BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outc...BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.展开更多
BACKGROUND: Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their e...BACKGROUND: Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their effects are stil inconclusive. This study aimed to evaluate the overal eff ect of probiotics on the prognosis of patients with sepsis.DATA RESOURCES: We searched several sources for published/presented studies, including Pub Med, EMBASE, Web of Science, the Cochrane Library and the US National Library of Medicine Clinical Trials Register(www.clinicaltrials.gov) updated through July 30, 2023, to identify all relevant randomized controlled trials(RCTs) or observational studies that assessed the effectiveness of probiotics or synbiotics in patients with sepsis and reported mortality. We focused primarily on mortality during the study period and analyzed secondary outcomes, including 28-day mortality, in-intensive care unit(ICU) mortality and other outcomes.RESULTS: Data from 405 patients in five RCTs and 108 patients in one cohort study were included in the analysis. The overall quality of the studies was satisfactory, but clinical heterogeneity existed. All adult studies reported a tendency for probiotics to reduce the mortality of patients with sepsis, and most studies reported a decreasing trend in the incidence of infectious complications, length of ICU stay and duration of antibiotic use. There was only one RCT involving children.CONCLUSION: Probiotics show promise for improving the prognosis of patients with sepsis, including reducing mortality and the incidence of infectious complications, particularly in adult patients. Despite the limited number of studies, especially in children, these findings will be encouraging for clinical practice in the treatment of sepsis and suggest that gut microbiota-targeted therapy may improve the prognosis of patients with sepsis.展开更多
The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for n...The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.展开更多
The importance and necessity of emulating the federation load during simulating was analyzed firstly.Then,the special federation load emulation tool,federation load simulator (FLS),was designed and implemented,by whic...The importance and necessity of emulating the federation load during simulating was analyzed firstly.Then,the special federation load emulation tool,federation load simulator (FLS),was designed and implemented,by which all of the vital essential characteristics of a simulation could be tested,e.g.the amount of federates,the joint/resigned speed of federate,the amount of object instances,the registered/deleted speed of instance in one single program,etc..The applications proved that FLS could provide a convenient,effective and adjustable simulation load testing environment during the procedure of run-time infrastructure(RTI)and interrelated tool federates researching,developing and performance testing.Furthermore,the FLS utilized all kinds of resources with high efficiency.展开更多
Background:Septic shock is a life-threatening disease with high mortality rates,and the relevant hub genes and biomarkers are poorly understood.We aimed to identify hub genes and prognostic biomarkers of mRNAs/IncRNAs...Background:Septic shock is a life-threatening disease with high mortality rates,and the relevant hub genes and biomarkers are poorly understood.We aimed to identify hub genes and prognostic biomarkers of mRNAs/IncRNAs in septic shock to rapidly and accurately diagnose infection,identify patients at a high risk of developing septic shock,and predict prognosis.Methods:Gene expression profiles of 279 patients with septic shock and 100 healthy controls were analyzed using bioinformatics methods.We screened for differentially expressed genes(DEGs),identified hub genes,and investigated the correlations between mRNA/lncRNA expression and disease severity/prognosis.Protein level validation was performed using blood proteomic data from an independent cohort study.Results:The protein-protein interaction network constructed using upregulated DEGs contained 102 nodes and 222 edges,with LTF,MMP8,MMP9,CEACAM8,CTSG,LCN2,and PRTN3 identified as hub genes.There was a possible association between LCN2 mRNA upregulation and increased severity of septic shock(odds ratio:1.518;95% confidence interval:0.999-2.305;P=0.050),approaching statistical significance,and BCL2A1 mRNA upregulation correlated with higher mortality risk(odds ratio:1.178;95% confidence interval:1.035-1.341;P=0.013).No significant prognostic correlation was observed for lncRNAs.The validation cohort confirmed significant upregulation of MMP9,CTSG,LCN2,LTF,and MMP8 proteins in patients with septic shock,with MMP9,LCN2,CTSG,and LTF exhibiting strong diagnostic performance(area under the curve>0.8).Conclusion:Seven hub genes related to septic shock were identified,including MMP9,LCN2,CTSG,and LTF,which could potentially function as candidate biotargets and biomarkers for the diagnosis and prognostic prediction of septic shock,though further validation is needed.Notably,LCN2 showed a trend toward association with disease severity,while BCL2A1 correlated with mortality risk.展开更多
Pelvic organ prolapse(POP),whose etiology is influenced by genetic and clinical risk factors,considerably impacts women’s quality of life.However,the genetic underpinnings in non-European populations and comprehensiv...Pelvic organ prolapse(POP),whose etiology is influenced by genetic and clinical risk factors,considerably impacts women’s quality of life.However,the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored.This study constructed the first polygenic risk score(PRS)for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study.We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls.Results showed that the case group exhibited a significantly higher PRS than the control group.Moreover,the odds ratio of the top 10%risk group was 2.6 times higher than that of the bottom 10%.A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths.As far as we know,the integrated prediction model,which combined PRS and clinical risk factors,demonstrated better predictive accuracy than other existing PRS models.This combined risk assessment model serves as a robust tool for POP risk prediction and stratification,thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.展开更多
Uterine myomas are the most prevalent benign gynecological tumors,affecting over 70%of women[1].They are often associated with significant morbidity,including anemia and infertility.In contrast,uterine sarcomas,althou...Uterine myomas are the most prevalent benign gynecological tumors,affecting over 70%of women[1].They are often associated with significant morbidity,including anemia and infertility.In contrast,uterine sarcomas,although rare,are highly malignant,with a five-year survival rate of 50%-55%in early stages and a stark decline to 8%-12%in advanced stages[2],[3].展开更多
