Objective To screen miRNA profiles of malignantly transformed human bronchial epithelial cells, 16HBE-T, induced by anti-benzo[a]pyrene-trans-7,8-diol-9,10-epoxide （anti-BPDE）, and to analyze putative miR-10a target...Objective To screen miRNA profiles of malignantly transformed human bronchial epithelial cells, 16HBE-T, induced by anti-benzo[a]pyrene-trans-7,8-diol-9,10-epoxide （anti-BPDE）, and to analyze putative miR-10a targets in 16HBE-T. Methods A novel microarray platform was employed to screen miRNA profiles of 16HBE-T cells transformed by anti-BPDE. Microarray data for miR-10a and miR-320 were validated using quantitative real time polymerase chain reaction （QRT-PCR）. The expression of a putative target for miR-10a, HOXA1, was analyzed by reverse transcription polymerase chain reaction （RT-PCR） and QRT-PCR. Results In comparison with the vehicle-treated cells （16HBE-N）, 16HBE-T exhibited differential expression of 54 miRNAs, in which, 45 were over-expressed and 9 were down-regulated. The five most highly expressed miRNAs were miR-494, miR-320, miR-498, miR-129, and miR-106a. The lowest expressed miRNAs were miR-10a, miR-493-5p, and miR-363＊. Three members of miR-17-92 cluster, miR-17-5p, miR-20a, and miR-92, showed significantly higher abundance in 16BHE-T as miR-21, miR-141, miR-27a, miR-27b, miR-16 and miRNAs of the let-7 family. The putative target for miR-10a, HOXA1 mRNA was up-regulated 3-9-fold in 16HBE-T, as compared with 16HBE-N. Conclusion The findings of the study provide information on differentially expressed miRNA in malignant 16HBE-T, and also suggest a potential role of these miRNAs in cell transformation induced by anti-BPDE. HOXA1 is similarly up-regulated, suggesting that miR-10a is associated with the process of HOXA 1-mediated transformation.展开更多
AIM： To detect whether there is Helicobacter pylori （Hpylori） colonization in the pharynx mucous membrane of healthy people and whether chronic pharyngitis is related to Hpylori infection. METHODS： Fifty cases of ...AIM： To detect whether there is Helicobacter pylori （Hpylori） colonization in the pharynx mucous membrane of healthy people and whether chronic pharyngitis is related to Hpylori infection. METHODS： Fifty cases of chronic pharyngitis refractory over three months were prospectively studied from March 2004 to August 2004 in the otolaryngology outpatient department of the Second Hospital of Xi＇an Jiaotong University. Template-directed dye-terminator incorporated with fluorescence polarization detection （TDI-FP） and modified Giemsa stain were used to examine pharynx mucous membrane tissue for H pylori colonization in the patients with chronic pharyngitis and the healthy people as a control group. RESULTS： In the control group, no people were detected to have Hpylori in the pharynx. In contrast, in 50 cases with chronic pharyngitis, 19 （38.0%） cases were H pylori positive with a TDI-FP assay and 4 （8%） cases were TDI-FP positive with Giemsa staining in the pharynx. Sixteen of the 50 pharyngitis cases had stomach ailment history, 11 cases （68.8%） of these 16 patients were determined to be H pylori positive in the pharynx with the TDI-FP assay. 2,2 test showed that this infection rate was remarkably higher （P= 0.0007） than that in the cases without stomach ailment history. Giemsa staining showed that 3 cases （18.8%） of the patients with stomach ailment history were infected with H pylori in the pharynx, which was remarkably higher （P = 0.042） than that in the patients without stomach ailment history （1 case, which was 2.9%）. CONCLUSION： H pylori may not be detected in the pharynx of healthy people. Chronic pharyngitis may be related to H pylori infection. The infection rate with Hpylori in the pharynx is higher in patients with stomach ailment histories than in patients without stomach ailment histories, suggesting that chronic pharyngitis may be related to stomach ailment history.展开更多
Previously we established Zygote Electroporation of Nucleases（ZEN） technology as an efficient and high-throughput way to generate genetically modified mouse models.However,there were significant variations of the ta...Previously we established Zygote Electroporation of Nucleases（ZEN） technology as an efficient and high-throughput way to generate genetically modified mouse models.However,there were significant variations of the targeting efficiency among different genomic loci using our previously published protocol.In this study,we improved the ZEN technology by delivering Cas9 protein into mouse zygotes through a series of electroporation.Using this approach,we were able to introduce precise nucleotide substitutions,large segment deletion and short segment insertion into targeted loci with high efficiency.展开更多
