ThePigeon-InspiredOptimization(PIO)algorithmconstitutes ametaheuristic method derived fromthe homing behaviour of pigeons.Initially formulated for three-dimensional path planning in unmanned aerial vehicles(UAVs),the ...ThePigeon-InspiredOptimization(PIO)algorithmconstitutes ametaheuristic method derived fromthe homing behaviour of pigeons.Initially formulated for three-dimensional path planning in unmanned aerial vehicles(UAVs),the algorithmhas attracted considerable academic and industrial interest owing to its effective balance between exploration and exploitation,coupled with advantages in real-time performance and robustness.Nevertheless,as applications have diversified,limitations in convergence precision and a tendency toward premature convergence have become increasingly evident,highlighting a need for improvement.This reviewsystematically outlines the developmental trajectory of the PIO algorithm,with a particular focus on its core applications in UAV navigation,multi-objective formulations,and a spectrum of variantmodels that have emerged in recent years.It offers a structured analysis of the foundational principles underlying the PIO.It conducts a comparative assessment of various performance-enhanced versions,including hybrid models that integrate mechanisms from other optimization paradigms.Additionally,the strengths andweaknesses of distinct PIOvariants are critically examined frommultiple perspectives,including intrinsic algorithmic characteristics,suitability for specific application scenarios,objective function design,and the rigor of the statistical evaluation methodologies employed in empirical studies.Finally,this paper identifies principal challenges within current PIO research and proposes several prospective research directions.Future work should focus on mitigating premature convergence by refining the two-phase search structure and adjusting the exponential decrease of individual numbers during the landmark operator.Enhancing parameter adaptation strategies,potentially using reinforcement learning for dynamic tuning,and advancing theoretical analyses on convergence and complexity are also critical.Further applications should be explored in constrained path planning,Neural Architecture Search(NAS),and other real-worldmulti-objective problems.For Multi-objective PIO(MPIO),key improvements include controlling the growth of the external archive and designing more effective selection mechanisms to maintain convergence efficiency.These efforts are expected to strengthen both the theoretical foundation and practical versatility of PIO and its variants.展开更多
Objective:To investigate the potential link between chromosomal polymorphisms in couples who had a medical history of idiopathic recurrent pregnancy loss.Methods:Cytogenetic investigation was conducted with mitogen(Ph...Objective:To investigate the potential link between chromosomal polymorphisms in couples who had a medical history of idiopathic recurrent pregnancy loss.Methods:Cytogenetic investigation was conducted with mitogen(Phytohemagglutinin-M,Gibco)stimulated blood T lymphocytes by Giemsa trypsin Giemsa banding and Ag-NOR banding on 580 couples with a history of idiopathic recurrent pregnancy loss and 240 couples from the general population.Thirty good chromosomal spreads were captured,karyotyped,and analyzed.The karyotypes were designated using the International System for Human Cytogenomic Nomenclature 2024.Pearson Chi-square test was used to compare the frequency of chromosomal polymorphism variations in the idiopathic recurrent pregnancy loss group with the general population group.Results:A conventional cytogenetic investigation revealed that 45.43%of couples experiencing idiopathic recurrent pregnancy loss presented with various types of chromosomal polymorphic variants,compared to 11.88%in the general population.The overall frequency of these chromosomal polymorphic variants was significantly higher in the idiopathic recurrent pregnancy loss group compared to the general population group(OR 9.97,95%CI 6.99-14.21;P<0.05).Additionally,the prevalence of polymorphic variants was higher among males(49.14%)than females(41.72%)(P=0.01).Conclusions:Chromosomal polymorphic analysis may play a crucial role in the assessment and careful clinical management of cases with idiopathic recurrent pregnancy loss,especially when no other conclusive reasons are identified during the initial evaluation.Therefore,heteromorphism should not be overlooked while investigating the causes of idiopathic recurrent pregnancy loss.展开更多
Dear Editor,We reported a Chinese family carrying a novel Crumbs homologue 1(CRB1)variant(c.1737_1755del).Consanguineous marriage resulted in a homozygous mutation,leading to the onset of Leber congenital amaurosis(LC...Dear Editor,We reported a Chinese family carrying a novel Crumbs homologue 1(CRB1)variant(c.1737_1755del).Consanguineous marriage resulted in a homozygous mutation,leading to the onset of Leber congenital amaurosis(LCA)in their offspring.展开更多