Dear Editor,Coronavirus disease 2019(COVID-19)is a serious respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Since the emergence of SARS-CoV-2,extensive research has been conduc...Dear Editor,Coronavirus disease 2019(COVID-19)is a serious respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Since the emergence of SARS-CoV-2,extensive research has been conducted to develop safe and effective vaccines against COVID-19,including messenger RNA(mRNA),viral vector,inactivated vaccines and protein subunit vaccines.展开更多
Adolescents represent a significant proportion of global psychiatric morbidity,with approximately 10%–20%affected by mental disorders,primarily including major depressive disorder(MDD),bipolar disorder(BD),and schizo...Adolescents represent a significant proportion of global psychiatric morbidity,with approximately 10%–20%affected by mental disorders,primarily including major depressive disorder(MDD),bipolar disorder(BD),and schizophrenia(SZ)[1,2].These mental disorders exhibit distinct clinical presentations compared with adult forms,including prominent somatic symptoms in MDD[3],rapid mood cycling in BD[4],and insidious onset in SZ[5].The symptom-based Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)framework faces challenges in differentiating these mental disorders because of overlapping manifestations and developmental heterogeneity[6],necessitating biologically anchored classification frameworks.展开更多
Hereditary cardiomyopathies and arrhythmias are major contributors to cardiovascular morbidity and mortality.The advent of next-generation sequencing(NGS)has made genetic testing more accessible,which is crucial for p...Hereditary cardiomyopathies and arrhythmias are major contributors to cardiovascular morbidity and mortality.The advent of next-generation sequencing(NGS)has made genetic testing more accessible,which is crucial for precise diagnosis and targeted therapeutic strategies.The aim of this study is to explore the landscape of genetic variants,the relationship between specific variants and clinical phenotypes,and the impact on clinical decision-making in China.A total of 1536 probands(median age,37 years;1025 males[66.7%])with suspected hereditary cardiomyopathy or arrhythmia(covering 15 clinical phenotypes)are recruited from 146 hospitals across 30 provinces and cities in China.Positive results are confirmed in 390 of 1536 probands,leading to a diagnostic yield of 25.4%.Forty-two and three-tenths percent(n=169)of family members carry the same variants as positive probands.Hypertrophic cardiomyopathy(HCM)and dilated cardiomyopathy(DCM)are the predominant phenotypes,with MYBPC3 variants having the highest frequency in HCM and TTN variants in DCM.In 76.9%of the positive probands,the identified variants are helpful in clinical management,family screening,and fertility.This large-scale study provides significant insights into the genetic landscape of hereditary cardiomyopathies and arrhythmias in China.展开更多
This commentary summarized the most important findings in the first half 2023 year based on Society of Gynecologic Oncology(SGO)annual meeting and publications in crucial journals.This commentary provided a comprehens...This commentary summarized the most important findings in the first half 2023 year based on Society of Gynecologic Oncology(SGO)annual meeting and publications in crucial journals.This commentary provided a comprehensive overview of notable developments in the field of gynecologic oncology throughout the first half of 2023,drawing insights from the Society of Gynecologic Oncology(SGO)Annual Meet-ing and pivotal publications in esteemed journals.The discourse delved into the forefront of molecular mechanisms,emphasizing critical themes such as homologous recombination repair deficiency,mismatch repair,immune check-point blockades,and anti-angiogenesis in various cancers.Specific attention was given to advancements in targeted and immunotherapeutic modalities,notably examining the efficacy and safety profiles of poly(ADP-Ribose)poly-merase inhibitors(PARPi)in ovarian cancer.Conclusively,the commentary underscored the transformative impact of molecularly guided therapies,marking them as pivotal in addressing refractory conditions and set the stage for heightened expectations in future advancements.PARP inhibitors have become the standard maintenance treatment for ovarian cancer.Among the first six articles,two(SOLO1 and PAOLA-1)summarized evidence supporting the improvement of overall survival with PARP inhibitors in maintenance therapy,while the NOVA study reported no benefit in overall survival.The first,fourth,and sixth arti-cles discussed the feasibility of PARP inhibitors,immune checkpoint inhibitors used alone or in combination in neo-adjuvant therapy(post-chemotherapy surgery).The latter two articles focused on the application of PD-1(immune checkpoint inhibitors)in locally advanced cervical cancer,demonstrating enhanced efficacy.Currently,immune checkpoint inhibitors are commonly used in advanced cervical and endometrial cancers due to their status as hot tumors.Their use,either alone or in combination with anti-angiogenic drugs,has shown better outcomes in recur-rent and advanced refractory endometrial and cervical cancers compared to traditional chemotherapy.A study from Huashan Hospital discussed the effectiveness of immune checkpoint inhibitors combined with anti-angiogenic therapy in recurrent cervical cancer,although there might be a typo as the initial mention was about endometrial cancer.The following article discussed late-stage endometrial cancer,finding no difference in survival between chem-otherapy and chemotherapy combined with radiation.Subsequent articles highlighted the superiority of immune checkpoint inhibitors combined with chemotherapy in treating recurrent endometrial cancer,as well as the efficacy of immune checkpoint inhibitors combined with anti-angiogenic therapy in endometrial cancer.The final article focused on the therapeutic effect of HER2-positive ADC class drugs in uterine cancer sarcoma.展开更多