Objective To map a mouse deafness gene, identify the underlying mutation and develop a mouse model for human deafness. Methods Genetic linkage cross and genome scan were used to map a novel mutation named hypoplasia...Objective To map a mouse deafness gene, identify the underlying mutation and develop a mouse model for human deafness. Methods Genetic linkage cross and genome scan were used to map a novel mutation named hypoplasia of the membranous labyrinth (hml), which causes hearing loss in mutant mice. Results ① hml was mapped on mouse Chr 10 (～43 cM from the centromere) suggests that the homologous human gene is on 12q22-q24, which was defined on the basis of known mouse-human homologies (OMIM, 2004). ② This study has generated 25 polymorphic microsatellite markers, placed 3 known human genes in the correct order in a high-resolution mouse map and narrowed the hml candidate gene region to a 500 kb area.展开更多
Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor （AR） is expressed in monocytes/macrophages, whic...Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor （AR） is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages （M-ARKO） were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type （WT） and M-ARKO mice （12-22 weeks of age, n = 12 per group） were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake （3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice） or total energy expenditure （0.6 ± 0.1 Kcal h-1 for WT mice vs 0.5 ± 0.1 Kcal h-1 for M-ARKO mice） were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice （1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02）. Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.展开更多
Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors relate...Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.展开更多
The rapid advancement of environmental sensing technologies and artificial intelligence(AI)has ushered in a new era of data-driven environmental health research,especially for the rapid development of exposomics.1,2 T...The rapid advancement of environmental sensing technologies and artificial intelligence(AI)has ushered in a new era of data-driven environmental health research,especially for the rapid development of exposomics.1,2 This surge in data collection and analysis capabilities brings unprecedented opportunities for scientific discovery,but also raises critical ethical concerns.Data ethics,the moral framework guiding data management,has become crucial for environmental researchers.The proliferation of advanced instruments,low-cost sensors,and digitalized knowledge has led to an explosion of environmental data.Concurrently,AI models can now derive complex patterns from these vast data sets without traditional hypothesis testing and features extraction,revolutionizing investigations into environmental health issues.However,these advancements bring challenges.Regulations like the EU’s General Data Protection Regulation(GDPR)have set new standards for data protection,3 highlighting the need for robust ethical frameworks in environmental health research.This study aims to explore key ethical considerations in data-driven environmental health studies,focusing on three main areas:data collection,analysis,and sharing.We propose a checklist of ethical guidelines for researchers,building upon existing frameworks.4 By addressing these ethical challenges,we can promote responsible data practices that maximize the benefits of AI and big data while maintaining scientific integrity and protecting individual privacy.展开更多
Dystrobrevin-binding protein 1 （Dtnbp1） is one of the earliest identified schizophrenia susceptibility genes. Reduced expression of DTNBP1 is commonly found in brain areas of schizophrenic patients. Dtnbp1-nuU mutan...Dystrobrevin-binding protein 1 （Dtnbp1） is one of the earliest identified schizophrenia susceptibility genes. Reduced expression of DTNBP1 is commonly found in brain areas of schizophrenic patients. Dtnbp1-nuU mutant mice exhibit abnormalities in beha- viors and impairments in neuronal activities. However, how diminished DTNBP1 expression contributes to clinical relevant fea- tures of schizophrenia remains to be illustrated. Here, using a conditional Dtnbp1 knockout mouse line, we identified an in vivo schizophrenia-relevant function of DTNBP1 in pyramidal neurons of the medial prefrontal cortex （mPFC）. We demonstrated that DTNBP1 elimination specifically in pyramidal neurons of the mPFC impaired mouse pre-pu[se inhibition （PPI） behavior and reduced perisomatic GABAergic synapses. We further revealed that loss of DTNBP1 in pyramidal neurons diminished activity- dependent secretion of brain-derived neurotrophic factor （BDNF）. Finally, we showed that chronic BDNF infusion in the mPFC fully rescued both GABAergic synaptic dysfunction and PPI behavioral deficit induced by DTNBP1 elimination from pyramidal neurons. Our findings highlight brain region- and cell type-specific functions of DTNBP1 in the pathogenesis of schizophrenia, and under- score BDNF restoration as a potential therapeutic strategy for schizophrenia.展开更多