NADC34-like porcine reproductive and respiratory syndrome virus(PRRSV),which first appeared in China in 2017,is currently one of the main epidemic strains in China.In this study,we found that a new variant of NADC34-l...NADC34-like porcine reproductive and respiratory syndrome virus(PRRSV),which first appeared in China in 2017,is currently one of the main epidemic strains in China.In this study,we found that a new variant of NADC34-like PRRSV evolved,named the L1A variant.The phylogenetics,epidemic status,and pathogenicity of the LA variants were subsequently comprehensively evaluated.Based on the results of the ORF5 phylogenetic analysis,the L1A variants were classified as NADC34-like PPRSV.All the strains had the same discontinuous 131-aa deletion in the NSP2 region(similar to that in the NADC30).Recombination analysis revealed that the L1A variants were recombinant viruses that contained an NADC30-like PRRSV skeleton,a nonstructural protein-encoding gene region obtained in part from JXA1-like PRRSV and a ORF2-ORF6 gene region partly obtained from NADC34-like PRRSV and that exhibited similar recombination patterns.We successfully isolated the L1A variant TZJ2756 from PAMs and Marc-145 cells.In animal experiments,TZJ2756 exhibited moderate pathogenicity in piglets,causing obvious clinical symptoms,namely,persistent fever,significantly reduced body weight,interstitial edema and severe interstitial pneumonia in the lungs,and prolonged high-load viremia.L1A variants have been detected in at least 12 provinces in China and share many similar epidemiological characteristics with the American L1C variant.This research will enhance our understanding of the prevalence of L1A variants and furnish valuable data for the ongoing monitoring of NADC34-like PRRSV in China.展开更多
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
Multiple nucleotide variants(MNVs)are frequently misannotated as separate single-nucleotide variants(SNVs)by widely utilized variant-calling pipelines,presenting substantial challenges in genetic testing and research....Multiple nucleotide variants(MNVs)are frequently misannotated as separate single-nucleotide variants(SNVs)by widely utilized variant-calling pipelines,presenting substantial challenges in genetic testing and research.The role of MNVs in genetic diagnosis remains inadequately characterized,particularly within large disease cohorts.In this study,we comprehensively investigate codon-level MNVs(cMNVs)across 157 hearing loss(HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium(CDGC)cohort.A total of 116 cMNVs are identified,occurring in 29.07%of HL cases.Among them,56.03%of cMNVs exhibit functional consequences distinct from constituent SNVs.Moreover,amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs.Notably,51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV,impacting genetic interpretation in 145 cases.Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses.These findings provide critical insights into the genomic characteristics,functional impacts,and diagnostic implications of cMNVs,underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.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
Barley(Hordeum vulgare L.)employs the Na^(+)transporter HvHKT1;1,which is an N^(+)-selective transporter.This study characterized the full-length HvHKT1;1(HvHKT1;1-FL)and three mRNA variants(HvHKT1;1-V1,-V2,and-V3),wh...Barley(Hordeum vulgare L.)employs the Na^(+)transporter HvHKT1;1,which is an N^(+)-selective transporter.This study characterized the full-length HvHKT1;1(HvHKT1;1-FL)and three mRNA variants(HvHKT1;1-V1,-V2,and-V3),which encode polypeptides of 64.7,54.0,40.5,and 32.9 kDa,respectively.Tissue-specific expression profiling revealed that HvHKT1;1-FL is the most abundant transcript across leaf,sheath,and root tissues under normal conditions,with the highest expression in leaves.Under 150 mM NaCl stress,HvHKT1;1-FL and its variants showed a dynamic,time-dependent expression pattern,with peak leaf expression at 2 h,sheath expression at 12 h,and root expression at 2 h,suggesting their roles in early stress response.Functional analysis using two-electrode voltage-clamp measurements demonstrated thatHvHKT1;1-FL is highly selective for Na^(+),withminimal conductance for K^(+),Li^(+),Rb^(+),or Cs^(+).It demonstrated high Na^(+)transport efficiency,characterized by higher Vmax and lower Km values,while the variants showed reducedNa^(+)currents,lowerVmax,and higherKmvalues,indicating decreasedNa^(+)transport capacity.Reversal potential analyses further confirmed Na^(+)selectivity,with HvHKT1;1-FL displaying the strongest preference for Na^(+).Notably,while all variants retained Na^(+)selectivity,they showed reduced efficiency,as indicated by a more negative reversal potential in low Na^(+)conditions.These findings highlight the functional diversity among HvHKT1;1 variants,with HvHKT1;1-FL playing a dominant role in Na^(+)transport.The tissue-specific regulation of these variants under salinity stress underscores their importance in barley’s adaptive responses.展开更多
