BACKGROUND MicroRNAs play a key role in regulating gene expression in human cells.Singlenucleotide variants in these molecules have been linked to cancer development,particularly breast cancer(BrC).AIM To analyze the ...BACKGROUND MicroRNAs play a key role in regulating gene expression in human cells.Singlenucleotide variants in these molecules have been linked to cancer development,particularly breast cancer(BrC).AIM To analyze the association of three microRNA polymorphisms with the risk of BrC in women from western Mexico.METHODS This case-control study included 71 women diagnosed with BrC and 215 women without BrC.Genotypes were determined using a real-time polymerase chain reaction allelic discrimination assay.Multiple genetic models-dominant,recessive,over-dominant,additive,and multiple comparison-were applied to assess the risk.RESULTS The over-dominant model showed that the C/T genotype of MIR196A2(rs11614913)is a protective factor against the ductal histological subtype of BrC in women from western Mexico[odds ratio(OR)=0.4687,95%confidence interval(CI):0.2205-0.9963,P=0.0489].A protective effect was also observed for the C/A genotype(OR=0.2612,95%CI:0.0900-0.7582,P=0.0135)and A allele(OR=0.2826,95%CI:0.0993-0.8044,P=0.0179)of MIR618(rs2682818).No significant association was found between MIR200C(rs73262897)and BrC risk.CONCLUSION The C/T genotype of rs11614913 in MIR196A2,and C/A genotype and A allele of rs2682818 in MIR618,are associated with a protective effect against BrC in women from western Mexico.展开更多
BACKGROUND The evolutionary mutational changes of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)since its emergence in Chhattisgarh,India in 2020 have warranted the need for the characterization of every ...BACKGROUND The evolutionary mutational changes of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)since its emergence in Chhattisgarh,India in 2020 have warranted the need for the characterization of every lineage/sublineage that has evolved until February 2024.AIM To unravel the evolutionary pathway of SARS-CoV-2 in Chhattisgarh from 2020 to February 2024.METHODS A total of 635 coronavirus disease 2019 cases obtained between 2020 and February 2024 were investigated by whole genome sequencing.RESULTS Whole genome sequencing analysis identified the evolution of SARS-CoV-2 into seventeen lineages from 2020 to 2024.SARS-CoV-2 initially emerged in Chhattisgarh in its Alpha(B.1.1.7)variant in 2020.Thereafter,it continuously underwent periodical mutational changes in the spike gene to further differentiate into various lineages/sublineages,viz.,Kappa,Delta,BA.1,and BA.2 in 2021;the Omicron lineage(BA.5,BA.2.12.1,BA.2.75,BQ.1,and XBB)in 2022;the new Omicron lineage(XBB.1.5,XBB.1.16,XBB.1.9.1,and XBB.2.3)in 2023;and finally to JN.1 in January and February 2024.The predominant lineages over these 4 years were BA.1.1.7(Alpha)in 2020,B.1.617.2(Delta)in the period between 2021 and mid-2022,B.1.1.529(Omicron)in late 2022 to 2023,and Omicron-JN.1 in early 2024.The presently circulating JN.1 lineage was observed harboring exclusive predominant mutations of E4554K,A570V,P621A,and P1143 L with 99%CONCLUSION SARS-CoV-2 from 2020 to 2024 has evolved into 17 lineages/sublineages in Chhattisgarh.The presently circulating JN.1 harbored 40 mutations,especially E554K,A570V,P621S,and P1143 L,capacitating the virus with features of host cell entry,stability,replication,rapid transmissibility,and crucial immune evasion.Therefore,earlier immunity from either vaccination or prior infection may not protect against the current lineage and increases the possibility of future outbreaks.Thus,the periodical genomic surveillance of SARS-CoV-2 is essential for the genomic blueprint of the circulating virus,which may help in updating the vaccine strain and various basic research for developing appropriate therapeutics and diagnostics.展开更多
The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findin...The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.展开更多
Background:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks.The pathogenicity of these variants evolves under immune press...Background:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks.The pathogenicity of these variants evolves under immune pressure and host factors.Understanding these changes is crucial for epidemic control and variant research.Methods:Human angiotensin-converting enzyme 2(hACE2)transgenic mice were in-tranasally challenged with the original strain WH-09 and the variants Delta,Beta,and Omicron BA.1,while BALB/c mice were challenged with Omicron subvariants BA.5,BF.7,and XBB.1.To compare the pathogenicity differences among variants,we con-ducted a comprehensive analysis that included clinical symptom observation,meas-urement of viral loads in the trachea and lungs,evaluation of pulmonary pathology,analysis of immune cell infiltration,and quantification of cytokine levels.Results:In hACE2 mice,the Beta variant caused significant weight loss,severe lung inflammation,increased inflammatory and chemotactic factor secretion,greater mac-rophage and neutrophil infiltration in the lungs,and higher viral loads with prolonged shedding duration.In contrast,BA.1 showed a significant reduction in pathogenicity.The BA.5,BF.7,and XBB.1 variants were less pathogenic than the WH-09,Beta,and Delta variants when infected in BALB/c mice.This was evidenced by reduced weight loss,diminished pulmonary pathology,decreased secretion of inflammatory factors and chemokines,reduced macrophage and neutrophil infiltration,as well as lower viral loads in both the trachea and lungs.Conclusion:In hACE2 mice,the Omicron variant demonstrated the lowest pathogenic-ity,while the Beta variant exhibited the highest.Pathogenicity of the Delta variant was comparable to the original WH-09 strain.Among BALB/c mice,Omicron subvari-ants BA.5,BF.7,and XBB.1 showed no statistically significant differences in virulence.展开更多
Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation a...Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.展开更多
On November 26,2021,a novel lineage (B.1.1.529) was categorized as the fifth virus of concern (VOC) and named Omicron by World Health Organization (WHO).Patients infected with COVID-19 Omicron variant are reported to ...On November 26,2021,a novel lineage (B.1.1.529) was categorized as the fifth virus of concern (VOC) and named Omicron by World Health Organization (WHO).Patients infected with COVID-19 Omicron variant are reported to have higher transmissibility,lower severity and mortality than those with previous subvariants.In terms of virulence,the Omicron subvariant is weaker than previous strains,with symptoms mostly being fever,running nose and other symptoms mainly seen in upper respiratory tract infections.However,the clinical characteristics of medical staff infected with Omicron variants have rarely been reported before.We conducted a survey in five centers and summarized these profiles to explore the clinical characteristics.展开更多