Developing a safe and effective vaccine remains a global priority for ending the human immunodeficiency virus(HIV)pandemic.All HIV vaccine trials with protein,DNA,non-replication vector or their combinations failed in...Developing a safe and effective vaccine remains a global priority for ending the human immunodeficiency virus(HIV)pandemic.All HIV vaccine trials with protein,DNA,non-replication vector or their combinations failed in the past.We constructed the HIV-1 CN54 env,gag,and pol genes into both DNA and replicating vaccinia virus Tiantan vectors.In phase Ia,12 healthy adults were given high(n=6)or low(n=6)doses of recombinant vaccinia virus Tiantan vaccine(rTV),to test its safety dose.In phase Ib,36 healthy adults were assigned to the DNA(n=6),DNA-L/rTV(n=12),DNA-H/rTV(n=12),and placebo(n=6)groups.The DNA vaccine was injected intramuscularly at weeks 0,4,and 8 and rTV with a bifurcated needle at week 12.All vaccines tested were safe and well-tolerated;most of the adverse events(AEs)were mild to moderate.The most commonly observed AEs were redness and papule at rTV vaccination sites and axillary enlarged lymph nodes at the same rTV vaccination arm.Smaller cutaneous lesions and shorter healing time were observed in smallpox vaccine experienced subjects.展开更多
Dear Editor,Neurodevelopmental disorders(NDD)are a group of diseases with high phenotypic heterogeneity characterized by inability in cognition,communication,psychological skills,and motor development.The common types...Dear Editor,Neurodevelopmental disorders(NDD)are a group of diseases with high phenotypic heterogeneity characterized by inability in cognition,communication,psychological skills,and motor development.The common types of NDDs include autism spectrum disorder(ASD),attention-deficit/hyperactivity disorder(ADHD),epilepsy,schizophrenia,etc.(Parenti et al.,2020).展开更多
Pancreatic cancer cachexia is a complex,multifactorial syndrome characterized by progressive wasting of skeletal muscle and adipose tissue,contributing to poor prognosis and high mortality in pancreatic cancer patient...Pancreatic cancer cachexia is a complex,multifactorial syndrome characterized by progressive wasting of skeletal muscle and adipose tissue,contributing to poor prognosis and high mortality in pancreatic cancer patients.While muscle and fat loss are the hallmark features,pancreatic cancer cachexia is increasingly recognized as a systemic disorder involving extensive metabolic and inflammatory disruptions across multiple organs.Tumor-derived cachexia-inducing factors play a central role in driving systemic inflammation,metabolic dysregulation,and neuroendocrine abnormalities,leading to anorexia,gut dysbiosis,cardiac dysfunction,and pancreatic exocrine and endocrine insufficiency.These multi-organ disturbances form a vicious cycle that accelerates disease progression and complicates clinical management.In this review,we provide a comprehensive overview of pancreatic cancer cachexia,including its definitions,classification,and heterogeneous clinical presentations.We further examine recent findings on the molecular mediators of cachexia and their role in inter-organ communication networks.Additionally,we highlight advances in experimental models that enable the dissection of pancreatic cancer cachexia pathophysiology,and discuss emerging mechanism-based therapeutic strategies aimed at disrupting the cachexia cycle.A deeper understanding of the systemic nature of pancreatic cancer cachexia and the crosstalk among affected organs may inform the development of multi-targeted interventions and hold promise for improving patient outcomes.展开更多
Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving...Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving such biased lineage commitment remains elusive.Here we show that MG53,also named as TRIM72,prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptorα(PPARα),thus maintaining intestinal epithelium integrity against noxious insults.Using genetic mouse models,we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice,whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage.Mechanistically,MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARαsignaling.Specifically,MG53 overexpression induced PPARαexpression at transcriptional level and concomitantly increased PPARαactivity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα.Furthermore,genetic ablation or pharmacological inhibition of PPARαabolished the protective effects of MG53.These findings reveal a crucial role of MG53-PPARαaxis in driving the secretory lineage commitment of ISCs,especially during injury response,highlighting the important therapeutic potential of targeting MG53-PPARαsignaling for IBD treatment and marking PPARαagonists as novel therapies for IBD caused by various etiologies.展开更多
Dear Editor,Due to the inaccessibility of early human embryos,little is known about the chromatin status during early human endothelial cell(EC)development.Despite studies showing the epigenomic landscape of primary E...Dear Editor,Due to the inaccessibility of early human embryos,little is known about the chromatin status during early human endothelial cell(EC)development.Despite studies showing the epigenomic landscape of primary EC lines or human pluripotent stem cell(hPSC)-derived ECs,the epigenetic dynamic and feature of intermediate progenitors,such as vascular mesoderm cells(VMCs)and endothelial progenitor cells(EPCs),are less known.Therefore,an epigenomic roadmap of human EC development may provide new knowledge about nascent EC formation.展开更多
Intestinal homeostasis is sustained by self-renewal of intestinal stem cells(ISCs),which continuously divide and produce proliferative transit-amplifying(TA)and then progenitor cells.Eukaryotic translation initiation ...Intestinal homeostasis is sustained by self-renewal of intestinal stem cells(ISCs),which continuously divide and produce proliferative transit-amplifying(TA)and then progenitor cells.Eukaryotic translation initiation factor 5A(eIF5A),a conserved translation factor,involves in a variety of cellular processes,yet its role in intestinal homeostasis remains unclear.Here,we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis.Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss,suppressed cell proliferation,and increased apoptosis within the crypts,concurrent with shortened gut length,reduced mouse body weight and rapid animal mortality.Consistently,Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes.Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins,particularly those involved in mitochondrial translation,upon eIF5A depletion.Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes,including Dars2,are highly expressed in ISC,TA and progenitor cells.Furthermore,eIF5A-deficient organoids exhibit impaired mitochondrial function,characterized by reduced ATP levels and increased reactive oxygen species(ROS).These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation,providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.展开更多
Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine.Panoramic variation analysis is imperative to analyze the disease phenotypes resul...Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine.Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation.Here,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and deafness.Homozygosity mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,p.Trp90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,p.Leu84^(*))were identified.A Tmem141^(p.Trp90^(*)/p.Trp90^(*))mouse model was generated.Behavioral studies showed impairments in learning ability and motor coordination.Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells.Transmission electron microscopy showed abnormal mitochondrial morphology.Furthermore,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model.Conclusively,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in patient.Notably,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.展开更多
Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how ...Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.展开更多
文摘BACKGROUND:Whether lipid-modifying drugs directly impact the outcome of sepsis remains uncertain.Therefore,systematic investigations are needed to explore the potential impact of lipid-related therapies on sepsis outcomes and to elucidate the underlying mechanisms involving circulating inflammatory cytokines,which may play critical roles in the pathogenesis of sepsis.This study aimed to utilize drug-target Mendelian randomization to assess the direct causal effects of genetically proxied lipid-modifying therapies on sepsis outcomes.METHODS:First,a two-sample Mendelian randomization study was conducted to validate the causal associations among high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and sepsis.A subsequent drug-target Mendelian randomization study assessed the direct causal effects of genetical y proxied lipid-modifying therapies on the risk of sepsis,sepsis-related critical care admission,and sepsis-related death.The identified lipid-modifying drug targets were subsequently explored for direct causal relationships with 36 circulating inflammatory cytokines.Finally,enrichment analyses of the identified cytokines were conducted to explore the potential relationships of lipid-modifying drugs with the inflammatory response.RESULTS:Genetically proxied cholesteryl ester transfer protein(CETP) inhibitors were significantly associated with sepsis-related critical care admission(OR=0.84,95% CI [0.74,0.95],P=0.008,) and sepsisrelated death(OR=0.68,95% CI [0.52,0.88],P=0.004).The genetically proxied CETP inhibitors were strongly associated with the levels of 15 circulating inflammatory cytokines.Enrichment analyses indicated that CETP inhibitors may modulate inflammatory cytokines and influence the inflammatory response pathway.CONCLUSION:This study supports a causal effect of genetically proxied CETP inhibitors in reducing the risk of sepsis-related critical care admission and death.These findings suggest that the underlying mechanism may involve the modulation of some circulating inflammatory cytokines,influencing the inflammatory response pathway.
基金supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-109)Chinese Academy of Medical Science Innovation Fund for Medical Sciences (CIFMS)(2021-I2M-1-020)。
文摘BACKGROUND: Sepsis, a common acute and critical disease, leads to 11 million deaths annually worldwide. Probiotics are living microorganisms that are beneficial to the host and may benefit sepsis outcomes, but their effects are stil inconclusive. This study aimed to evaluate the overal eff ect of probiotics on the prognosis of patients with sepsis.DATA RESOURCES: We searched several sources for published/presented studies, including Pub Med, EMBASE, Web of Science, the Cochrane Library and the US National Library of Medicine Clinical Trials Register(www.clinicaltrials.gov) updated through July 30, 2023, to identify all relevant randomized controlled trials(RCTs) or observational studies that assessed the effectiveness of probiotics or synbiotics in patients with sepsis and reported mortality. We focused primarily on mortality during the study period and analyzed secondary outcomes, including 28-day mortality, in-intensive care unit(ICU) mortality and other outcomes.RESULTS: Data from 405 patients in five RCTs and 108 patients in one cohort study were included in the analysis. The overall quality of the studies was satisfactory, but clinical heterogeneity existed. All adult studies reported a tendency for probiotics to reduce the mortality of patients with sepsis, and most studies reported a decreasing trend in the incidence of infectious complications, length of ICU stay and duration of antibiotic use. There was only one RCT involving children.CONCLUSION: Probiotics show promise for improving the prognosis of patients with sepsis, including reducing mortality and the incidence of infectious complications, particularly in adult patients. Despite the limited number of studies, especially in children, these findings will be encouraging for clinical practice in the treatment of sepsis and suggest that gut microbiota-targeted therapy may improve the prognosis of patients with sepsis.
基金funded by the Starting Fund from Zhejiang University to N.L.and grants to X.L.from National Natural Science Foundation of China(82170120 and 81670108)CAMS Initiative for Innovative Medicine(2017-12M-B&R-04)+2 种基金Medical Epigenetics Research Cen-ter,CAMS(2018PT31015)the State Key Laboratory of Medical Molecular Biology(2060204)Haihe L aboratory of Cell Ecosystem Innovation Fund(22HHXBSS00008).
文摘The post-transcriptional regulation of mRNA is a crucial component of gene expression.The disruption of this process has detrimental effects on the normal development and gives rise to various diseases.Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease.Through a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell development.FAM46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific enhancer.We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner.Furthermore,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis.In conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.
文摘The importance and necessity of emulating the federation load during simulating was analyzed firstly.Then,the special federation load emulation tool,federation load simulator (FLS),was designed and implemented,by which all of the vital essential characteristics of a simulation could be tested,e.g.the amount of federates,the joint/resigned speed of federate,the amount of object instances,the registered/deleted speed of instance in one single program,etc..The applications proved that FLS could provide a convenient,effective and adjustable simulation load testing environment during the procedure of run-time infrastructure(RTI)and interrelated tool federates researching,developing and performance testing.Furthermore,the FLS utilized all kinds of resources with high efficiency.
