Detection and treatment of drug resistance in extrapulmonary tuberculosis(EPTB)is a major challenge worldwide.Drug resistance in EPTB has not been studied extensively.However,patients with drug-resistant EPTB have bee...Detection and treatment of drug resistance in extrapulmonary tuberculosis(EPTB)is a major challenge worldwide.Drug resistance in EPTB has not been studied extensively.However,patients with drug-resistant EPTB have been reported to have poor outcomes[1].Rifampicin and isoniazid are the cornerstone drugs in the management of EPTB.Resistance in Mycobacterium(M.)tuberculosis to these drugs commonly arises due to mutations in the‘rpoB’gene and‘katG&inhA’genes,which confer resistance to rifampicin and isoniazid,respectively.Treatment outcomes are affected by the presence of these mutations.In addition,anatomical and physiological barriers impede the effective delivery of drugs to the affected extrapulmonary site[1].An analysis of the frequency of mutations in drug resistant M.tuberculosis strains causing EPTB in our region can help identify patterns of drug resistance.This,in turn,can provide inputs that may be used for modifying standard treatment regimens to make them more effective.The present study aims to identify the frequency and pattern of mutations in the‘rpoB’gene and‘katG&inhA’genes in M.tuberculosis strains isolated from EPTB samples.展开更多
Plants possess a hydrophobic layer of wax on their aerial surface,consisting mainly of amorphous intra-cuticular wax and epicuticular wax crystals(Kunst and Samuels,2003).This waxy coating contains a wide variety of v...Plants possess a hydrophobic layer of wax on their aerial surface,consisting mainly of amorphous intra-cuticular wax and epicuticular wax crystals(Kunst and Samuels,2003).This waxy coating contains a wide variety of very-long-chain fatty acids(VLCFAs)and their derivatives,including alkanes,alcohols,aldehydes,esters,and ketones.展开更多
BACKGROUND In this case report,we aimed to raise awareness regarding arrhythmogenic cardiomyopathy(ACM)with inflammatory“hot phase”episodes in pediatric patients,which is often misdiagnosed as myocarditis.This condi...BACKGROUND In this case report,we aimed to raise awareness regarding arrhythmogenic cardiomyopathy(ACM)with inflammatory“hot phase”episodes in pediatric patients,which is often misdiagnosed as myocarditis.This condition,caused by aseptic intracellular inflammation,can be misdiagnosed as acute coronary syndrome or myocardial viral infection,with the latter being particularly common in children.Here,we report two pediatric cases of ACM with“hot phase”episodes and discuss the molecular mechanisms leading to aseptic myocardial inflammation due to desmosome and cytoskeletal damage.CASE SUMMARY The first patient(aged 13 years)was hospitalized after experiencing a single episode of syncope,chest pain,and palpitation.Clinical examination revealed elevated troponin levels,complete right bundle branch block,right ventricular dilation,and normal coronary arteries.Cardiac magnetic resonance imaging(MRI)revealed extensive fibrotic changes in the right ventricle,which was consistent with ACM,and a pathogenic variant in DSG2 confirmed the diagnosis.The second patient(aged 4 years)presented with chest pain and elevated troponin levels.Electrocardiography revealed a left bundle branch block,while echocardiography showed reduced left ventricular contractility.Cardiac MRI demonstrated left ventricular dilation and subepicardial fibrosis.The phenotypic features,such as curly-wool hair,hyperkeratosis,and onychodystrophy,suggested a genetic nature of the disease.Two mutations identified in DSP confirmed the diagnosis of Carvajal syndrome with intermittent“hot phase”episodes.CONCLUSION ACM in children can present with nonspecific inflammatory symptoms,which may be misdiagnosed as myocarditis or coronary artery pathology.展开更多
Imagine a future where a single vaccine could protect you from a multitude of influenza strains,offering broad immunity with minimal risk.This vision is now closer to reality,thanks to a recent study that harnesses th...Imagine a future where a single vaccine could protect you from a multitude of influenza strains,offering broad immunity with minimal risk.This vision is now closer to reality,thanks to a recent study that harnesses the power of cellular proteins to create a new generation of live attenuated vaccines that outsmart flu’s relentless mutations.展开更多