ObjectivesThe PTPRQ gene is essential for preserving the structure and function of stereocilia in inner ear.However,research on splicing mutations within this gene is limited.This study aims to investigate novel splic...ObjectivesThe PTPRQ gene is essential for preserving the structure and function of stereocilia in inner ear.However,research on splicing mutations within this gene is limited.This study aims to investigate novel splicing mutations in PTPRQ,clarify their molecular mechanisms,and provide new insights into the genetic factors associated with hearing loss,ultimately enhancing diagnostic accuracy.MethodClinical data and peripheral blood samples were obtained from members of a family with congenital hearing loss.Variants were identified through high-throughput sequencing and confirmed by Sanger sequencing to ensure genealogical co-segregation.The splicing effects of PTPRQ variants were evaluated using bioinformatics tools and minigene assays.ResultsWe used whole exome sequencing to identify novel double compound heterozygous splice-altering variants(c.5426+1 G>A and c.6603-3 T>G)in the PTPRQ gene with DFNB84A.We molecularly characterized these variants,and they were found to co-segregate with the disease within the family.Minigene assays and Sanger sequencing confirmed that the c.6603-3 T>G variant caused exon 43 skipping,resulting in a frameshift mutation(p.Ser2201ArgfsTer112).Further bioinformatic analysis supported these findings.ConclusionsThis study identifies a novel compound heterozygous splicing variant in the PTPRQ gene in a Chinese family with DFNB84A,expanding the known spectrum of PTPRQ mutations.These findings enhance the understanding of PTPRQ-related hearing loss and may aid in early diagnosis,prevention,and therapeutic strategies.展开更多
The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KC...The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear.In this study,a large-scale cohort comprising 1135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival(OS).Based on the survival evaluation of all five KCNQ family genes,KCNQ1 was selected for subsequent genetic analysis.In both Cox regression model and stepwise Cox regression model used to evaluate survival-related genetic variants,we found that KCNQ1 rs10832417G>T was associated with an increased OS in gastric cancer patients(adjusted hazards ratio[HR]=0.84,95%confidence interval[CI]:0.72–0.98,P=0.023).Subsequently,a nomogram was constructed to enhance the prognostic capacity and clinical translation of rs10832417 variants.The rs10832417 T allele was predicted to increase the minimum free energy of the secondary structure.Furthermore,we observed that gastric cancer patients with downregulated KCNQ1expression had a poorer survival across multiple public datasets.The findings of the present study indicate that KCNQ1 rs10832417 may serve as an independent prognostic predictor of gastric cancer,providing novel insights into the progression and survival of the disease.展开更多
Although variant selection during the phase transformation of zirconium(Zr)alloys has been studied extensively,studies on the formation mechanism of microstructural characteristics related to a variant selection remai...Although variant selection during the phase transformation of zirconium(Zr)alloys has been studied extensively,studies on the formation mechanism of microstructural characteristics related to a variant selection remain limited.The formation mechanisms of the self-accommodation morphology and inter-variant boundary characteristics of a variants in homogenized Zr-2.5Nb alloy cooled by water quenching(WQ),furnace cooling(FC),and air cooling(AC)were systematically investigated from the perspective of local strain during phase transformation.The a variants exhibited triangular morphologies in both the WQ and AC samples,and a colony morphology in the FC sample.Further,there were five types of inter-variant boundaries:TypeI<0001>/10.53°,Typell<1120>/60°,Type Ill<1.377 I 2.3770.359>/60.83°,Type IV<10553>/63.26°,and Type V<12.381.380>/90°.The proportion of Type ll is up to 98%in the AC sample and 57.9%in the WQ sample;the Type I was very low in all three samples;and a high proportion of the Type V was observed in the FC sample(23.6%).The self-accommodation morphology of a variants is closely related to the equivalent strain(Evm)during the variant selection.Theoretical calculations indicated that,for a specific 2-variant combinations,there were always one or more 3-variant combinations with a lower Evm than the 2-variant combinations.A lower eym contributes to the presence of 3-variant combinations,which forms a triangle morphology.The formation of inter-variant boundaries is determined by the type and frequency of variants as well as the eym of the 2-variant combinations.The order of the mean values of evm for the five types of boundaries was Type II(0.0757),Type III(0.0859),Type IV(0.1012),Type V(0.1112),and Type I(0.1307).That is,Type II is the easiest and Type I is the most difficult,which resulted in a very high fraction of Type ll and a very low fraction of Type I in the WQ,AC,and FC samples.The presence of a high fraction of Type V in the FC sample was related to the type and fraction of each variant.展开更多
Objective Patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection frequently develop central nervous system damage,yet the mechanisms driving this pathology remain unclear.This study investi...Objective Patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection frequently develop central nervous system damage,yet the mechanisms driving this pathology remain unclear.This study investigated the primary pathways and key factors underlying brain tissue damage induced by the SARS-CoV-2 beta variant(lineage B.1.351).Methods K18-hACE2 and C57BL/6 mice were intranasally infected with the SARS-CoV-2 beta variant.Viral replication,pathological phenotypes,and brain transcriptomes were analyzed.Gene Ontology(GO)analysis was performed to identify altered pathways.Expression changes of host genes were verified using reverse transcription-quantitative polymerase chain reaction and Western blot.Results Pathological alterations were observed in the lungs of both mouse strains.However,only K18-hACE2 mice exhibited elevated viral RNA loads and infectious titers in the brain at 3 days post-infection,accompanied by neuropathological injury and weight loss.GO analysis of infected K18-hACE2 brain tissue revealed significant dysregulation of genes associated with innate immunity and antiviral defense responses,including type I interferons,pro-inflammatory cytokines,Toll-like receptor signaling components,and interferon-stimulated genes.Neuroinflammation was evident,alongside activation of apoptotic and pyroptotic pathways.Furthermore,altered neural cell marker expression suggested viral-induced neuroglial activation,resulting in caspase 4 and lipocalin 2 release and disruption of neuronal molecular networks.Conclusion These findings elucidate mechanisms of neuropathogenicity associated with the SARS-CoV-2 beta variant and highlight therapeutic targets to mitigate COVID-19-related neurological dysfunction.展开更多
Somatic variants in the cancer genome influence gene expression through diverse mechanisms depending on their specific locations.However,a systematic evaluation of the effects of somatic variants located in 3'untr...Somatic variants in the cancer genome influence gene expression through diverse mechanisms depending on their specific locations.However,a systematic evaluation of the effects of somatic variants located in 3'untranslated regions(3'UTRs)on alternative polyadenylation(APA)of m RNA remains lacking.In this study,we analyze 10,199 tumor samples across 32 cancer types and identify 1333 somatic single nucleotide variants(SNVs)associated with abnormal 3'UTR APA.Mechanistically,these 3'UTR SNVs can alter cisregulatory elements,such as the poly(A)signal and UGUA motif,leading to changes in APA.Minigene assays confirm that 3'UTR SNVs in multiple genes,including RPS23 and CHTOP,induce aberrant APA.Among affected genes,62 exhibit differential stability between tandem 3'UTR isoforms,including HSPA4and UCK2,validated by experimental assays.Finally,we establish that SNV-related abnormal APA usage serves as an additional layer of expression regulation for tumor-suppressor gene HMGN2 in breast cancer.Collectively,this study reveals 3'UTR APA as a critical mechanism mediating the functional impact of somatic noncoding variants in human cancers.展开更多
Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains...Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.展开更多
Nonobstructive azoospermia(NOA),one of the most severe types of male infertility,etiology often remains unclear in most cases.Therefore,this study aimed to detect four biallelic detrimental variants(0.5%)in the minich...Nonobstructive azoospermia(NOA),one of the most severe types of male infertility,etiology often remains unclear in most cases.Therefore,this study aimed to detect four biallelic detrimental variants(0.5%)in the minichromosome maintenance domain containing 2(MCMDC2)genes in 768 NOA patients by whole-exome sequencing(WES).Hematoxylin and eosin(H&E)demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients(c.1360G>T,c.1956G>T,and c.685C>T)and hypospermatogenesis in one patient(c.94G>T),as further confirmed through immunofluorescence(IF)staining.The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis.The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses.The results revealed four MCMDC2 variants related to NOA,which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.展开更多
The selection of twin variants plays a critical role in shaping the deformation texture and mechanical properties of magnesium alloys that are limited by slip systems and diverse twinning modes.In this study,we invest...The selection of twin variants plays a critical role in shaping the deformation texture and mechanical properties of magnesium alloys that are limited by slip systems and diverse twinning modes.In this study,we investigated the twin variant selection and the effect of twinning activity on the strain hardening of a hot-rolled AZ31 magnesium alloy by quasi-in-situ EBSD.Moreover,the Schmid factors and the displacement gradient tensors were computed to evaluate the activation of twin variants.The results reveal that the yield strength increased progressively after each deformation step,driven by grain subdivision and texture hardening induced by extension{1012}twinning and the Basinski effect at large strains.The nucleation and growth of the{1012}twins occurred either sequentially or simultaneously during the plastic deformation.At low plastic strains,the activation of most twin variants followed the high Schmid factor criterion while the other twin variants with lower Schmid factors were activated due to the interactions with preexisting twins characterized by high misorientation angles(around 60°).Additionally,this non-Schmid factor scenario was also attributed to low coordinated strain requirements from neighboring grains,showing the critical role of local deformation accommodation in the twinning process.These findings advance the fundamental understanding of the twin variant selection and its implications for the microstructure-property relationship in magnesium alloys for structural applications.展开更多
Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous famil...Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing.The affected individuals present with global developmental delay,intellectual disability,and dysmorphisms.To assess the pathogenicity of the variants,functional studies are performed in Drosophila and patient-derived cells.The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system(CNS).Loss of med16 leads to a reduction in eclosion and lifespan,as well as impaired synaptic transmission.In neurons differentiated from the patient-derived induced pluripotent stem cells(iPSCs),the neurite outgrowth is impaired and rescued by expression of exogenous MED16.The patient-associated variants behave as loss-of-function(LoF)alleles in flies and iPSCs.Additionally,the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls.In summary,our findings support that MED16 is important for appropriate development and function,and that biallelic MED16 variants cause a neurodevelopmental disease.展开更多
AIM:To analyze the pathogenicity and clinical features of patients in a consanguineous cone-rod dystrophy(CRD)family due to heterozygous variants in the GUCY2D gene.METHODS:Whole exome sequencing was used to screen fo...AIM:To analyze the pathogenicity and clinical features of patients in a consanguineous cone-rod dystrophy(CRD)family due to heterozygous variants in the GUCY2D gene.METHODS:Whole exome sequencing was used to screen for pathogenic genes and candidate pathogenic variants were obtained by bioinformatics analysis.Sanger sequencing was used for validation and familial cosegregation analysis to determine pathogenic variants.Pymol software was applied to produce a 3D structure image of the protein to analyze the structural and functional alterations of the protein.The pathogenicity of genetic variants was evaluated according to ACMG guidelines.RESULTS:The chief clinical symptoms of this proband included obvious visual impairment,protanopia and deuteranopia,peripheral punctate pigment,arteriolar attenuation,structural and functional abnormalities revealed by optical coherence tomography(OCT)and electroretinography(ERG)including thinning of the outer retinal layer,a discontinuous external limiting membrane(ELM)and ellipsoid zone(EZ),granular hyperreflective projections between the retinal pigment epithelium and the interdigitation zone,severe attenuation of photopic responses with mild reduced scotopic responses.Wholeexome sequencing revealed that the proband carried a heterozygous variant of the GUCY2D gene:c.2512C>T:p.Arg838Cys.Three-dimensional molecular structure analysis of the protein revealed that amino acid 838 was mutated from polar positively charged arginine to polar uncharged cysteine,and the spatial structure of the protein changed greatly.Sanger sequencing co-segregation analysis confirmed that such a variant was detected in neither the phenotypically normal parents nor the daughter of the proband,which was presumed to be a de novo one.The variant was determined to be pathogenic according to ACMG guidelines.The heterozygous variant at the same site was detected in the abnormal proband’s son with moderate attenuation of photopic electroretinographic responses and normal scotopic electroretinographic responses,supporting autosomal dominant inheritance.CONCLUSION:The de novo variant causing atypical autosomal dominant CRD is identified in a Chinese consanguineous family and this variant passes through this family in an autosomal dominant mode of inheritance,revealing the complex diversity and unpredictability of the inheritance mode for common single-gene genetic disease.展开更多