Graves*orbitopathy(GO),the most severe manifestation of Graves'hyperthyroidism(GH),is an autoimmune-mediated inflammatory disorder,and treatments often exhibit a low efficacy.CD4+T cells have been reported to play...Graves*orbitopathy(GO),the most severe manifestation of Graves'hyperthyroidism(GH),is an autoimmune-mediated inflammatory disorder,and treatments often exhibit a low efficacy.CD4+T cells have been reported to play vital roles in GO progression.To explore the pathogenic CD4-f T cell types that drive GO progression,we applied single-cell RNA sequencing(scRNA-Seq),T cell receptor sequencing(TCR-Seq),flow cytometry,immunofluorescence and mixed lymphocyte reaction(MLR)assays to evaluate CD4+T cells from GO and GH patients.scRNA-Seq revealed the novel GO-spedfic cell type CD4+cytotoxic T lymphocytes(CTLs),which are characterized by chemotactic and inflammatory features.The clonal expansion of this CD4+CTL population,as demonstrated by TCR-Seq,along with their strong cytotoxic response to autoantigens,localization in orbital sites,and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-y-secreting CD4+CTLs in GO.Therefore,cytotoxic pathways may become potential therapeutic targets for GO.展开更多
Thanatomicrobiome,or the postmortem microbiome,has been recognized as a useful microbial marker of the time and location of host death.In this mini-review,we compare the experimental methods commonly applied to thanat...Thanatomicrobiome,or the postmortem microbiome,has been recognized as a useful microbial marker of the time and location of host death.In this mini-review,we compare the experimental methods commonly applied to thanatomicrobiome studies to the state-of-the-art methodologies in the microbiome field.Then,we review present findings in thanatomicrobiome studies,focusing on the diversity of the thanatomicrobiome composition and prediction models that have been proposed.Finally,we discuss potential improvements and future directions of the field.展开更多
The tumor ecosystem with heterogeneous cellularcompositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. Theextracellular matrix (ECM), the major component of th...The tumor ecosystem with heterogeneous cellularcompositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. Theextracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumorcells and stromal cells have also enjoyed tremendouslyincreased attention. Like the other components of the tumormicroenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We reviewrecent studies of the complex roles the tumor ECM plays incancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular,biophysical, and mechanochemical interactions between theECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment.We further discuss the strategies to target and modify thetumor ECM to improve cancer therapy.展开更多
Microsatellite instability(MSI)is a key biomarker for cancer therapy and prognosis.Traditional experimental assays are laborious and time-consuming,and next-generation sequencingbased computational methods do not work...Microsatellite instability(MSI)is a key biomarker for cancer therapy and prognosis.Traditional experimental assays are laborious and time-consuming,and next-generation sequencingbased computational methods do not work on leukemia samples,paraffin-embedded samples,or patient-derived xenografts/organoids,due to the requirement of matched normal samples.Herein,we developed MSIsensor-pro,an open-source single sample MSI scoring method for research and clinical applications.MSIsensor-pro introduces a multinomial distribution model to quantify polymerase slippages for each tumor sample and a discriminative site selection method to enable MSI detection without matched normal samples.We demonstrate that MSIsensor-pro is an ultrafast,accurate,and robust MSI calling method.Using samples with various sequencing depths and tumor purities,MSIsensor-pro significantly outperformed the current leading methods in both accuracy and computational cost.MSIsensor-pro is available at https://github.com/xjtu-omics/msisensor-pro and free for non-commercial use,while a commercial license is provided upon request.展开更多