Body weight is a polygenic trait with intricate inheritance patterns.Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits.In thi...Body weight is a polygenic trait with intricate inheritance patterns.Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits.In this study,we conducted an extensive characterization of regulatory variants associated with body weight-related traits in cattle using multi-omics analysis.First,we identified seven candidate genes by integrating selective sweep analysis and multiple genome-wide association study(GWAS)strategies using imputed whole-genome sequencing data from a population of 1577 individuals.Subsequently,we uncovered 3340 eGenes(genes whose expression levels are associated with genetic variants)across 227 muscle samples.Transcriptome-wide association studies(TWASs)further revealed a total of 532 distinct candidate genes associated with body weight-related traits.Colocalization analyses unveiled 44 genes shared between expression quantitative trait loci(eQTLs)and GWAS signals.Moreover,a comprehensive analysis by integrating GWAS,selective sweep,eQTL,TWAS,epigenomic profiling,and molecular validation highlighted a positively selected genomic region on Bos taurus autosome 6(BTA6).This locus harbors pleiotropic genes(LAP3,MED28,and NCAPG)and a prioritized functional variant involved in the complex regulation of body weight.Additionally,convergent evolution analysis and phenome-wide association studies underscored the conservation of this locus across species.Our study provides a comprehensive understanding of the genetic regulation of body weight through multi-omics analysis in cattle.Our findings contribute to unraveling the genetic mechanisms governing weight-related traits and shed valuable light on the genetic improvement of farm animals.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
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
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
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
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
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
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
基金supported by the National Natural Science Foundation of China under grant number 62066016the Natural Science Foundation of Hunan Province of China under grant number 2024JJ7395+2 种基金International and Regional Science and Technology Cooperation and Exchange Program of the Hunan Association for Science and Technology under grant number 025SKX-KJ-04Hunan Provincial Postgraduate Research Innovation Project under grant numberCX20251611Liye Qin Bamboo Slips Research Special Project of JishouUniversity 25LYY03.
文摘ThePigeon-InspiredOptimization(PIO)algorithmconstitutes ametaheuristic method derived fromthe homing behaviour of pigeons.Initially formulated for three-dimensional path planning in unmanned aerial vehicles(UAVs),the algorithmhas attracted considerable academic and industrial interest owing to its effective balance between exploration and exploitation,coupled with advantages in real-time performance and robustness.Nevertheless,as applications have diversified,limitations in convergence precision and a tendency toward premature convergence have become increasingly evident,highlighting a need for improvement.This reviewsystematically outlines the developmental trajectory of the PIO algorithm,with a particular focus on its core applications in UAV navigation,multi-objective formulations,and a spectrum of variantmodels that have emerged in recent years.It offers a structured analysis of the foundational principles underlying the PIO.It conducts a comparative assessment of various performance-enhanced versions,including hybrid models that integrate mechanisms from other optimization paradigms.Additionally,the strengths andweaknesses of distinct PIOvariants are critically examined frommultiple perspectives,including intrinsic algorithmic characteristics,suitability for specific application scenarios,objective function design,and the rigor of the statistical evaluation methodologies employed in empirical studies.Finally,this paper identifies principal challenges within current PIO research and proposes several prospective research directions.Future work should focus on mitigating premature convergence by refining the two-phase search structure and adjusting the exponential decrease of individual numbers during the landmark operator.Enhancing parameter adaptation strategies,potentially using reinforcement learning for dynamic tuning,and advancing theoretical analyses on convergence and complexity are also critical.Further applications should be explored in constrained path planning,Neural Architecture Search(NAS),and other real-worldmulti-objective problems.For Multi-objective PIO(MPIO),key improvements include controlling the growth of the external archive and designing more effective selection mechanisms to maintain convergence efficiency.These efforts are expected to strengthen both the theoretical foundation and practical versatility of PIO and its variants.
基金funded by the Technology Development Board(TDB)of India's Ministry of Science and Technology(TDB/M-25/2018-19).