Dear Editor,A 34-year-old male presented to West China Hospital due to a 6-year history of infertility.The patient had experienced recurrent respiratory tract infections since early childhood and had been previously d...Dear Editor,A 34-year-old male presented to West China Hospital due to a 6-year history of infertility.The patient had experienced recurrent respiratory tract infections since early childhood and had been previously diagnosed with primary ciliary dyskinesia(PCD)at an external institution.CT imaging confirmed situs inversus totalis,establishing a diagnosis of Kartagener syndrome[1].展开更多
Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced ...Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.展开更多
Dear Editor,Mutations in genomic sequences exhibit a strong correlation with various pathological processes of cancers[1].Currently,the next-generation sequencing technique[2]and polymerase chain reaction(PCR)were the...Dear Editor,Mutations in genomic sequences exhibit a strong correlation with various pathological processes of cancers[1].Currently,the next-generation sequencing technique[2]and polymerase chain reaction(PCR)were the established benchmarks for analyzing DNA mutations.However,the two methods necessitate intricate experimental preparation,costly instrumentation,and skilled personnel,making them challenging for rapid mutations analysis.More importantly,these methods lack adequate accuracy for one base mutations analysis[3].Therefore,the development of a reliable and exceptionally sensitive mutation analysis approach holds immense importance in cancer diagnosis and treatment.展开更多
Mutations in the cyclin-dependent kinase-like 5 gene(CDKL5)cause a severe neurodevelopmental disorder,yet the impact of truncating mutations remains unclear.Here,we introduce the Cdkl5^(492stop) mouse model,mimicking ...Mutations in the cyclin-dependent kinase-like 5 gene(CDKL5)cause a severe neurodevelopmental disorder,yet the impact of truncating mutations remains unclear.Here,we introduce the Cdkl5^(492stop) mouse model,mimicking C-terminal truncating mutations in patients.492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors,alongside other behavioral deficits.After creating cell lines with various Cdkl5 truncating mutations,we found that these mutations are regulated by the nonsense-mediated RNA decay pathway.Most truncating mutations result in CDKL5 protein loss,leading to multiple disease phenotypes,and offering new insights into the pathogenesis of CDKL5 disorder.展开更多
Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small population...Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small populations,genetic purging that occurs under the pressure of natural selection acts as an opposing force,contributing to a reduction of deleterious alleles.Both inbreeding and genetic purging are paramount in the field of conservation genomics.The Amur tiger(Panthera tigris altaica)lives in small populations in the forests of Northeast Asia and is among the most endangered animals on the planet.Using genome-wide assessment and comparison,we reveal substantially higher and more extensive inbreeding in wild Amur tigers(F_(ROH)=0.50)than in captive individuals(F_(ROH)=0.24).However,a relatively reduced number of lossof-function mutations in wild Amur tigers is observed compared to captive individuals,indicating genetic purging of inbreeding load with relatively large-effect alleles.The higher ratio of homozygous mutation load and number of fixed damaging alleles in the wild population indicates a less-efficient genetic purging,with purifying selection also contributing to this process.These findings provide valuable insights for the future conservation of Amur tigers.展开更多
Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in viv...Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.展开更多
Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study...Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.展开更多
The use of RNA interference(RNAi)technology to control pests is explored by researchers globally.Even though RNA is a new class of pest control compound unlike conventional chemical pesticides,the evolution of pest re...The use of RNA interference(RNAi)technology to control pests is explored by researchers globally.Even though RNA is a new class of pest control compound unlike conventional chemical pesticides,the evolution of pest resistance needs to be considered.Here,we first investigate RNAi-based biopesticide resistance of Fusarium asiaticum,which is responsible for devastating diseases of plants,for example,Fusarium head blight.Five resistant strains were isolated from 500 strains that treated with UV-mutagenesis.The mutation common to all of the five resistant mutants occurred in the gene encoding Dicer2(point mutations at codon 1005 and 1007),which were under strong purifying selection pressure.To confirm whether the mutations in Dicer2 confer resistance to RNAi,we exchanged the Dicer2 locus between the sensitive strain and the resistant strain by homologous double exchange.The transformed mutants,Dicer2^(R1005D)and Dicer2^(E1007H),exhibited resistance to dsRNA in vitro.Further study showed that mutations of R1005D and E1007H affected the intramolecular interactions of Dicer2,resulting in the dysfunction of RNase III domain of Dicer2.The amount of sRNAs produced by Dicer2^(R1005D)and Dicer2^(E1007H)was extremely reduced along with variation of sRNA length.Together,these findings revealed a new potential mechanism of RNAi resistance and provided insight into RNAi-related biopesticide deployment for fungal control.展开更多