Short tandem repeat(STR)profiling is one of the mostly used systems for forensic applications.In certain circumstances,STR profiling is time-consuming and costly,which potentially leads to delays in criminal investiga...Short tandem repeat(STR)profiling is one of the mostly used systems for forensic applications.In certain circumstances,STR profiling is time-consuming and costly,which potentially leads to delays in criminal investigations.LGC(Laboratory of the Government Chemist,UK)Forensics has developed a robust STR profiling platform called the ParaDNAVR Intelligence Test System which can provide early tactical intelligence and aid investigators in making informed decisions on sample prioritization for detection.Here,we validated the ParaDNA^(■) intelligence test for its application in forensic cases using a range of mock evidence items following guidelines set by the Scientific Working Group on DNA Analysis Methods(SWGDAM).Specifically,we tested the sensitivity and accuracy of the ParaDNA intelligence test,as well as the success rates for detecting mock samples and for use in case scenarios.Our findings demonstrate that the ParaDNA intelligence test generates useful DNA profiles,especially for samples such as blood,saliva,and semen that contain ample DNA,indicating the benefits of including ParaDNA as a prior step in forensic STR profiling pipelines.展开更多
The scant hair mutant mouse(locus symbol:snthr1Bao) is a recessive mutation that originated in an ethylnitrosourea chemical carcinogenesis study using the DBA/2J inbred strain.The gene responsible for the mutation was...The scant hair mutant mouse(locus symbol:snthr1Bao) is a recessive mutation that originated in an ethylnitrosourea chemical carcinogenesis study using the DBA/2J inbred strain.The gene responsible for the mutation was previously determined to be phospholipase C,delta 1(Plcd1;mutant allele symbol Plcd1snthr1Bao).To map the modifiers of Plcd1,an intercross(DBA/2J-snthr1Bao/snthr1Bao × C57BL/6J+/+) was conducted.The F2 mutant progeny exhibited a variety of alopecia phenotypes;all F2 mutants(n=507) were classified into 3 groups(mild,moderate,and severe alopecia) and genotyped based on 96 microsatellites.A major QTL was identified on mouse chromosome(mChr) 15 at 12 cM with an LOD score greater than 7(P < 0.0001).Three minor QTLs were detected on mChr 2,5,and 7 at 40,84 and 48 cM,respectively.The QTLs on mChr 7 and 15 were associated with minor alopecia while the QTLs on mChr 2 and 5 were associated with moderate to severe alopecia.No antagonistic or synergistic effects among or between the 4 QTLs were found.Integrating the functions of the 4 potential regulatory QTLs and mutant Plcd1snthr1Bao,we found that these QTLs might contribute to variations of scant hair severity by altering the Ca2+ signal pathways in mouse skin.展开更多
Complex structural variants(CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.However,detecting the compounded mutational...Complex structural variants(CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.However,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery compared with simple structural variants.Here,we systematically analyzed the multi-breakpoint connection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.展开更多
基金supported by the National Natural Science Foundation of China(No.30571546,30771780)the Scientific Research Foundation of the State Education Ministry for Returned Overseas Chinese Scholars(2007-24)+1 种基金the Natural Science Foundation of Guangdong Province(No.07117550)the Natural Science Key Program of Higher Education Institutions of Guangdong Province,China(No.06Z021).
文摘Objective To screen miRNA profiles of malignantly transformed human bronchial epithelial cells, 16HBE-T, induced by anti-benzo[a]pyrene-trans-7,8-diol-9,10-epoxide （anti-BPDE）, and to analyze putative miR-10a targets in 16HBE-T. Methods A novel microarray platform was employed to screen miRNA profiles of 16HBE-T cells transformed by anti-BPDE. Microarray data for miR-10a and miR-320 were validated using quantitative real time polymerase chain reaction （QRT-PCR）. The expression of a putative target for miR-10a, HOXA1, was analyzed by reverse transcription polymerase chain reaction （RT-PCR） and QRT-PCR. Results In comparison with the vehicle-treated cells （16HBE-N）, 16HBE-T exhibited differential expression of 54 miRNAs, in which, 45 were over-expressed and 9 were down-regulated. The five most highly expressed miRNAs were miR-494, miR-320, miR-498, miR-129, and miR-106a. The lowest expressed miRNAs were miR-10a, miR-493-5p, and miR-363＊. Three members of miR-17-92 cluster, miR-17-5p, miR-20a, and miR-92, showed significantly higher abundance in 16BHE-T as miR-21, miR-141, miR-27a, miR-27b, miR-16 and miRNAs of the let-7 family. The putative target for miR-10a, HOXA1 mRNA was up-regulated 3-9-fold in 16HBE-T, as compared with 16HBE-N. Conclusion The findings of the study provide information on differentially expressed miRNA in malignant 16HBE-T, and also suggest a potential role of these miRNAs in cell transformation induced by anti-BPDE. HOXA1 is similarly up-regulated, suggesting that miR-10a is associated with the process of HOXA 1-mediated transformation.