Dear Editor,Enterovirus 71(EV71)is the main pathogen of hand,foot,and mouth disease(HFMD),which is a serious public health threat,especially in the Asia-Pacific region(Wu et al.,2013).Due to the lack of effective anti...Dear Editor,Enterovirus 71(EV71)is the main pathogen of hand,foot,and mouth disease(HFMD),which is a serious public health threat,especially in the Asia-Pacific region(Wu et al.,2013).Due to the lack of effective antivirals for treatment,supportive therapy remains to be the primary measure for severe infections of EV71.EV71 belongs to the genus Enterovirus in the family of Picornavirridae.EV71 encodes a polyprotein that is proteolytically cleaved into four structural proteins and seven nonstructural proteins,i.e.,VP1 to VP4,2A to 2C,and 3A to 3D.Moreover,an alternative encoding strategy of harboring a novel open reading frame encoding a short peptide has been recently reported in gut epithelial cells infected with some enteroviruses(Lulla et al.,2019).Structural proteins play a key role in the packaging and maturation of virus particles,while non-structural proteins are mainly involved in the replication process of virus.Among them,the 3D polymerase(3Dpol)protein functions as an RNA-dependent RNA polymerase(RdRP)that is essential for viral RNA synthesis(Wu et al.,2010).展开更多
In this study,Ti-6.5Al-3.5Mo-1.5Zr-0.3Si(TC11)titanium alloy samples are fabricated via arc-wire directed energy deposition(AW-DED)and laser powder bed fusion(L-PBF).The variant-selection(VS)mechanism of the𝛼g...In this study,Ti-6.5Al-3.5Mo-1.5Zr-0.3Si(TC11)titanium alloy samples are fabricated via arc-wire directed energy deposition(AW-DED)and laser powder bed fusion(L-PBF).The variant-selection(VS)mechanism of the𝛼grain boundary(α_(GB))and the intragranular microstructure are characterized via electron backscatter diffraction,and the related formation mechanisms are discussed.The continuous α_(GB) maintained Burgers orientation relationships with one of the adjacent lamellas in the AW-DED sample and the adjacent acicular α’laths in the l-PBF sample as much as possible,respectively.For the intragranular microstructure,the VS of the colony and basket-weave microstructures maintained a common{1120}pole with one of their adjacent microstructures in the AW-DED sample.The VS of the acicular α’lath in the intragranular region is maintained as the common{0001}pole and{1120}pole section as much as possible with the adjacent acicular α’lath.Type-2(60°/[1120])bound-aries dominated the colony microstructure and the basket-weave microstructure because of their low cooling rate in the AW-DED sample.By contrast,type-4(63.26°/[10553])boundaries are composed of the acicular α’lath owing to their high cooling rate in the l-PBF sample during deposition.展开更多
Recently,inspired by a modified generalized shift-splitting iteration method for complex symmetric linear systems,we propose two variants of the modified generalized shift-splitting iteration(MGSS)methods for solving ...Recently,inspired by a modified generalized shift-splitting iteration method for complex symmetric linear systems,we propose two variants of the modified generalized shift-splitting iteration(MGSS)methods for solving com-plex symmetric linear systems.One is a parameterized MGSS iteration method and the other is a modified parameterized MGSS iteration method.We prove that the proposed methods are convergent under appropriate constraints on the parameters.In addition,we also give the eigenvalue distributions of differ-ent preconditioned matrices to verify the effectiveness of the preconditioners proposed in this paper.展开更多
Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).Wit...Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).With a prevalence of 3.8/100,000(Barisic et al.,2014),CFM is the second most common congenital craniofacial abnormality(Li et al.,2022;Luo et al.,2023).Most cases are sporadic,but familial ones suggest autosomal dominant(AD)or autosomal recessive(AR)(Beleza-Meireles et al.,2014).In 2023,Quiat et al.and Mao et al.successively identified FOXI3 variants in 16 pedigrees and 10 sporadic cases,respectively,accounting for 3.1%of CFM cases(Mao et al.,2023;Quiat et al.,2023).FOX/3 has surpassed SF3B2 as the most frequently identified pathogenic gene for CFM to date(Timberlake et al.,2021;Mao et al.,2023;Quiat et al.,2023).In this study,we performed whole-exome sequencing(WES)on 201 CFM pedigrees and detected FOX/3 variants in 8 AD-inherited pedigrees with 24 patients and 28 unaffected individuals(Fig.1A).展开更多
基金Supported by Patronage of the Autonomous University of Nayarit,Quality Postgraduate Program with resources from the 15%Special Tax allocated to the UAN 2022.
文摘BACKGROUND MicroRNAs play a key role in regulating gene expression in human cells.Singlenucleotide variants in these molecules have been linked to cancer development,particularly breast cancer(BrC).AIM To analyze the association of three microRNA polymorphisms with the risk of BrC in women from western Mexico.METHODS This case-control study included 71 women diagnosed with BrC and 215 women without BrC.Genotypes were determined using a real-time polymerase chain reaction allelic discrimination assay.Multiple genetic models-dominant,recessive,over-dominant,additive,and multiple comparison-were applied to assess the risk.RESULTS The over-dominant model showed that the C/T genotype of MIR196A2(rs11614913)is a protective factor against the ductal histological subtype of BrC in women from western Mexico[odds ratio(OR)=0.4687,95%confidence interval(CI):0.2205-0.9963,P=0.0489].A protective effect was also observed for the C/A genotype(OR=0.2612,95%CI:0.0900-0.7582,P=0.0135)and A allele(OR=0.2826,95%CI:0.0993-0.8044,P=0.0179)of MIR618(rs2682818).No significant association was found between MIR200C(rs73262897)and BrC risk.CONCLUSION The C/T genotype of rs11614913 in MIR196A2,and C/A genotype and A allele of rs2682818 in MIR618,are associated with a protective effect against BrC in women from western Mexico.
文摘BACKGROUND The evolutionary mutational changes of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)since its emergence in Chhattisgarh,India in 2020 have warranted the need for the characterization of every lineage/sublineage that has evolved until February 2024.AIM To unravel the evolutionary pathway of SARS-CoV-2 in Chhattisgarh from 2020 to February 2024.METHODS A total of 635 coronavirus disease 2019 cases obtained between 2020 and February 2024 were investigated by whole genome sequencing.RESULTS Whole genome sequencing analysis identified the evolution of SARS-CoV-2 into seventeen lineages from 2020 to 2024.SARS-CoV-2 initially emerged in Chhattisgarh in its Alpha(B.1.1.7)variant in 2020.Thereafter,it continuously underwent periodical mutational changes in the spike gene to further differentiate into various lineages/sublineages,viz.,Kappa,Delta,BA.1,and BA.2 in 2021;the Omicron lineage(BA.5,BA.2.12.1,BA.2.75,BQ.1,and XBB)in 2022;the new Omicron lineage(XBB.1.5,XBB.1.16,XBB.1.9.1,and XBB.2.3)in 2023;and finally to JN.1 in January and February 2024.The predominant lineages over these 4 years were BA.1.1.7(Alpha)in 2020,B.1.617.2(Delta)in the period between 2021 and mid-2022,B.1.1.529(Omicron)in late 2022 to 2023,and Omicron-JN.1 in early 2024.The presently circulating JN.1 lineage was observed harboring exclusive predominant mutations of E4554K,A570V,P621A,and P1143 L with 99%CONCLUSION SARS-CoV-2 from 2020 to 2024 has evolved into 17 lineages/sublineages in Chhattisgarh.The presently circulating JN.1 harbored 40 mutations,especially E554K,A570V,P621S,and P1143 L,capacitating the virus with features of host cell entry,stability,replication,rapid transmissibility,and crucial immune evasion.Therefore,earlier immunity from either vaccination or prior infection may not protect against the current lineage and increases the possibility of future outbreaks.Thus,the periodical genomic surveillance of SARS-CoV-2 is essential for the genomic blueprint of the circulating virus,which may help in updating the vaccine strain and various basic research for developing appropriate therapeutics and diagnostics.