BACKGROUND Pancreatic cancer(PC)is a highly malignant tumor that is resistant to chemotherapy,radiotherapy and immunotherapy.Combination chemotherapy regimens are the standard first-line regimens for metastatic diseas...BACKGROUND Pancreatic cancer(PC)is a highly malignant tumor that is resistant to chemotherapy,radiotherapy and immunotherapy.Combination chemotherapy regimens are the standard first-line regimens for metastatic disease,with a median survival<12 months.Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC,evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.CASE SUMMARY We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months,anorexia and abdominal pain.Imaging showed extensive lesions involving the pancreas,liver,bones,muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9(CA19-9)and carcinoembryonic antigen(CEA).Biopsy yielded a diagnosis of PC.Treatment with gemcitabine and nab-paclitaxel was initiated,but the disease progressed in<2 months even though the patient’s general condition improved.Molecular testing revealed the presence of BRAF mutation.Dabrafenib/trametinib combination therapy was introduced,and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels,but he died after 2 months of treatment.CONCLUSION BRAF alterations are infrequent in PC.This case highlights the significance of molecular profiling in patients with PC,especially in patients with a high tumor burden.展开更多
In the multilayer film-substrate system,thermal stress concentration and stress mutations cause film buckling,delamination and cracking,leading to device failure.In this paper,we investigated a multilayer film system ...In the multilayer film-substrate system,thermal stress concentration and stress mutations cause film buckling,delamination and cracking,leading to device failure.In this paper,we investigated a multilayer film system composed of a substrate and three film layers.The thermal stress distribution inside the structure was calculated by the finite element method,revealing significant thermal stress differences between the layers.This is mainly due to the mismatch of the coefficient of thermal expansion between materials.Different materials respond differently to changes in external temperature,leading to compression between layers.There are obvious thermal stress concentration points at the corners of the base layer and the transition layer,which is due to the sudden change of the shape at the geometric section of the structure,resulting in a sudden increase in local stress.To address this issue,we chamfered the substrate and added an intermediate layer between the substrate and the transition layer to assess whether these modifications could reduce or eliminate the thermal stress concentration points and extend the service life of the multilayer structure.The results indicate that chamfering and adding the intermediate layer effectively reduce stress discontinuities and mitigate thermal stress concentration points,thereby improving interlayer bonding strength.展开更多
Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, grow...Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, growingevidence indicates that AR dysfunction also disrupts systemic metabolic homeostasis, predisposing affectedindividuals to insulin resistance and type 2 diabetes mellitus. This article synthesizes recent advances in genetics,transcriptomics, and physiology to elucidate how AR mutations drive tissue-specific metabolic reprogramming inkey organs, including pancreatic β-cells, skeletal muscle, liver, and adipose tissue. Particular attention is given to anewly identified familial AR variant (c.2117A>G;p.Asn706Ser), which not only broadens the known mutationalspectrum of AIS but also underscores the clinical importance of early metabolic risk screening in this population.We further examine how pubertal stage, hormone replacement therapy, and sex-specific signaling pathwaysinteract to influence long-term metabolic outcomes. Lastly, we propose an integrative management framework thatincorporates genetic diagnosis, endocrine surveillance, and personalized pharmacological strategies aimed atreducing the risk of type 2 diabetes mellitus and cardiometabolic complications in individuals with AIS. Distinctfrom previous AIS-centered reviews, this work integrates metabolic and endocrine perspectives into the traditionaldevelopmental paradigm, offering a more comprehensive understanding of disease risk and translational management.展开更多