基金Supported by a grant from the Bureau of Health in Shaanxi Province,No.2002 02D24 and grants No.NSFC30440080No.NIDCD R21 DC005846
文摘AIM： To detect whether there is Helicobacter pylori （Hpylori） colonization in the pharynx mucous membrane of healthy people and whether chronic pharyngitis is related to Hpylori infection. METHODS： Fifty cases of chronic pharyngitis refractory over three months were prospectively studied from March 2004 to August 2004 in the otolaryngology outpatient department of the Second Hospital of Xi＇an Jiaotong University. Template-directed dye-terminator incorporated with fluorescence polarization detection （TDI-FP） and modified Giemsa stain were used to examine pharynx mucous membrane tissue for H pylori colonization in the patients with chronic pharyngitis and the healthy people as a control group. RESULTS： In the control group, no people were detected to have Hpylori in the pharynx. In contrast, in 50 cases with chronic pharyngitis, 19 （38.0%） cases were H pylori positive with a TDI-FP assay and 4 （8%） cases were TDI-FP positive with Giemsa staining in the pharynx. Sixteen of the 50 pharyngitis cases had stomach ailment history, 11 cases （68.8%） of these 16 patients were determined to be H pylori positive in the pharynx with the TDI-FP assay. 2,2 test showed that this infection rate was remarkably higher （P= 0.0007） than that in the cases without stomach ailment history. Giemsa staining showed that 3 cases （18.8%） of the patients with stomach ailment history were infected with H pylori in the pharynx, which was remarkably higher （P = 0.042） than that in the patients without stomach ailment history （1 case, which was 2.9%）. CONCLUSION： H pylori may not be detected in the pharynx of healthy people. Chronic pharyngitis may be related to H pylori infection. The infection rate with Hpylori in the pharynx is higher in patients with stomach ailment histories than in patients without stomach ailment histories, suggesting that chronic pharyngitis may be related to stomach ailment history.
基金supported by the National Cancer Institute(grant No.P30CA034196)supported by the National Natural Science Foundation of China (No.31471215)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA01010409)the National High Technology Research and Development Program("863" Program) of China(No.2015AA020307)
文摘Previously we established Zygote Electroporation of Nucleases（ZEN） technology as an efficient and high-throughput way to generate genetically modified mouse models.However,there were significant variations of the targeting efficiency among different genomic loci using our previously published protocol.In this study,we improved the ZEN technology by delivering Cas9 protein into mouse zygotes through a series of electroporation.Using this approach,we were able to introduce precise nucleotide substitutions,large segment deletion and short segment insertion into targeted loci with high efficiency.
文摘Objective To map a mouse deafness gene, identify the underlying mutation and develop a mouse model for human deafness. Methods Genetic linkage cross and genome scan were used to map a novel mutation named hypoplasia of the membranous labyrinth (hml), which causes hearing loss in mutant mice. Results ① hml was mapped on mouse Chr 10 (～43 cM from the centromere) suggests that the homologous human gene is on 12q22-q24, which was defined on the basis of known mouse-human homologies (OMIM, 2004). ② This study has generated 25 polymorphic microsatellite markers, placed 3 known human genes in the correct order in a high-resolution mouse map and narrowed the hml candidate gene region to a 500 kb area.