基金supported by the National High Level Hospital Clinical Research Funding[grant number 2022-PUMCH-B-109]the Chinese Academy of Medical Science Innovation Fund for Medical Sciences(CIFMS)[grant number 2021-I2M-1-020].
文摘Background:Septic shock is a life-threatening disease with high mortality rates,and the relevant hub genes and biomarkers are poorly understood.We aimed to identify hub genes and prognostic biomarkers of mRNAs/IncRNAs in septic shock to rapidly and accurately diagnose infection,identify patients at a high risk of developing septic shock,and predict prognosis.Methods:Gene expression profiles of 279 patients with septic shock and 100 healthy controls were analyzed using bioinformatics methods.We screened for differentially expressed genes(DEGs),identified hub genes,and investigated the correlations between mRNA/lncRNA expression and disease severity/prognosis.Protein level validation was performed using blood proteomic data from an independent cohort study.Results:The protein-protein interaction network constructed using upregulated DEGs contained 102 nodes and 222 edges,with LTF,MMP8,MMP9,CEACAM8,CTSG,LCN2,and PRTN3 identified as hub genes.There was a possible association between LCN2 mRNA upregulation and increased severity of septic shock(odds ratio:1.518;95% confidence interval:0.999-2.305;P=0.050),approaching statistical significance,and BCL2A1 mRNA upregulation correlated with higher mortality risk(odds ratio:1.178;95% confidence interval:1.035-1.341;P=0.013).No significant prognostic correlation was observed for lncRNAs.The validation cohort confirmed significant upregulation of MMP9,CTSG,LCN2,LTF,and MMP8 proteins in patients with septic shock,with MMP9,LCN2,CTSG,and LTF exhibiting strong diagnostic performance(area under the curve>0.8).Conclusion:Seven hub genes related to septic shock were identified,including MMP9,LCN2,CTSG,and LTF,which could potentially function as candidate biotargets and biomarkers for the diagnosis and prognostic prediction of septic shock,though further validation is needed.Notably,LCN2 showed a trend toward association with disease severity,while BCL2A1 correlated with mortality risk.
基金funded by the National Natural Science Foundation of China(Nos.82171621 to Lei Li,82271656 to Lan Zhu,82171614 to Na Chen)the National High Level Hospital Clinical Research Funding(No.2022-PUMCH-A-231 to Lei Li)+2 种基金the National Key Research and Development Program of China(Nos.2023YFC2706000,2023YFC2706001,2021YFC2701301 to Lan Zhu,2021YFC2701400 to Shan Deng)Beijing Natural Science Foundation(No.7232125 to Na Chen)CAMS Initiative Fund to Medical Sciences(No.2022-I2M-C&T-B-029 to Na Chen).
文摘Pelvic organ prolapse(POP),whose etiology is influenced by genetic and clinical risk factors,considerably impacts women’s quality of life.However,the genetic underpinnings in non-European populations and comprehensive risk models integrating genetic and clinical factors remain underexplored.This study constructed the first polygenic risk score(PRS)for POP in the Chinese population by utilizing 20 disease-associated variants from the largest existing genome-wide association study.We analyzed a discovery cohort of 576 cases and 623 controls and a validation cohort of 264 cases and 200 controls.Results showed that the case group exhibited a significantly higher PRS than the control group.Moreover,the odds ratio of the top 10%risk group was 2.6 times higher than that of the bottom 10%.A high PRS was significantly correlated with POP occurrence in women older than 50 years old and in those with one or no childbirths.As far as we know,the integrated prediction model,which combined PRS and clinical risk factors,demonstrated better predictive accuracy than other existing PRS models.This combined risk assessment model serves as a robust tool for POP risk prediction and stratification,thereby offering insights into individualized preventive measures and treatment strategies in future clinical practice.
基金supported by the Independent Research Fund of the State Key Laboratory of Complex,Severe,and Rare Diseases(2025-I-PY-010)Beijing Municipal Natural Science Foundation(Z220013)+4 种基金the National Natural Science Foundation of China(82271656,82530054,and 82171621)the National Key R&D Program of China(2023YFC2706001)the National High Level Hospital Clinical Research Funding(2025-PUMCH-C-037 and 2022-PUMCHC-060)CAMS Initiative for Innovative Medicine(2021-I2M-1-004)Barnhart Family Distinguished Professorship from the University of Texas MD Anderson Cancer Center.
文摘Uterine myomas are the most prevalent benign gynecological tumors,affecting over 70%of women[1].They are often associated with significant morbidity,including anemia and infertility.In contrast,uterine sarcomas,although rare,are highly malignant,with a five-year survival rate of 50%-55%in early stages and a stark decline to 8%-12%in advanced stages[2],[3].
基金supported by grants from the National Key R&D Program of China(2023YFC2507102)Special Foundation for Taishan Scholars Program of Shandong Province(No.tsqnz20240855)+3 种基金National High-Level Hospital Clinical Research Funding(2022-PUMCH-A-114)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS2022-I2M-2-001,CIFMS2022-I2M-1-011 and 2022-I2M-CoV19-003)the National Natural Science Foundation of China(82341064 and 82271656)State Key Laboratory Special Fund(2060204).