文摘The recent study of Ding et al provides valuable insights into the functional implications of novel mitochondrial tRNATrp and tRNASer(AGY)variants in type 2 diabetes mellitus(T2DM).This editorial explores their findings,highlighting the role of mitochondrial dysfunction in the pathogenesis of T2DM.By examining the molecular mechanisms through which these tRNA variants contribute to disease progression,the study introduces new targets for therapeutic strategies.We discuss the broader implications of these results,emphasizing the importance of understanding mitochondrial genetics in addressing T2DM.
基金National Science and Technology Infrastructure of China,Grant/Award Number:National Pathogen Resource Center-NPRC-32National Key Research and Development Program of China,Grant/Award Number:2023YFF0724800CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-035。
文摘Background:New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)continue to drive global epidemics and pose significant health risks.The pathogenicity of these variants evolves under immune pressure and host factors.Understanding these changes is crucial for epidemic control and variant research.Methods:Human angiotensin-converting enzyme 2(hACE2)transgenic mice were in-tranasally challenged with the original strain WH-09 and the variants Delta,Beta,and Omicron BA.1,while BALB/c mice were challenged with Omicron subvariants BA.5,BF.7,and XBB.1.To compare the pathogenicity differences among variants,we con-ducted a comprehensive analysis that included clinical symptom observation,meas-urement of viral loads in the trachea and lungs,evaluation of pulmonary pathology,analysis of immune cell infiltration,and quantification of cytokine levels.Results:In hACE2 mice,the Beta variant caused significant weight loss,severe lung inflammation,increased inflammatory and chemotactic factor secretion,greater mac-rophage and neutrophil infiltration in the lungs,and higher viral loads with prolonged shedding duration.In contrast,BA.1 showed a significant reduction in pathogenicity.The BA.5,BF.7,and XBB.1 variants were less pathogenic than the WH-09,Beta,and Delta variants when infected in BALB/c mice.This was evidenced by reduced weight loss,diminished pulmonary pathology,decreased secretion of inflammatory factors and chemokines,reduced macrophage and neutrophil infiltration,as well as lower viral loads in both the trachea and lungs.Conclusion:In hACE2 mice,the Omicron variant demonstrated the lowest pathogenic-ity,while the Beta variant exhibited the highest.Pathogenicity of the Delta variant was comparable to the original WH-09 strain.Among BALB/c mice,Omicron subvari-ants BA.5,BF.7,and XBB.1 showed no statistically significant differences in virulence.
基金the National Natural Science Foundation of China,GrantNos.82100321 and 82370353.
文摘Congenital heart disease(CHD)is the mnost comman birth defect,with 34%of cases attrib utedto genetic variants.NOTCH1,a multi-domain transmembrane protein,regulates heart developmert bycontrolling the differantiation and migration of myocardial mesoderm cells,and different variants are presentin differnt types of CHD.In this review,we aim to provide a detailed description of NOTCH1 structuraldomains and their functions,highlighting NOTCH1 variants in CHD and the molecular mechanisms throughwhich they contribute to CHD occurrence,NOTCH1 has two main domains,the NOTCH extracellulardomain(NBCD)and the NOTCH intracellular domain(NICD).NECD facilitates ligand binding and NICDformation,while the NICD functions as a transcrip tion factor,forming complexes with co-factors in thenucleus to initiate gene transcription.Amnong the NOTCH1 variants associated with CHD occurrence,most are loss-of-function variants.Moreover,most of the variants are located in theEGF-like domain.Themolecular mechanism behind the NOTCH1 variant-associated CHD occurrence appears to be either due to aloss-of-function or missense variant.In the loss-of-function mutations,NOTCH1 haploinsufficiency is notedand directly reduces theNICD production,causing CHD ocaurrence.In the less common case of missensevariant,only a mild NOTCH1 malfuncticn is observed,but insufficient to directly lead to CHD occurrence.However,when a missense variant is combined with a risk factor,such as exposure to an environmentaltoxin,the cumulative effect can lead to CHD.Understanding the genetic and molecular mechanisms linkingNOTCH1 variants to CHD is crucial for improving clinical management and patient quality of life.
文摘On November 26,2021,a novel lineage (B.1.1.529) was categorized as the fifth virus of concern (VOC) and named Omicron by World Health Organization (WHO).Patients infected with COVID-19 Omicron variant are reported to have higher transmissibility,lower severity and mortality than those with previous subvariants.In terms of virulence,the Omicron subvariant is weaker than previous strains,with symptoms mostly being fever,running nose and other symptoms mainly seen in upper respiratory tract infections.However,the clinical characteristics of medical staff infected with Omicron variants have rarely been reported before.We conducted a survey in five centers and summarized these profiles to explore the clinical characteristics.
基金supported in part by the Natural Science Foundation of Shandong Province(no.ZR2022QH373,ZR2022QH292 and ZR2023MH2474).
文摘ObjectivesThe PTPRQ gene is essential for preserving the structure and function of stereocilia in inner ear.However,research on splicing mutations within this gene is limited.This study aims to investigate novel splicing mutations in PTPRQ,clarify their molecular mechanisms,and provide new insights into the genetic factors associated with hearing loss,ultimately enhancing diagnostic accuracy.MethodClinical data and peripheral blood samples were obtained from members of a family with congenital hearing loss.Variants were identified through high-throughput sequencing and confirmed by Sanger sequencing to ensure genealogical co-segregation.The splicing effects of PTPRQ variants were evaluated using bioinformatics tools and minigene assays.ResultsWe used whole exome sequencing to identify novel double compound heterozygous splice-altering variants(c.5426+1 G>A and c.6603-3 T>G)in the PTPRQ gene with DFNB84A.We molecularly characterized these variants,and they were found to co-segregate with the disease within the family.Minigene assays and Sanger sequencing confirmed that the c.6603-3 T>G variant caused exon 43 skipping,resulting in a frameshift mutation(p.Ser2201ArgfsTer112).Further bioinformatic analysis supported these findings.ConclusionsThis study identifies a novel compound heterozygous splicing variant in the PTPRQ gene in a Chinese family with DFNB84A,expanding the known spectrum of PTPRQ mutations.These findings enhance the understanding of PTPRQ-related hearing loss and may aid in early diagnosis,prevention,and therapeutic strategies.