文摘Androgen deprivation in men leads to increased adiposity, but the mechanisms underlying androgen regulation of fat mass have not been fully defined. Androgen receptor （AR） is expressed in monocytes/macrophages, which are resident in key metabolic tissues and influence energy metabolism in surrounding cells. Male mice bearing a cell-specific knockout of the AR in monocytes/macrophages （M-ARKO） were generated to determine whether selective loss of androgen signaling in these cells would lead to altered body composition. Wild-type （WT） and M-ARKO mice （12-22 weeks of age, n = 12 per group） were maintained on a regular chow diet for 8 weeks and then switched to a high-fat diet for 8 additional weeks. At baseline and on both the regular chow and high-fat diets, no differences in lean mass or fat mass were observed between groups. Consistent with the absence of differential body weight or adiposity, no differences in food intake （3.0 ± 0.5 g per day for WT mice vs 2.8 ± 0.4 g per day for M-ARKO mice） or total energy expenditure （0.6 ± 0.1 Kcal h-1 for WT mice vs 0.5 ± 0.1 Kcal h-1 for M-ARKO mice） were evident between groups during high-fat feeding. Liver weight was greater in M-ARKO than that in WT mice （1.5 ± 0.1 g vs 1.3 ± 0.0 g, respectively, P = 0.02）. Finally, M-ARKO mice did not exhibit impairments in glucose tolerance or insulin sensitivity relative to WT mice at any study time point. In aggregate, these findings suggest that AR signaling specifically in monocytes/macrophages does not contribute to the regulation of systemic energy balance, adiposity, or insulin sensitivity in male mice.
基金supported by the Canadian Institute of Health Research(CIHR)-Natural Sciences and Engineering Research Council(NSERC)of Canada Collaborative Health Research Projects program(Grant No.:355935)as well as by NSERC through the Industrial Research Chair(IRC)program(Program No.:#IRCPJ 184412e15).
文摘Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumor characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this study, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3 h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40, and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.
文摘The rapid advancement of environmental sensing technologies and artificial intelligence(AI)has ushered in a new era of data-driven environmental health research,especially for the rapid development of exposomics.1,2 This surge in data collection and analysis capabilities brings unprecedented opportunities for scientific discovery,but also raises critical ethical concerns.Data ethics,the moral framework guiding data management,has become crucial for environmental researchers.The proliferation of advanced instruments,low-cost sensors,and digitalized knowledge has led to an explosion of environmental data.Concurrently,AI models can now derive complex patterns from these vast data sets without traditional hypothesis testing and features extraction,revolutionizing investigations into environmental health issues.However,these advancements bring challenges.Regulations like the EU’s General Data Protection Regulation(GDPR)have set new standards for data protection,3 highlighting the need for robust ethical frameworks in environmental health research.This study aims to explore key ethical considerations in data-driven environmental health studies,focusing on three main areas:data collection,analysis,and sharing.We propose a checklist of ethical guidelines for researchers,building upon existing frameworks.4 By addressing these ethical challenges,we can promote responsible data practices that maximize the benefits of AI and big data while maintaining scientific integrity and protecting individual privacy.
文摘Dystrobrevin-binding protein 1 （Dtnbp1） is one of the earliest identified schizophrenia susceptibility genes. Reduced expression of DTNBP1 is commonly found in brain areas of schizophrenic patients. Dtnbp1-nuU mutant mice exhibit abnormalities in beha- viors and impairments in neuronal activities. However, how diminished DTNBP1 expression contributes to clinical relevant fea- tures of schizophrenia remains to be illustrated. Here, using a conditional Dtnbp1 knockout mouse line, we identified an in vivo schizophrenia-relevant function of DTNBP1 in pyramidal neurons of the medial prefrontal cortex （mPFC）. We demonstrated that DTNBP1 elimination specifically in pyramidal neurons of the mPFC impaired mouse pre-pu[se inhibition （PPI） behavior and reduced perisomatic GABAergic synapses. We further revealed that loss of DTNBP1 in pyramidal neurons diminished activity- dependent secretion of brain-derived neurotrophic factor （BDNF）. Finally, we showed that chronic BDNF infusion in the mPFC fully rescued both GABAergic synaptic dysfunction and PPI behavioral deficit induced by DTNBP1 elimination from pyramidal neurons. Our findings highlight brain region- and cell type-specific functions of DTNBP1 in the pathogenesis of schizophrenia, and under- score BDNF restoration as a potential therapeutic strategy for schizophrenia.