BACKGROUND Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I(rtCYE/rtCYEI)mutations in the hepatitis B virus(HBV)reverse-transcriptase(RT)region are associated with tenofovir disoproxil fumarate(TDF)resistance is ...BACKGROUND Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I(rtCYE/rtCYEI)mutations in the hepatitis B virus(HBV)reverse-transcriptase(RT)region are associated with tenofovir disoproxil fumarate(TDF)resistance is controversial.AIM To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection.METHODS A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled.All patients received nucleoside/nucleotide analogues(NAs)therapy,and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis.RESULTS The detection rates of a single mutation of rtS106C,rtH126Y,rtD134E,and rtL269I were 8.21%,3.20%,2.55%and 61.49%in 23718 genotype C patients,and 1.31%,1.76%,0.21%,and 92.33%in 4266 genotype B patients,respectively.The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients,accounting for 0.042%of all patients.These 12 patients had received NA treatments except TDF before testing.Among them,6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations,and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations.Compared with the wild-type(WT)strain,the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%,and TDF susceptibility reduced by less than 2-fold,but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility.Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain.In the clinic,emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment.CONCLUSION HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.展开更多
Background:Strong sex disparities have been observed among patients with bladder cancer(BCa).FGFR3 is one of the most frequently mutated genes in bladder cancer,and there are inconsistencies in its frequency in male a...Background:Strong sex disparities have been observed among patients with bladder cancer(BCa).FGFR3 is one of the most frequently mutated genes in bladder cancer,and there are inconsistencies in its frequency in male and female patients.Methods:Here,we conducted a meta-analysis comparing the FGFR3 somatic mutation frequency in men and women among 7351 patients with BCa from 18 cohorts.Results:We showed that female patients had a 1.32 times higher risk of having FGFR3 somatic mutations than males.This difference was attributed to mutations occurring at the 2 most frequently mutated sites,S249 and Y375.Additionally,nonsense mutations were more likely to be found in women,whereas indel/frameshift mutations were almost exclusively found in men;however,no difference was noted for missense mutations.Conclusions:A female sex bias in FGFR3 somatic mutationswas observed in BCa.Well-powered individual participant data analyses addressing the possible confounding effects of other factors(eg,age,ethnicity,smoking status,muscle invasiveness,and molecular subtype),as well as analyses integrating omics and functional investigations,are warranted to further validate and explain the mechanisms of the current findings.展开更多
BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to ...BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.展开更多
Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer pa...Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer patients is dynamic.By dynamically monitoring the evolution of genes status,differential genes and concomitant genes related to progressive disease could be confirmed early,so as to achieve a more accurate and comprehensive insight of the whole process management of targeted therapy for lung cancer patients.Under the guidance of accurate genetic testing results,it is helpful to provide patients with more effective,long-term,and stable individualized targeted therapy.展开更多