基金supported by grants from the National Natural Science Foundation of China(Grant No.82273458 to Jinfei Chen)the Start-up Fund for the Recruited Talents of the First Affiliated Hospital of Wenzhou Medical University(Grant No.2021QD025 to Jinfei Chen)。
文摘The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear.In this study,a large-scale cohort comprising 1135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival(OS).Based on the survival evaluation of all five KCNQ family genes,KCNQ1 was selected for subsequent genetic analysis.In both Cox regression model and stepwise Cox regression model used to evaluate survival-related genetic variants,we found that KCNQ1 rs10832417G>T was associated with an increased OS in gastric cancer patients(adjusted hazards ratio[HR]=0.84,95%confidence interval[CI]:0.72–0.98,P=0.023).Subsequently,a nomogram was constructed to enhance the prognostic capacity and clinical translation of rs10832417 variants.The rs10832417 T allele was predicted to increase the minimum free energy of the secondary structure.Furthermore,we observed that gastric cancer patients with downregulated KCNQ1expression had a poorer survival across multiple public datasets.The findings of the present study indicate that KCNQ1 rs10832417 may serve as an independent prognostic predictor of gastric cancer,providing novel insights into the progression and survival of the disease.
基金financially supported by the National Natural Science Foundation of China(No.52275161)the Key Projects of International Science and Technology Cooperation in Shaanxi Province(No.2024GH-ZDXM-01)+2 种基金the Shaanxi Science and Technology Innovation Team(No.2023-CX-TD-50)the Shaanxi Qin Chuangyuan Scientists and Engineers(No.2022KXJ-145)the National Natural Science Foundation of Jiangsu Province of China(No.BK20241873),and Shaanxi Province Science and Technology Department-Shaanxi International Science and Technology Cooperation Base(No.2020GHJD-10).
文摘Although variant selection during the phase transformation of zirconium(Zr)alloys has been studied extensively,studies on the formation mechanism of microstructural characteristics related to a variant selection remain limited.The formation mechanisms of the self-accommodation morphology and inter-variant boundary characteristics of a variants in homogenized Zr-2.5Nb alloy cooled by water quenching(WQ),furnace cooling(FC),and air cooling(AC)were systematically investigated from the perspective of local strain during phase transformation.The a variants exhibited triangular morphologies in both the WQ and AC samples,and a colony morphology in the FC sample.Further,there were five types of inter-variant boundaries:TypeI<0001>/10.53°,Typell<1120>/60°,Type Ill<1.377 I 2.3770.359>/60.83°,Type IV<10553>/63.26°,and Type V<12.381.380>/90°.The proportion of Type ll is up to 98%in the AC sample and 57.9%in the WQ sample;the Type I was very low in all three samples;and a high proportion of the Type V was observed in the FC sample(23.6%).The self-accommodation morphology of a variants is closely related to the equivalent strain(Evm)during the variant selection.Theoretical calculations indicated that,for a specific 2-variant combinations,there were always one or more 3-variant combinations with a lower Evm than the 2-variant combinations.A lower eym contributes to the presence of 3-variant combinations,which forms a triangle morphology.The formation of inter-variant boundaries is determined by the type and frequency of variants as well as the eym of the 2-variant combinations.The order of the mean values of evm for the five types of boundaries was Type II(0.0757),Type III(0.0859),Type IV(0.1012),Type V(0.1112),and Type I(0.1307).That is,Type II is the easiest and Type I is the most difficult,which resulted in a very high fraction of Type ll and a very low fraction of Type I in the WQ,AC,and FC samples.The presence of a high fraction of Type V in the FC sample was related to the type and fraction of each variant.
基金supported by the National Key Research and Development Program of China(2023YFC3041500).
文摘Objective Patients with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection frequently develop central nervous system damage,yet the mechanisms driving this pathology remain unclear.This study investigated the primary pathways and key factors underlying brain tissue damage induced by the SARS-CoV-2 beta variant(lineage B.1.351).Methods K18-hACE2 and C57BL/6 mice were intranasally infected with the SARS-CoV-2 beta variant.Viral replication,pathological phenotypes,and brain transcriptomes were analyzed.Gene Ontology(GO)analysis was performed to identify altered pathways.Expression changes of host genes were verified using reverse transcription-quantitative polymerase chain reaction and Western blot.Results Pathological alterations were observed in the lungs of both mouse strains.However,only K18-hACE2 mice exhibited elevated viral RNA loads and infectious titers in the brain at 3 days post-infection,accompanied by neuropathological injury and weight loss.GO analysis of infected K18-hACE2 brain tissue revealed significant dysregulation of genes associated with innate immunity and antiviral defense responses,including type I interferons,pro-inflammatory cytokines,Toll-like receptor signaling components,and interferon-stimulated genes.Neuroinflammation was evident,alongside activation of apoptotic and pyroptotic pathways.Furthermore,altered neural cell marker expression suggested viral-induced neuroglial activation,resulting in caspase 4 and lipocalin 2 release and disruption of neuronal molecular networks.Conclusion These findings elucidate mechanisms of neuropathogenicity associated with the SARS-CoV-2 beta variant and highlight therapeutic targets to mitigate COVID-19-related neurological dysfunction.
