPS) and suggest that PcG-bound chromatin is in part organized through phase-separated condensates.

biochemistry↗

bioRxiv2018

Genome structure and evolution of Antirrhnum majus L.

Snapdragon (Antirrhinum majus L.), a member of Plantaginaceae, is an important model for plant genetics and molecular studies on plant growth and development, transposon biology and self-incompatibility. Here we report a high-quality genome assembly of A. majus cultivated JI7 (A. majus cv.JI7) of a 510 Mb with 37,714 annotated protein-coding genes. The scaffolds covering 97.12% of the assembled genome were anchored on 8 chromosomes. Comparative and evolutionary analyses revealed that Plantaginaceae and Solanaceae diverged from their most recent ancestor around 62 million years ago (MYA). We also revealed the genetic architectures associated with complex traits such as flower asymmetry and self-incompatibility including a unique TCP duplication around 46-49 MYA and a near complete{psi} S-locus of ca.2 Mb. The genome sequence obtained in this study not only provides the first genome sequenced from Plantaginaceae but also bring the popular plant model system of Antirrhinum into a genomic age.

genomics↗

bioRxiv2018

Base pair editing of goat embryos: nonsense codon introgression into FGF5 to improve cashmere yield

The ability to alter single bases without DNA double strand breaks provides a potential solution for multiplex editing of livestock genomes for quantitative traits. Here, we report using a single base editing system, Base Editor 3 (BE3), to induce nonsense codons (C-to-T transitions) at four target sites in caprine FGF5. All five progenies produced from microinjected single-cell embryos had alleles with a targeted nonsense mutation and yielded expected phenotypes. The effectiveness of BE3 to make single base changes varied considerably based on sgRNA design. Also, the rate of mosaicism differed between animals, target sites, and tissue type. PCR amplicon and whole genome resequencing analyses for off-target changes caused by BE3 were low at a genome-wide scale. This study provides first evidence of base editing in livestock, thus presenting a potentially better method to introgress complex human disease alleles into large animal models and provide genetic improvement of complex health and production traits in a single generation.

genetics↗

bioRxiv2018

Proteomic Analysis of Rat Serum Revealed the Effects of Chronic Sleep Deprivation on Metabolic, Cardiovascular and Nervous System

Sleep is an essential and fundamental physiological process that plays crucial roles in the balance of psychological and physical health. Sleep disorder may lead to adverse health outcomes. The effects of sleep deprivation were extensively studied, but its mechanism is still not fully understood. The present study aimed to identify the alterations of serum proteins associated with chronic sleep deprivation, and to seek for potential biomarkers of sleep disorder mediated diseases. A label-free quantitative proteomics technology was used to survey the global changes of serum proteins between normal rats and chronic sleep deprivation rats. A total of 309 proteins were detected in the serum samples and among them, 117 proteins showed more than 1.8-folds abundance alterations between the two groups. Functional enrichment and network analyses of the differential proteins revealed a close relationship between chronic sleep deprivation and several biological processes including energy metabolism, cardiovascular function and nervous function. And four proteins including pyruvate kinase M1, clusterin, kininogen1 and profilin-1were identified as potential biomarkers for chronic sleep deprivation. The four candidates were validated via parallel reaction monitoring (PRM) based targeted proteomics. In addition, protein expression alteration of the four proteins was confirmed in myocardium and brain of rat model. In summary, the comprehensive proteomic study revealed the biological impacts of chronic sleep deprivation and discovered several potential biomarkers. This study provides further insight into the pathological and molecular mechanisms underlying sleep disorders at protein level.

bioinformatics↗

bioRxiv2018

Microbial Biomarkers of Intestinal Barrier Maturation in Preterm Infants

Intestinal barrier immaturity, or \"leaky gut,\" is the proximate cause of susceptibility to necrotizing enterocolitis in preterm neonates. However, the impact of intestinal microbiota development on intestinal mucosal barrier maturation has not been evaluated in this population. In this study, we investigated a longitudinally sampled cohort of 38 preterm infants monitored for intestinal permeability (IP) and fecal microbiota during the first two weeks of life. Rapid decrease in IP indicating intestinal barrier function maturation correlated with significant increase in community diversity. In particular, members of the Clostridiales and Bifidobacterium were highly transcriptionally active, and progressively increasing abundance in Clostridiales was significantly associated with decreased gut permeability. Further, neonatal factors previously identified to promote intestinal barrier maturation, including early exclusive breastmilk feeding and low antibiotic exposure, favor the early colonization of the gut microbiota by members of the Clostridiales, which altogether are associated with improved intestinal barrier function in preterm infants.

microbiology↗

bioRxiv2018

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

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

molecular biology↗

bioRxiv2017

Gut microbiota analysis in rats with methamphetamine-induced conditioned place preference

Methamphetamine abuse is a major public health crisis. Because accumulating evidence supports the hypothesis that the gut microbiota plays an important role in central nervous system (CNS) function, and research on the roles of the microbiome in CNS disorders holds conceivable promise for developing novel therapeutic avenues for treating CNS disorders, we sought to determine whether administration of methamphetamine leads to alterations in the intestinal microbiota. In this study, the gut microbiota profiles of rats with methamphetamine-induced conditioned place preference (CPP) were analysed through 16S rRNA gene sequencing. The faecal microbial diversity was slightly higher in the METH CPP group. The propionate-producing genus Phascolarctobacterium was attenuated in the METH CPP group, and the family Ruminococcaceae was elevated in the METH CPP group. Short chain fatty acid analysis revealed that the concentrations of propionate were decreased in the faecal matter of METH-administered rats. These findings provide direct evidence that administration of METH causes gut dysbiosis, enable a better understanding of the function of gut microbiota in the process of drug abuse, and provide a new paradigm for addiction treatment.

microbiology↗