文摘Objective:To investigate the potential link between chromosomal polymorphisms in couples who had a medical history of idiopathic recurrent pregnancy loss.Methods:Cytogenetic investigation was conducted with mitogen(Phytohemagglutinin-M,Gibco)stimulated blood T lymphocytes by Giemsa trypsin Giemsa banding and Ag-NOR banding on 580 couples with a history of idiopathic recurrent pregnancy loss and 240 couples from the general population.Thirty good chromosomal spreads were captured,karyotyped,and analyzed.The karyotypes were designated using the International System for Human Cytogenomic Nomenclature 2024.Pearson Chi-square test was used to compare the frequency of chromosomal polymorphism variations in the idiopathic recurrent pregnancy loss group with the general population group.Results:A conventional cytogenetic investigation revealed that 45.43%of couples experiencing idiopathic recurrent pregnancy loss presented with various types of chromosomal polymorphic variants,compared to 11.88%in the general population.The overall frequency of these chromosomal polymorphic variants was significantly higher in the idiopathic recurrent pregnancy loss group compared to the general population group(OR 9.97,95%CI 6.99-14.21;P<0.05).Additionally,the prevalence of polymorphic variants was higher among males(49.14%)than females(41.72%)(P=0.01).Conclusions:Chromosomal polymorphic analysis may play a crucial role in the assessment and careful clinical management of cases with idiopathic recurrent pregnancy loss,especially when no other conclusive reasons are identified during the initial evaluation.Therefore,heteromorphism should not be overlooked while investigating the causes of idiopathic recurrent pregnancy loss.
基金Supported by the National Natural Science Foundation of China(No.81970804)Natural Science Foundation of Hunan Province(No.2021JJ30949).
文摘Dear Editor,We reported a Chinese family carrying a novel Crumbs homologue 1(CRB1)variant(c.1737_1755del).Consanguineous marriage resulted in a homozygous mutation,leading to the onset of Leber congenital amaurosis(LCA)in their offspring.
基金supported by grants from the National Natural Science Foundation of China(32172890 and 32002315)the National Key Research and Development Program of China(2022YFF0711004)+3 种基金the Natural Science Foundation of Heilongjiang Province,China(YQ2022C042)the State Key Laboratory of Veterinary Biotechnology Foundation of China(SKLVBF202208)the Postdoctoral Fellowship Program of CPSF,China(GZC20233062)the National Center of Technology Innovation for Pigs,China(NCTIP-XD/C09)。
文摘NADC34-like porcine reproductive and respiratory syndrome virus(PRRSV),which first appeared in China in 2017,is currently one of the main epidemic strains in China.In this study,we found that a new variant of NADC34-like PRRSV evolved,named the L1A variant.The phylogenetics,epidemic status,and pathogenicity of the LA variants were subsequently comprehensively evaluated.Based on the results of the ORF5 phylogenetic analysis,the L1A variants were classified as NADC34-like PPRSV.All the strains had the same discontinuous 131-aa deletion in the NSP2 region(similar to that in the NADC30).Recombination analysis revealed that the L1A variants were recombinant viruses that contained an NADC30-like PRRSV skeleton,a nonstructural protein-encoding gene region obtained in part from JXA1-like PRRSV and a ORF2-ORF6 gene region partly obtained from NADC34-like PRRSV and that exhibited similar recombination patterns.We successfully isolated the L1A variant TZJ2756 from PAMs and Marc-145 cells.In animal experiments,TZJ2756 exhibited moderate pathogenicity in piglets,causing obvious clinical symptoms,namely,persistent fever,significantly reduced body weight,interstitial edema and severe interstitial pneumonia in the lungs,and prolonged high-load viremia.L1A variants have been detected in at least 12 provinces in China and share many similar epidemiological characteristics with the American L1C variant.This research will enhance our understanding of the prevalence of L1A variants and furnish valuable data for the ongoing monitoring of NADC34-like PRRSV in China.
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.
基金supported by the Key Project of the National Natural Science Foundation of China(82030030)the National Natural Science Foundation of China(82171836)+1 种基金the Science and Technology Department of Sichuan Province(2024NSFSC0648)the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC20002).
文摘Multiple nucleotide variants(MNVs)are frequently misannotated as separate single-nucleotide variants(SNVs)by widely utilized variant-calling pipelines,presenting substantial challenges in genetic testing and research.The role of MNVs in genetic diagnosis remains inadequately characterized,particularly within large disease cohorts.In this study,we comprehensively investigate codon-level MNVs(cMNVs)across 157 hearing loss(HL)-related genes in 11,467 HL cases and 7258 controls from the Chinese Deafness Gene Consortium(CDGC)cohort.A total of 116 cMNVs are identified,occurring in 29.07%of HL cases.Among them,56.03%of cMNVs exhibit functional consequences distinct from constituent SNVs.Moreover,amino acid substitutions exclusive to cMNVs cause more substantial physicochemical disruptions than those associated with SNVs.Notably,51 cMNVs show pathogenicity classifications that diverge from at least one constituent SNV,impacting genetic interpretation in 145 cases.Pathogenicity interpretation of cMNV facilitates definitive genetic diagnoses in eight HL cases that would otherwise have been subject to misdiagnoses or missed diagnoses.These findings provide critical insights into the genomic characteristics,functional impacts,and diagnostic implications of cMNVs,underscoring their clinical significance in genetic diagnosis and emphasizing the necessity for comprehensive and accurate detection and interpretation of cMNVs in genetic testing and research.