基金financially supported by the National Key R&D Program of China(2023YFC3603300,2021YFA0909300)National Natural Science Foundation of China(92249302,32370592,32400437)China Postdoctoral Science Foundation(BX20230073 and 2023M740709)。
文摘Somatic variants in the cancer genome influence gene expression through diverse mechanisms depending on their specific locations.However,a systematic evaluation of the effects of somatic variants located in 3'untranslated regions(3'UTRs)on alternative polyadenylation(APA)of m RNA remains lacking.In this study,we analyze 10,199 tumor samples across 32 cancer types and identify 1333 somatic single nucleotide variants(SNVs)associated with abnormal 3'UTR APA.Mechanistically,these 3'UTR SNVs can alter cisregulatory elements,such as the poly(A)signal and UGUA motif,leading to changes in APA.Minigene assays confirm that 3'UTR SNVs in multiple genes,including RPS23 and CHTOP,induce aberrant APA.Among affected genes,62 exhibit differential stability between tandem 3'UTR isoforms,including HSPA4and UCK2,validated by experimental assays.Finally,we establish that SNV-related abnormal APA usage serves as an additional layer of expression regulation for tumor-suppressor gene HMGN2 in breast cancer.Collectively,this study reveals 3'UTR APA as a critical mechanism mediating the functional impact of somatic noncoding variants in human cancers.
基金supported by the Medical Science Data Center at Shanghai Medical College of Fudan Universitysupported by grants from National Natural Science Foundation of China (81974229and 82171167 to W.F.,82330049 to W.Z.)+2 种基金Xiamen Municipal Major Project of High-Quality Development of Health and Wellness Technology Program (2024-GZL-GD06 to W.F.)National Key R&D Program of China (2022YFA0806603 to W.F.)Science and Technology Program of Guangzhou,China (2024A04J4924 to C.H.)
文摘Chromodomain helicase DNA binding protein 7(CHD7),an ATP-dependent chromatin remodeler,plays versatile roles in neurodevelopment.However,the functional significance of its ATPase/nucleosome remodeling activity remains incompletely understood.Here,we generate genetically engineered mouse embryonic stem cell lines harboring either an inducible Chd7 knockout or an ATPase-deficient missense variant identified in individuals with CHD7-related disorders.Through in vitro neural induction and differentiation assays combined with mouse brain analyses,we demonstrate that CHD7 enzymatic activity is indispensable for gene regulation and neurite development.Mechanistic studies integrating transcriptomic and epigenomic profiling reveal that CHD7 enzymatic activity is essential for establishing a permissive chromatin landscape at target genes,marked by the open chromatin architecture and active histone modifications.Collectively,our findings underscore the pivotal role of CHD7 enzymatic activity in neurodevelopment and provide critical insights into the pathogenic mechanisms of CHD7 missense variants in human diseases.
基金supported by the National Key Research and Development Program of China(2022YFC2702700)the National Natural Science Foundation of China(No.82171586)+1 种基金Inner Mongolia Academy of Medical Sciences Public Hospital Joint Science and Technology Project(2023GLLH0045)Specific Project of Shanghai Jiao Tong University for“Invigorating Inner Mongolia through Science and Technology”(2022XYJG001-01-19).
文摘Nonobstructive azoospermia(NOA),one of the most severe types of male infertility,etiology often remains unclear in most cases.Therefore,this study aimed to detect four biallelic detrimental variants(0.5%)in the minichromosome maintenance domain containing 2(MCMDC2)genes in 768 NOA patients by whole-exome sequencing(WES).Hematoxylin and eosin(H&E)demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients(c.1360G>T,c.1956G>T,and c.685C>T)and hypospermatogenesis in one patient(c.94G>T),as further confirmed through immunofluorescence(IF)staining.The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis.The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses.The results revealed four MCMDC2 variants related to NOA,which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
文摘The selection of twin variants plays a critical role in shaping the deformation texture and mechanical properties of magnesium alloys that are limited by slip systems and diverse twinning modes.In this study,we investigated the twin variant selection and the effect of twinning activity on the strain hardening of a hot-rolled AZ31 magnesium alloy by quasi-in-situ EBSD.Moreover,the Schmid factors and the displacement gradient tensors were computed to evaluate the activation of twin variants.The results reveal that the yield strength increased progressively after each deformation step,driven by grain subdivision and texture hardening induced by extension{1012}twinning and the Basinski effect at large strains.The nucleation and growth of the{1012}twins occurred either sequentially or simultaneously during the plastic deformation.At low plastic strains,the activation of most twin variants followed the high Schmid factor criterion while the other twin variants with lower Schmid factors were activated due to the interactions with preexisting twins characterized by high misorientation angles(around 60°).Additionally,this non-Schmid factor scenario was also attributed to low coordinated strain requirements from neighboring grains,showing the critical role of local deformation accommodation in the twinning process.These findings advance the fundamental understanding of the twin variant selection and its implications for the microstructure-property relationship in magnesium alloys for structural applications.
基金supported by the National Key R&D Program of China (2020YFA0112500 and 2021YFA1100400)the National Natural Science Foundation of China (32271019 and 12411530079)+6 种基金the Natural Science Foundation of Shanghai Municipality (22ZR1462600)supported by the Natural Science Foundation of Hunan Province, China (2022JJ40206)Ruixin project of Hunan Provincial Maternal and Child Health Care Hospital (2023RX01)supported by the Clinical Research Center Projects for Genetic Birth Defects and Rare Diseases in Hunan Province (2023SK4053)Major Scientific and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province (2019SK1010)supported by the Model Organisms Screening Center of the UDN by U54NS093793 of the NIH (NINDS)supported by the Office of Research Infrastructure Programs of the NIH (awards R24 OD022005 and R24 OD031447).
文摘Mediator Complex Subunit 16(MED16,MIM:604062)is a member of the Mediator complex,which controls many aspects of transcriptional activity in all eukaryotes.Here,we report two individuals from a non-consanguineous family with biallelic variants in MED16 identified by exome sequencing.The affected individuals present with global developmental delay,intellectual disability,and dysmorphisms.To assess the pathogenicity of the variants,functional studies are performed in Drosophila and patient-derived cells.The fly ortholog med16 is expressed in neurons and some glia of the developing central nervous system(CNS).Loss of med16 leads to a reduction in eclosion and lifespan,as well as impaired synaptic transmission.In neurons differentiated from the patient-derived induced pluripotent stem cells(iPSCs),the neurite outgrowth is impaired and rescued by expression of exogenous MED16.The patient-associated variants behave as loss-of-function(LoF)alleles in flies and iPSCs.Additionally,the transcription of genes related to neuronal maturation and function is preferentially altered in patient cells relative to differentiated H9 controls.In summary,our findings support that MED16 is important for appropriate development and function,and that biallelic MED16 variants cause a neurodevelopmental disease.
基金Supported by the National Natural Science Foundation of China(No.82260206)Natural Science Foundation of Ningxia(No.2022AAC03387)+1 种基金Major Achievement Transformation Project of Ningxia Hui Autonomous Region(No.2022CJE09011)the Key Research Development Project of Ningxia Hui Autonomous Region(No.2024BEG02017).