基金supported by the National Key R&D Program of China(Grant nos.2018YFC1311500(B.S.),2017YFC0907500(K.Y.)and 2018YFC0910400(K.Y.))National Science Foundation of China(NSFC)(Grant nos.81970679(B.S.),81500690(Y.W.),and 31671372(K.Y.))+3 种基金Natural Science Foundation of Shaanxi Province(2018JM70990(Y.W.))Key Research and Development Project of Shaanxi Province(Grant no.2017ZDXM-SF-060(B.S.))Fundamental Research Funds for the Central Universities(1191329875(Y.W.))the China Postdoctoral Science Foundation(224646(Y.W.)).
文摘Graves*orbitopathy(GO),the most severe manifestation of Graves'hyperthyroidism(GH),is an autoimmune-mediated inflammatory disorder,and treatments often exhibit a low efficacy.CD4+T cells have been reported to play vital roles in GO progression.To explore the pathogenic CD4-f T cell types that drive GO progression,we applied single-cell RNA sequencing(scRNA-Seq),T cell receptor sequencing(TCR-Seq),flow cytometry,immunofluorescence and mixed lymphocyte reaction(MLR)assays to evaluate CD4+T cells from GO and GH patients.scRNA-Seq revealed the novel GO-spedfic cell type CD4+cytotoxic T lymphocytes(CTLs),which are characterized by chemotactic and inflammatory features.The clonal expansion of this CD4+CTL population,as demonstrated by TCR-Seq,along with their strong cytotoxic response to autoantigens,localization in orbital sites,and potential relationship with disease relapse provide strong evidence for the pathogenic roles of GZMB and IFN-y-secreting CD4+CTLs in GO.Therefore,cytotoxic pathways may become potential therapeutic targets for GO.
基金This study is supported by the National Natural Science Foundation of China[grant numbers 81601651 and 81625013]the Science and Technology Committee of Shanghai Municipality[grant numbers 16dz1205500,16DZ2290900 and 17DZ2273200]+1 种基金the National Key R&D Program of China[grant number 2016YFC0800703]the Ministry of Finance of China[grant number GY2016D1].
文摘Thanatomicrobiome,or the postmortem microbiome,has been recognized as a useful microbial marker of the time and location of host death.In this mini-review,we compare the experimental methods commonly applied to thanatomicrobiome studies to the state-of-the-art methodologies in the microbiome field.Then,we review present findings in thanatomicrobiome studies,focusing on the diversity of the thanatomicrobiome composition and prediction models that have been proposed.Finally,we discuss potential improvements and future directions of the field.
基金This work was partially supported by the National Institute of Health grants from NCI(R01CA201340)NEI(1R01EY028450).
文摘The tumor ecosystem with heterogeneous cellularcompositions and the tumor microenvironment has increasingly become the focus of cancer research in recent years. Theextracellular matrix (ECM), the major component of the tumor microenvironment, and its interactions with the tumorcells and stromal cells have also enjoyed tremendouslyincreased attention. Like the other components of the tumormicroenvironment, the ECM in solid tumors differs significantly from that in normal organs and tissues. We reviewrecent studies of the complex roles the tumor ECM plays incancer progression, from tumor initiation, growth to angiogenesis and invasion. We highlight that the biomolecular,biophysical, and mechanochemical interactions between theECM and cells not only regulate the steps of cancer progression, but also affect the efficacy of systemic cancer treatment.We further discuss the strategies to target and modify thetumor ECM to improve cancer therapy.
基金supported by the National Key R&D Program of China(Grant Nos.2018YFC0910400 and 2017YFC0907500)the National Natural Science Foundation of China(Grant Nos.31671372,61702406,31701739,and 31970317)+2 种基金the National Science and Technology Major Project of China(Grant No.2018ZX10302205)the‘‘World-Class Universities and the Characteristic Development Guidance Funds for the Central Universities”the General Financial Grant from the China Postdoctoral Science Foundation(Grant Nos.2017M623178 and 2017M623188)
文摘Microsatellite instability(MSI)is a key biomarker for cancer therapy and prognosis.Traditional experimental assays are laborious and time-consuming,and next-generation sequencingbased computational methods do not work on leukemia samples,paraffin-embedded samples,or patient-derived xenografts/organoids,due to the requirement of matched normal samples.Herein,we developed MSIsensor-pro,an open-source single sample MSI scoring method for research and clinical applications.MSIsensor-pro introduces a multinomial distribution model to quantify polymerase slippages for each tumor sample and a discriminative site selection method to enable MSI detection without matched normal samples.We demonstrate that MSIsensor-pro is an ultrafast,accurate,and robust MSI calling method.Using samples with various sequencing depths and tumor purities,MSIsensor-pro significantly outperformed the current leading methods in both accuracy and computational cost.MSIsensor-pro is available at https://github.com/xjtu-omics/msisensor-pro and free for non-commercial use,while a commercial license is provided upon request.