In Senegal in particular, ovarian cancer, which is one of the most common gynecological cancers, accounts for 2.8% of deaths. The most important risk factor is genetic, with 10% of cases occurring in a context of gene...In Senegal in particular, ovarian cancer, which is one of the most common gynecological cancers, accounts for 2.8% of deaths. The most important risk factor is genetic, with 10% of cases occurring in a context of genetic predisposition. The sequencing of the human genome, which has led to the discovery of millions of sequence variations, makes it possible to study variations within sequences. These variations are limited to Single Nucleotide Polymorphisms (SNPs) and this common form of polymorphism occurs approximately every 1000 bases in the human genome and 1.8 million SNPs are currently listed according to [1]. The aim of this study is to gain a better understanding of the impact of mutations in the D-loop region of mtDNA on ovarian cancer in Senegalese women. This study involved searching for mutations in our study population after DNA extraction and sequencing. Mutations were found after a comparison of our sequences with the Cambridge reference sequence (NC_012920). The mutations found in the DNA studied extend from position 7 to position 16568 and most of these mutations are located in the hypervariate zones (HV1 and HV2). Heteroplasmy with three mutant alleles was also found in certain variants. Common mutations were found in both healthy and cancerous tissues, with almost identical frequencies in both types of tissue. This enabled us to understand the spread of tumor cells throughout the ovary.展开更多
文摘Detection and treatment of drug resistance in extrapulmonary tuberculosis(EPTB)is a major challenge worldwide.Drug resistance in EPTB has not been studied extensively.However,patients with drug-resistant EPTB have been reported to have poor outcomes[1].Rifampicin and isoniazid are the cornerstone drugs in the management of EPTB.Resistance in Mycobacterium(M.)tuberculosis to these drugs commonly arises due to mutations in the‘rpoB’gene and‘katG&inhA’genes,which confer resistance to rifampicin and isoniazid,respectively.Treatment outcomes are affected by the presence of these mutations.In addition,anatomical and physiological barriers impede the effective delivery of drugs to the affected extrapulmonary site[1].An analysis of the frequency of mutations in drug resistant M.tuberculosis strains causing EPTB in our region can help identify patterns of drug resistance.This,in turn,can provide inputs that may be used for modifying standard treatment regimens to make them more effective.The present study aims to identify the frequency and pattern of mutations in the‘rpoB’gene and‘katG&inhA’genes in M.tuberculosis strains isolated from EPTB samples.
基金supported by grants from the National Natural Science Foundation of China(Grant No.31972405).
文摘Plants possess a hydrophobic layer of wax on their aerial surface,consisting mainly of amorphous intra-cuticular wax and epicuticular wax crystals(Kunst and Samuels,2003).This waxy coating contains a wide variety of very-long-chain fatty acids(VLCFAs)and their derivatives,including alkanes,alcohols,aldehydes,esters,and ketones.
基金Supported by Russian Science Foundation,No.24-15-20026/12.04.2024St.Petersburg Research Foundation,No.24-15-20026/24.05.2024.
文摘BACKGROUND In this case report,we aimed to raise awareness regarding arrhythmogenic cardiomyopathy(ACM)with inflammatory“hot phase”episodes in pediatric patients,which is often misdiagnosed as myocarditis.This condition,caused by aseptic intracellular inflammation,can be misdiagnosed as acute coronary syndrome or myocardial viral infection,with the latter being particularly common in children.Here,we report two pediatric cases of ACM with“hot phase”episodes and discuss the molecular mechanisms leading to aseptic myocardial inflammation due to desmosome and cytoskeletal damage.CASE SUMMARY The first patient(aged 13 years)was hospitalized after experiencing a single episode of syncope,chest pain,and palpitation.Clinical examination revealed elevated troponin levels,complete right bundle branch block,right ventricular dilation,and normal coronary arteries.Cardiac magnetic resonance imaging(MRI)revealed extensive fibrotic changes in the right ventricle,which was consistent with ACM,and a pathogenic variant in DSG2 confirmed the diagnosis.The second patient(aged 4 years)presented with chest pain and elevated troponin levels.Electrocardiography revealed a left bundle branch block,while echocardiography showed reduced left ventricular contractility.Cardiac MRI demonstrated left ventricular dilation and subepicardial fibrosis.The phenotypic features,such as curly-wool hair,hyperkeratosis,and onychodystrophy,suggested a genetic nature of the disease.Two mutations identified in DSP confirmed the diagnosis of Carvajal syndrome with intermittent“hot phase”episodes.CONCLUSION ACM in children can present with nonspecific inflammatory symptoms,which may be misdiagnosed as myocarditis or coronary artery pathology.