文摘Dear Editor,Coronavirus disease 2019(COVID-19)is a serious respiratory disease caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Since the emergence of SARS-CoV-2,extensive research has been conducted to develop safe and effective vaccines against COVID-19,including messenger RNA(mRNA),viral vector,inactivated vaccines and protein subunit vaccines.
基金supported by the Ministry of Science and Technology of China(2022YFA0806000)the National Natural Science Foundation of China Grants(32150005)+3 种基金the Clinical Research Operating Fund of Central High level hospitals(2022-PUMCH-E-001)the Medical and Scientific Innovation Project of the Chinese Academy of Medical Sciences(2022-12M-1-004)the Talent Program of the Chinese Academy of Medical Sciences(2022-RC310-10)Research Funds from the Health@InnoHK Program launched by the Innovation Technology Commission of the Hong Kong Special Administrative Region,and STI2030-Major Projects(2022ZD0212900).
文摘Adolescents represent a significant proportion of global psychiatric morbidity,with approximately 10%–20%affected by mental disorders,primarily including major depressive disorder(MDD),bipolar disorder(BD),and schizophrenia(SZ)[1,2].These mental disorders exhibit distinct clinical presentations compared with adult forms,including prominent somatic symptoms in MDD[3],rapid mood cycling in BD[4],and insidious onset in SZ[5].The symptom-based Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition(DSM-5)framework faces challenges in differentiating these mental disorders because of overlapping manifestations and developmental heterogeneity[6],necessitating biologically anchored classification frameworks.
基金supported by Science,Technology&Innovation Project of Xiongan New Area(2023XAGG0069)National Key Research and Development Program of China(2022YFC2703100)+2 种基金National High Level Hospital Clinical Research Funding(2022-PUMCH-D-002)the National Natural Science Foundation of China(824B2011 to Z.W.)National High Level Hospital Clinical Research Funding(2023-PUMCH-E-012).
文摘Hereditary cardiomyopathies and arrhythmias are major contributors to cardiovascular morbidity and mortality.The advent of next-generation sequencing(NGS)has made genetic testing more accessible,which is crucial for precise diagnosis and targeted therapeutic strategies.The aim of this study is to explore the landscape of genetic variants,the relationship between specific variants and clinical phenotypes,and the impact on clinical decision-making in China.A total of 1536 probands(median age,37 years;1025 males[66.7%])with suspected hereditary cardiomyopathy or arrhythmia(covering 15 clinical phenotypes)are recruited from 146 hospitals across 30 provinces and cities in China.Positive results are confirmed in 390 of 1536 probands,leading to a diagnostic yield of 25.4%.Forty-two and three-tenths percent(n=169)of family members carry the same variants as positive probands.Hypertrophic cardiomyopathy(HCM)and dilated cardiomyopathy(DCM)are the predominant phenotypes,with MYBPC3 variants having the highest frequency in HCM and TTN variants in DCM.In 76.9%of the positive probands,the identified variants are helpful in clinical management,family screening,and fertility.This large-scale study provides significant insights into the genetic landscape of hereditary cardiomyopathies and arrhythmias in China.
基金supported by the State Key Laboratory for Complex,Severe and Rare Diseases in Peking Union Medical College Hospital。
文摘This commentary summarized the most important findings in the first half 2023 year based on Society of Gynecologic Oncology(SGO)annual meeting and publications in crucial journals.This commentary provided a comprehensive overview of notable developments in the field of gynecologic oncology throughout the first half of 2023,drawing insights from the Society of Gynecologic Oncology(SGO)Annual Meet-ing and pivotal publications in esteemed journals.The discourse delved into the forefront of molecular mechanisms,emphasizing critical themes such as homologous recombination repair deficiency,mismatch repair,immune check-point blockades,and anti-angiogenesis in various cancers.Specific attention was given to advancements in targeted and immunotherapeutic modalities,notably examining the efficacy and safety profiles of poly(ADP-Ribose)poly-merase inhibitors(PARPi)in ovarian cancer.Conclusively,the commentary underscored the transformative impact of molecularly guided therapies,marking them as pivotal in addressing refractory conditions and set the stage for heightened expectations in future advancements.PARP inhibitors have become the standard maintenance treatment for ovarian cancer.Among the first six articles,two(SOLO1 and PAOLA-1)summarized evidence supporting the improvement of overall survival with PARP inhibitors in maintenance therapy,while the NOVA study reported no benefit in overall survival.The first,fourth,and sixth arti-cles discussed the feasibility of PARP inhibitors,immune checkpoint inhibitors used alone or in combination in neo-adjuvant therapy(post-chemotherapy surgery).The latter two articles focused on the application of PD-1(immune checkpoint inhibitors)in locally advanced cervical cancer,demonstrating enhanced efficacy.Currently,immune checkpoint inhibitors are commonly used in advanced cervical and endometrial cancers due to their status as hot tumors.Their use,either alone or in combination with anti-angiogenic drugs,has shown better outcomes in recur-rent and advanced refractory endometrial and cervical cancers compared to traditional chemotherapy.A study from Huashan Hospital discussed the effectiveness of immune checkpoint inhibitors combined with anti-angiogenic therapy in recurrent cervical cancer,although there might be a typo as the initial mention was about endometrial cancer.The following article discussed late-stage endometrial cancer,finding no difference in survival between chem-otherapy and chemotherapy combined with radiation.Subsequent articles highlighted the superiority of immune checkpoint inhibitors combined with chemotherapy in treating recurrent endometrial cancer,as well as the efficacy of immune checkpoint inhibitors combined with anti-angiogenic therapy in endometrial cancer.The final article focused on the therapeutic effect of HER2-positive ADC class drugs in uterine cancer sarcoma.