基金This study was supported by grants from National Key R&D Program of China[grant number 2016YFC0800703]the National Natural Science Foundation of China[grant number 81601651 and 81625013]+2 种基金the Ministry of Finance of China[grant number GY2016D1,GY2018G-9,KF1813]the Shanghai Science and Technology Innovation Fund[grant number 16DZ1205500,16DZ2290900,17DZ2273200]the funders had no role in study design,data analysis,decision to publish,or preparation of the manuscript.
文摘Short tandem repeat(STR)profiling is one of the mostly used systems for forensic applications.In certain circumstances,STR profiling is time-consuming and costly,which potentially leads to delays in criminal investigations.LGC(Laboratory of the Government Chemist,UK)Forensics has developed a robust STR profiling platform called the ParaDNAVR Intelligence Test System which can provide early tactical intelligence and aid investigators in making informed decisions on sample prioritization for detection.Here,we validated the ParaDNA^(■) intelligence test for its application in forensic cases using a range of mock evidence items following guidelines set by the Scientific Working Group on DNA Analysis Methods(SWGDAM).Specifically,we tested the sensitivity and accuracy of the ParaDNA intelligence test,as well as the success rates for detecting mock samples and for use in case scenarios.Our findings demonstrate that the ParaDNA intelligence test generates useful DNA profiles,especially for samples such as blood,saliva,and semen that contain ample DNA,indicating the benefits of including ParaDNA as a prior step in forensic STR profiling pipelines.
基金supported by the National Natural Science Foundation of China (30670231 and 30400266)the Scientific Research Foundation for the Returned Overseas Chinese Scholars,Ministry of Education of China
文摘The scant hair mutant mouse(locus symbol:snthr1Bao) is a recessive mutation that originated in an ethylnitrosourea chemical carcinogenesis study using the DBA/2J inbred strain.The gene responsible for the mutation was previously determined to be phospholipase C,delta 1(Plcd1;mutant allele symbol Plcd1snthr1Bao).To map the modifiers of Plcd1,an intercross(DBA/2J-snthr1Bao/snthr1Bao × C57BL/6J+/+) was conducted.The F2 mutant progeny exhibited a variety of alopecia phenotypes;all F2 mutants(n=507) were classified into 3 groups(mild,moderate,and severe alopecia) and genotyped based on 96 microsatellites.A major QTL was identified on mouse chromosome(mChr) 15 at 12 cM with an LOD score greater than 7(P < 0.0001).Three minor QTLs were detected on mChr 2,5,and 7 at 40,84 and 48 cM,respectively.The QTLs on mChr 7 and 15 were associated with minor alopecia while the QTLs on mChr 2 and 5 were associated with moderate to severe alopecia.No antagonistic or synergistic effects among or between the 4 QTLs were found.Integrating the functions of the 4 potential regulatory QTLs and mutant Plcd1snthr1Bao,we found that these QTLs might contribute to variations of scant hair severity by altering the Ca2+ signal pathways in mouse skin.
基金supported by the National Key R&D Program of China(Grant Nos.2018YFC0910400 and 2017YFC0907500)the National Science Foundation of China(Grant Nos.31671372,61702406,and 31701739)+3 种基金the Fundamental Research Funds for the Central Universitiesthe World-Class Universities(Disciplines)the Characteristic Development Guidance Funds for the Central Universitiesthe Shanghai Municipal Science and Technology Major Project(Grant No.2017SHZDZX01)。
文摘Complex structural variants(CSVs) are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.However,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery compared with simple structural variants.Here,we systematically analyzed the multi-breakpoint connection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70%,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.