文摘AIM:To analyze the pathogenicity and clinical features of patients in a consanguineous cone-rod dystrophy(CRD)family due to heterozygous variants in the GUCY2D gene.METHODS:Whole exome sequencing was used to screen for pathogenic genes and candidate pathogenic variants were obtained by bioinformatics analysis.Sanger sequencing was used for validation and familial cosegregation analysis to determine pathogenic variants.Pymol software was applied to produce a 3D structure image of the protein to analyze the structural and functional alterations of the protein.The pathogenicity of genetic variants was evaluated according to ACMG guidelines.RESULTS:The chief clinical symptoms of this proband included obvious visual impairment,protanopia and deuteranopia,peripheral punctate pigment,arteriolar attenuation,structural and functional abnormalities revealed by optical coherence tomography(OCT)and electroretinography(ERG)including thinning of the outer retinal layer,a discontinuous external limiting membrane(ELM)and ellipsoid zone(EZ),granular hyperreflective projections between the retinal pigment epithelium and the interdigitation zone,severe attenuation of photopic responses with mild reduced scotopic responses.Wholeexome sequencing revealed that the proband carried a heterozygous variant of the GUCY2D gene:c.2512C>T:p.Arg838Cys.Three-dimensional molecular structure analysis of the protein revealed that amino acid 838 was mutated from polar positively charged arginine to polar uncharged cysteine,and the spatial structure of the protein changed greatly.Sanger sequencing co-segregation analysis confirmed that such a variant was detected in neither the phenotypically normal parents nor the daughter of the proband,which was presumed to be a de novo one.The variant was determined to be pathogenic according to ACMG guidelines.The heterozygous variant at the same site was detected in the abnormal proband’s son with moderate attenuation of photopic electroretinographic responses and normal scotopic electroretinographic responses,supporting autosomal dominant inheritance.CONCLUSION:The de novo variant causing atypical autosomal dominant CRD is identified in a Chinese consanguineous family and this variant passes through this family in an autosomal dominant mode of inheritance,revealing the complex diversity and unpredictability of the inheritance mode for common single-gene genetic disease.
基金supported by Hubei Provincial Natural Science Foundation of China(2025AFB822)National Key Research and Development Program of China(No.2022YFD1800100)National Natural Science Foundation of China(32100110).
文摘Dear Editor,Enterovirus 71(EV71)is the main pathogen of hand,foot,and mouth disease(HFMD),which is a serious public health threat,especially in the Asia-Pacific region(Wu et al.,2013).Due to the lack of effective antivirals for treatment,supportive therapy remains to be the primary measure for severe infections of EV71.EV71 belongs to the genus Enterovirus in the family of Picornavirridae.EV71 encodes a polyprotein that is proteolytically cleaved into four structural proteins and seven nonstructural proteins,i.e.,VP1 to VP4,2A to 2C,and 3A to 3D.Moreover,an alternative encoding strategy of harboring a novel open reading frame encoding a short peptide has been recently reported in gut epithelial cells infected with some enteroviruses(Lulla et al.,2019).Structural proteins play a key role in the packaging and maturation of virus particles,while non-structural proteins are mainly involved in the replication process of virus.Among them,the 3D polymerase(3Dpol)protein functions as an RNA-dependent RNA polymerase(RdRP)that is essential for viral RNA synthesis(Wu et al.,2010).
文摘In this study,Ti-6.5Al-3.5Mo-1.5Zr-0.3Si(TC11)titanium alloy samples are fabricated via arc-wire directed energy deposition(AW-DED)and laser powder bed fusion(L-PBF).The variant-selection(VS)mechanism of the𝛼grain boundary(α_(GB))and the intragranular microstructure are characterized via electron backscatter diffraction,and the related formation mechanisms are discussed.The continuous α_(GB) maintained Burgers orientation relationships with one of the adjacent lamellas in the AW-DED sample and the adjacent acicular α’laths in the l-PBF sample as much as possible,respectively.For the intragranular microstructure,the VS of the colony and basket-weave microstructures maintained a common{1120}pole with one of their adjacent microstructures in the AW-DED sample.The VS of the acicular α’lath in the intragranular region is maintained as the common{0001}pole and{1120}pole section as much as possible with the adjacent acicular α’lath.Type-2(60°/[1120])bound-aries dominated the colony microstructure and the basket-weave microstructure because of their low cooling rate in the AW-DED sample.By contrast,type-4(63.26°/[10553])boundaries are composed of the acicular α’lath owing to their high cooling rate in the l-PBF sample during deposition.
基金supported by the National Natural Science Foundation of China(Grant No.12371378)by the Natural Science Foundation of Fujian Province(Grant Nos.2024J01980,2024J08242).
文摘Recently,inspired by a modified generalized shift-splitting iteration method for complex symmetric linear systems,we propose two variants of the modified generalized shift-splitting iteration(MGSS)methods for solving com-plex symmetric linear systems.One is a parameterized MGSS iteration method and the other is a modified parameterized MGSS iteration method.We prove that the proposed methods are convergent under appropriate constraints on the parameters.In addition,we also give the eigenvalue distributions of differ-ent preconditioned matrices to verify the effectiveness of the preconditioners proposed in this paper.
基金support in this study.This work was supported by the National Natural Science Foundation of China(82271889,82172105)the National Key Research and Development Program of China(2021YFC2701000)Shanghai Natural Science Foundation(23ZR1409400,24ZR1409400).
文摘Craniofacial microsomia(CFM)is a congenital malformation with maxillary and/or mandibular hypoplasia,skin tags,and ear malformations(Luo et al.,2023).Microtia,in its mildest form,can occur alone(Quiat et al.,2023).With a prevalence of 3.8/100,000(Barisic et al.,2014),CFM is the second most common congenital craniofacial abnormality(Li et al.,2022;Luo et al.,2023).Most cases are sporadic,but familial ones suggest autosomal dominant(AD)or autosomal recessive(AR)(Beleza-Meireles et al.,2014).In 2023,Quiat et al.and Mao et al.successively identified FOXI3 variants in 16 pedigrees and 10 sporadic cases,respectively,accounting for 3.1%of CFM cases(Mao et al.,2023;Quiat et al.,2023).FOX/3 has surpassed SF3B2 as the most frequently identified pathogenic gene for CFM to date(Timberlake et al.,2021;Mao et al.,2023;Quiat et al.,2023).In this study,we performed whole-exome sequencing(WES)on 201 CFM pedigrees and detected FOX/3 variants in 8 AD-inherited pedigrees with 24 patients and 28 unaffected individuals(Fig.1A).