基金supported by the grants from National Major Science and Technology Projects of China(NO.2008ZX10001-010)EU Research and Innovation(NO.China-HIV-Vac III).
文摘Developing a safe and effective vaccine remains a global priority for ending the human immunodeficiency virus(HIV)pandemic.All HIV vaccine trials with protein,DNA,non-replication vector or their combinations failed in the past.We constructed the HIV-1 CN54 env,gag,and pol genes into both DNA and replicating vaccinia virus Tiantan vectors.In phase Ia,12 healthy adults were given high(n=6)or low(n=6)doses of recombinant vaccinia virus Tiantan vaccine(rTV),to test its safety dose.In phase Ib,36 healthy adults were assigned to the DNA(n=6),DNA-L/rTV(n=12),DNA-H/rTV(n=12),and placebo(n=6)groups.The DNA vaccine was injected intramuscularly at weeks 0,4,and 8 and rTV with a bifurcated needle at week 12.All vaccines tested were safe and well-tolerated;most of the adverse events(AEs)were mild to moderate.The most commonly observed AEs were redness and papule at rTV vaccination sites and axillary enlarged lymph nodes at the same rTV vaccination arm.Smaller cutaneous lesions and shorter healing time were observed in smallpox vaccine experienced subjects.
基金supported by the National Key Research and Development Program of China(2022YFC2703900)the CAMS Innovation Fund for Medical Sciences(2021-I2M-1018)+1 种基金the National Natural Science Foundation of China(82394420 and 82394423)the Theranostics and Translational Research Facility of National Infrastructures for Translational Medicine,Institute of Clinical Medicine,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College for the support。
文摘Dear Editor,Neurodevelopmental disorders(NDD)are a group of diseases with high phenotypic heterogeneity characterized by inability in cognition,communication,psychological skills,and motor development.The common types of NDDs include autism spectrum disorder(ASD),attention-deficit/hyperactivity disorder(ADHD),epilepsy,schizophrenia,etc.(Parenti et al.,2020).
基金supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project(grant numbers 2024ZD0525502/2024ZD0525500)the National High Level Hospital Clinical Research Funding(grant number 2022-PUMCH-D-001)CAMS Innovation Fund for Medical Sciences(CIFMS)(grant numbers 2021-I2M-1-002,2023-I2M-2-002)to W.W.
文摘Pancreatic cancer cachexia is a complex,multifactorial syndrome characterized by progressive wasting of skeletal muscle and adipose tissue,contributing to poor prognosis and high mortality in pancreatic cancer patients.While muscle and fat loss are the hallmark features,pancreatic cancer cachexia is increasingly recognized as a systemic disorder involving extensive metabolic and inflammatory disruptions across multiple organs.Tumor-derived cachexia-inducing factors play a central role in driving systemic inflammation,metabolic dysregulation,and neuroendocrine abnormalities,leading to anorexia,gut dysbiosis,cardiac dysfunction,and pancreatic exocrine and endocrine insufficiency.These multi-organ disturbances form a vicious cycle that accelerates disease progression and complicates clinical management.In this review,we provide a comprehensive overview of pancreatic cancer cachexia,including its definitions,classification,and heterogeneous clinical presentations.We further examine recent findings on the molecular mediators of cachexia and their role in inter-organ communication networks.Additionally,we highlight advances in experimental models that enable the dissection of pancreatic cancer cachexia pathophysiology,and discuss emerging mechanism-based therapeutic strategies aimed at disrupting the cachexia cycle.A deeper understanding of the systemic nature of pancreatic cancer cachexia and the crosstalk among affected organs may inform the development of multi-targeted interventions and hold promise for improving patient outcomes.
基金funded by National Key R&D Program of China(2022YFA1303003,2018YFA0800701,2018YFA0507603,and 2018YFA0800501)National Natural Science Foundation of China(81770376,81630008,81790621,31521062,31671177,and 81370234).
文摘Emerging evidence suggests that priming intestinal stem cells(ISCs)towards secretory progenitor cells is beneficial for maintaining gut homeostasis against inflammatory bowel disease(IBD).However,the mechanism driving such biased lineage commitment remains elusive.Here we show that MG53,also named as TRIM72,prompts ISCs to secretory lineages via upregulating peroxisome proliferator-activated receptorα(PPARα),thus maintaining intestinal epithelium integrity against noxious insults.Using genetic mouse models,we found that MG53 deficiency leads to exacerbated intestinal damage caused by various injuries in mice,whereas MG53 overexpression in ISCs is sufficient to ameliorate such damage.Mechanistically,MG53 promoted asymmetric division of ISCs to generate more progenitor cells of secretory lineages via activating PPARαsignaling.Specifically,MG53 overexpression induced PPARαexpression at transcriptional level and concomitantly increased PPARαactivity by elevating the contents of a panel of unsaturated fatty acids in the intestine that serve as potent endogenous agonists of PPARα.Furthermore,genetic ablation or pharmacological inhibition of PPARαabolished the protective effects of MG53.These findings reveal a crucial role of MG53-PPARαaxis in driving the secretory lineage commitment of ISCs,especially during injury response,highlighting the important therapeutic potential of targeting MG53-PPARαsignaling for IBD treatment and marking PPARαagonists as novel therapies for IBD caused by various etiologies.