文摘Imagine a future where a single vaccine could protect you from a multitude of influenza strains,offering broad immunity with minimal risk.This vision is now closer to reality,thanks to a recent study that harnesses the power of cellular proteins to create a new generation of live attenuated vaccines that outsmart flu’s relentless mutations.
基金supported by the Natural Science Foundation of China(824B2017 to Xiong Y)Sichuan Science and Technology Program(2025YFHZ0212 to Qin F).
文摘Dear Editor,A 34-year-old male presented to West China Hospital due to a 6-year history of infertility.The patient had experienced recurrent respiratory tract infections since early childhood and had been previously diagnosed with primary ciliary dyskinesia(PCD)at an external institution.CT imaging confirmed situs inversus totalis,establishing a diagnosis of Kartagener syndrome[1].
基金supported by Decit/SCTIE-Ministério da Saúde,Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Fundação de AmparoàPesquisa do Estado de Alagoas(FAPEAL)and Secretaria de Estado da Saúde de Alagoas(SESAU-AL)[PPSUS 60030000841/2016].
文摘Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.
文摘Dear Editor,Mutations in genomic sequences exhibit a strong correlation with various pathological processes of cancers[1].Currently,the next-generation sequencing technique[2]and polymerase chain reaction(PCR)were the established benchmarks for analyzing DNA mutations.However,the two methods necessitate intricate experimental preparation,costly instrumentation,and skilled personnel,making them challenging for rapid mutations analysis.More importantly,these methods lack adequate accuracy for one base mutations analysis[3].Therefore,the development of a reliable and exceptionally sensitive mutation analysis approach holds immense importance in cancer diagnosis and treatment.
基金supported by the Innovation of Science and Technology 2030-Major Project"Platform of Nonhuman Primate Models"(2021ZD0200900)the Ministry of Science and Technology(2018YFA0801404)+1 种基金the National Natural Science Foundation of China(82021001)the Shanghai Municipal Science and Technology Major Project.
文摘Mutations in the cyclin-dependent kinase-like 5 gene(CDKL5)cause a severe neurodevelopmental disorder,yet the impact of truncating mutations remains unclear.Here,we introduce the Cdkl5^(492stop) mouse model,mimicking C-terminal truncating mutations in patients.492stop/Y mice exhibit altered dendritic spine morphology and spontaneous seizure-like behaviors,alongside other behavioral deficits.After creating cell lines with various Cdkl5 truncating mutations,we found that these mutations are regulated by the nonsense-mediated RNA decay pathway.Most truncating mutations result in CDKL5 protein loss,leading to multiple disease phenotypes,and offering new insights into the pathogenesis of CDKL5 disorder.
基金supported by the Fundamental Research Funds for the Central Universities of China(2572022DQ03)the National Natural Science Foundation of China(32170517)+2 种基金the Guangdong Provincial Key Laboratory of Genome Read and Write(2017B030301011)the Start-up Scientific Foundation of Northeast Forestry University(60201524043)supported by China National GeneBank(CNGB).
文摘Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small populations,genetic purging that occurs under the pressure of natural selection acts as an opposing force,contributing to a reduction of deleterious alleles.Both inbreeding and genetic purging are paramount in the field of conservation genomics.The Amur tiger(Panthera tigris altaica)lives in small populations in the forests of Northeast Asia and is among the most endangered animals on the planet.Using genome-wide assessment and comparison,we reveal substantially higher and more extensive inbreeding in wild Amur tigers(F_(ROH)=0.50)than in captive individuals(F_(ROH)=0.24).However,a relatively reduced number of lossof-function mutations in wild Amur tigers is observed compared to captive individuals,indicating genetic purging of inbreeding load with relatively large-effect alleles.The higher ratio of homozygous mutation load and number of fixed damaging alleles in the wild population indicates a less-efficient genetic purging,with purifying selection also contributing to this process.These findings provide valuable insights for the future conservation of Amur tigers.
基金supported by the Natural Science Foundation of Fujian Province,No.2020J02027the National Natural Science Foundation of China,No.31970461the Foundation of NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primate,Fujian Maternity and Child Health Hospital,No.2022-NHP-05(all to WC).