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supported by JSPS KAKENHI Grant Number JP20K06708 to Maki Katsuhara,and an OU fellowship to Shahin Imran.
文摘Barley(Hordeum vulgare L.)employs the Na^(+)transporter HvHKT1;1,which is an N^(+)-selective transporter.This study characterized the full-length HvHKT1;1(HvHKT1;1-FL)and three mRNA variants(HvHKT1;1-V1,-V2,and-V3),which encode polypeptides of 64.7,54.0,40.5,and 32.9 kDa,respectively.Tissue-specific expression profiling revealed that HvHKT1;1-FL is the most abundant transcript across leaf,sheath,and root tissues under normal conditions,with the highest expression in leaves.Under 150 mM NaCl stress,HvHKT1;1-FL and its variants showed a dynamic,time-dependent expression pattern,with peak leaf expression at 2 h,sheath expression at 12 h,and root expression at 2 h,suggesting their roles in early stress response.Functional analysis using two-electrode voltage-clamp measurements demonstrated thatHvHKT1;1-FL is highly selective for Na^(+),withminimal conductance for K^(+),Li^(+),Rb^(+),or Cs^(+).It demonstrated high Na^(+)transport efficiency,characterized by higher Vmax and lower Km values,while the variants showed reducedNa^(+)currents,lowerVmax,and higherKmvalues,indicating decreasedNa^(+)transport capacity.Reversal potential analyses further confirmed Na^(+)selectivity,with HvHKT1;1-FL displaying the strongest preference for Na^(+).Notably,while all variants retained Na^(+)selectivity,they showed reduced efficiency,as indicated by a more negative reversal potential in low Na^(+)conditions.These findings highlight the functional diversity among HvHKT1;1 variants,with HvHKT1;1-FL playing a dominant role in Na^(+)transport.The tissue-specific regulation of these variants under salinity stress underscores their importance in barley’s adaptive responses.
基金supported by the National Key R&D Program of China(Grant No.2022YFF1000600)the National Natural Science Foundation of China(Grant No.31972554)+4 种基金supported by the Agricultural Science and Technology Innovation Program of the Chinese Academy of Agricultural Sciences(Grant Nos.ASTIP-IAS-TS-16 and ASTIP-IAS03)the National Beef Cattle Industrial Technology System(Grant No.CARS-37)supported in part by the Agriculture and Food Research Initiative(AFRI)(Grant Nos.2019-67015-29321 and 2021-67015-33409)from the United States Department of Agriculture(USDA)National Institute of Food and Agriculture(NIFA)Animal Genome and Reproduction ProgramsLingyang Xu was supported by the Elite Youth Scientists Program of the Chinese Academy of Agricultural Sciences.
文摘Body weight is a polygenic trait with intricate inheritance patterns.Functional genomics enriched with multi-layer annotations offers essential resources for exploring the genetic architecture of complex traits.In this study,we conducted an extensive characterization of regulatory variants associated with body weight-related traits in cattle using multi-omics analysis.First,we identified seven candidate genes by integrating selective sweep analysis and multiple genome-wide association study(GWAS)strategies using imputed whole-genome sequencing data from a population of 1577 individuals.Subsequently,we uncovered 3340 eGenes(genes whose expression levels are associated with genetic variants)across 227 muscle samples.Transcriptome-wide association studies(TWASs)further revealed a total of 532 distinct candidate genes associated with body weight-related traits.Colocalization analyses unveiled 44 genes shared between expression quantitative trait loci(eQTLs)and GWAS signals.Moreover,a comprehensive analysis by integrating GWAS,selective sweep,eQTL,TWAS,epigenomic profiling,and molecular validation highlighted a positively selected genomic region on Bos taurus autosome 6(BTA6).This locus harbors pleiotropic genes(LAP3,MED28,and NCAPG)and a prioritized functional variant involved in the complex regulation of body weight.Additionally,convergent evolution analysis and phenome-wide association studies underscored the conservation of this locus across species.Our study provides a comprehensive understanding of the genetic regulation of body weight through multi-omics analysis in cattle.Our findings contribute to unraveling the genetic mechanisms governing weight-related traits and shed valuable light on the genetic improvement of farm animals.
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 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 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.