基金the National Key R&D Program of China Grants 2022YFA1103103 and 2023YFA1800302the National Natural Science Foundation of China(NSFC)Grants 32270784 and 31970819 to J.N。
文摘Dear Editor,Due to the inaccessibility of early human embryos,little is known about the chromatin status during early human endothelial cell(EC)development.Despite studies showing the epigenomic landscape of primary EC lines or human pluripotent stem cell(hPSC)-derived ECs,the epigenetic dynamic and feature of intermediate progenitors,such as vascular mesoderm cells(VMCs)and endothelial progenitor cells(EPCs),are less known.Therefore,an epigenomic roadmap of human EC development may provide new knowledge about nascent EC formation.
基金supported by grants from the National Key Research and Development Program of China(2023YFA1800600)the Natural Science Foundation of China(31988101,92354306)+2 种基金the Beijing Science and Technology Plan(Z231100007223006)the Shenzhen Medical Research Fund(B2302022)the Natural Science Foundation of Jiangxi Province(20224 ACB209001).
文摘Intestinal homeostasis is sustained by self-renewal of intestinal stem cells(ISCs),which continuously divide and produce proliferative transit-amplifying(TA)and then progenitor cells.Eukaryotic translation initiation factor 5A(eIF5A),a conserved translation factor,involves in a variety of cellular processes,yet its role in intestinal homeostasis remains unclear.Here,we demonstrate that eIF5A is indispensable for maintaining intestinal epithelial homeostasis.Conditional knockout of Eif5a in the adult mouse intestinal epithelium leads to stem cell loss,suppressed cell proliferation,and increased apoptosis within the crypts,concurrent with shortened gut length,reduced mouse body weight and rapid animal mortality.Consistently,Eif5a deletion in intestinal organoids also exhibits resembling cellular phenotypes.Mass spectrometry analysis reveals a significant downregulation of mitochondrial proteins,particularly those involved in mitochondrial translation,upon eIF5A depletion.Analysis of a published single-cell RNA sequencing dataset shows that mitochondrial translation-related genes,including Dars2,are highly expressed in ISC,TA and progenitor cells.Furthermore,eIF5A-deficient organoids exhibit impaired mitochondrial function,characterized by reduced ATP levels and increased reactive oxygen species(ROS).These findings highlight a critical role for eIF5A in sustaining intestinal epithelial homeostasis by regulating mitochondrial translation,providing a new insight into the molecular mechanism underlying intestinal stem cell renewal and tissue maintenance.
基金supported by the National Natural Science Foundation of China(82171620 and 81830043)the National Key R&D Program of China(2021YFC2701403 and 2018YFC2002201)the National High Level Hospital Clinical Research Funding(2022-PUMCH-A-205 and 2022-PUMCH-A-114)。
基金supported by the National Natural Science Foundation of China(NSFC)(Nos.82001221 and 81788101)the National Key Research and Development Program of China(Nos.2022YFC2703900 and 2022YFC2703903)the CAMS Innovation Fund for Medical Sciences(CIFMS)(Nos.2021-I2M-1-018,2022-I2M-JB-004 and 2017-I2M-B&R-05).
文摘Highly clinical and genetic heterogeneity of neurodevelopmental disorders presents a major challenge in clinical genetics and medicine.Panoramic variation analysis is imperative to analyze the disease phenotypes resulting from multilocus genomic variation.Here,a Pakistani family with parental consanguinity was presented,characterized with severe intellectual disability(ID),spastic paraplegia,and deafness.Homozygosity mapping,integrated single nucleotide polymorphism(SNP)array,whole-exome sequencing,and whole-genome sequencing were performed,and homozygous variants in TMEM141(c.270G>A,p.Trp90^(*)),DDHD2(c.411+767_c.1249-327del),and LHFPL5(c.250delC,p.Leu84^(*))were identified.A Tmem141^(p.Trp90^(*)/p.Trp90^(*))mouse model was generated.Behavioral studies showed impairments in learning ability and motor coordination.Brain slice electrophysiology and Golgi staining demonstrated deficient synaptic plasticity in hippocampal neurons and abnormal dendritic branching in cerebellar Purkinje cells.Transmission electron microscopy showed abnormal mitochondrial morphology.Furthermore,studies on a human in vitro neuronal model(SH-SY5Y cells)with stable shRNA-mediated knockdown of TMEM141 showed deleterious effect on bioenergetic function,possibly explaining the pathogenesis of replicated phenotypes in the cross-species mouse model.Conclusively,panoramic variation analysis revealed that multilocus genomic variations of TMEM141,DDHD2,and LHFPL5 together caused variable phenotypes in patient.Notably,the biallelic loss-of-function variants of TMEM141 were responsible for syndromic ID.
基金funding from the National Science Foundation of China(31930016)the Peking-Tsinghua Center for Life Sciences+4 种基金ZW received funding from the State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases(2024KF00001)the National Science Foundation of China(82350119)CCW received funding from the Talent Introduction Funds from the Chinese Academy of Medical Science(2022-RC310-10)the National Science Foundation of China(32150005)the Research Funds from Health@InnoHK Program,launched by the Innovation Technology Commission of the Hong Kong Special Administrative Region.
文摘Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites.In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells,we performed a comprehensive genome-scale CRISPR screening of cancer cells.We found that four molecules belonging to the butyrophilin(BTN)family,specifically BTN2A1,BTN3A1,BTN3A2,and BTN3A3,are critically important and play unique,nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells.The coordinated function of these BTN molecules was driven by synchronized gene expression,which was regulated by IFN-γsignaling and the RFX complex.Additionally,an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells.Through our research,we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells.Moreover,our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.