文摘Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.
基金supported by the National Natural Science Foundation(82271057)the Natural Science Foundation of Hunan Province(2023JJ30818),China。
文摘Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.
基金funded by the National Natural Science Foundation of China(32372585)the Natural Science Foundation of Jiangsu Province,China(BK20231471)the National Training Program of Innovation and Entrepreneurship for Undergraduates,China(202210307013Z)。
文摘The use of RNA interference(RNAi)technology to control pests is explored by researchers globally.Even though RNA is a new class of pest control compound unlike conventional chemical pesticides,the evolution of pest resistance needs to be considered.Here,we first investigate RNAi-based biopesticide resistance of Fusarium asiaticum,which is responsible for devastating diseases of plants,for example,Fusarium head blight.Five resistant strains were isolated from 500 strains that treated with UV-mutagenesis.The mutation common to all of the five resistant mutants occurred in the gene encoding Dicer2(point mutations at codon 1005 and 1007),which were under strong purifying selection pressure.To confirm whether the mutations in Dicer2 confer resistance to RNAi,we exchanged the Dicer2 locus between the sensitive strain and the resistant strain by homologous double exchange.The transformed mutants,Dicer2^(R1005D)and Dicer2^(E1007H),exhibited resistance to dsRNA in vitro.Further study showed that mutations of R1005D and E1007H affected the intramolecular interactions of Dicer2,resulting in the dysfunction of RNase III domain of Dicer2.The amount of sRNAs produced by Dicer2^(R1005D)and Dicer2^(E1007H)was extremely reduced along with variation of sRNA length.Together,these findings revealed a new potential mechanism of RNAi resistance and provided insight into RNAi-related biopesticide deployment for fungal control.
基金Supported by Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province.
文摘BACKGROUND Pancreatic cancer(PC)is a highly malignant tumor that is resistant to chemotherapy,radiotherapy and immunotherapy.Combination chemotherapy regimens are the standard first-line regimens for metastatic disease,with a median survival<12 months.Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC,evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.CASE SUMMARY We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months,anorexia and abdominal pain.Imaging showed extensive lesions involving the pancreas,liver,bones,muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9(CA19-9)and carcinoembryonic antigen(CEA).Biopsy yielded a diagnosis of PC.Treatment with gemcitabine and nab-paclitaxel was initiated,but the disease progressed in<2 months even though the patient’s general condition improved.Molecular testing revealed the presence of BRAF mutation.Dabrafenib/trametinib combination therapy was introduced,and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels,but he died after 2 months of treatment.CONCLUSION BRAF alterations are infrequent in PC.This case highlights the significance of molecular profiling in patients with PC,especially in patients with a high tumor burden.
基金the support of the National Natural Science Foundation of China(Grant Nos.51606158,11604311 and 12074151)the Guangxi Science and Technology Base and Talent Special Project(Grant No.AD21075009)+2 种基金the Sichuan Science and Technology Program(Grant No.2021JDRC0022)the Open Fund of the Key Laboratory for Metallurgical Equipment and Control Technology of Ministry of Education in Wuhan University of Science and Technology,People's Republic of China(Grant Nos.MECOF2022B01 and MECOF2023B04)the Guangxi Key Laboratory of Precision Navigation Technology and Application,Guilin University of Electronic Technology(Grant No.DH202321)。
文摘In the multilayer film-substrate system,thermal stress concentration and stress mutations cause film buckling,delamination and cracking,leading to device failure.In this paper,we investigated a multilayer film system composed of a substrate and three film layers.The thermal stress distribution inside the structure was calculated by the finite element method,revealing significant thermal stress differences between the layers.This is mainly due to the mismatch of the coefficient of thermal expansion between materials.Different materials respond differently to changes in external temperature,leading to compression between layers.There are obvious thermal stress concentration points at the corners of the base layer and the transition layer,which is due to the sudden change of the shape at the geometric section of the structure,resulting in a sudden increase in local stress.To address this issue,we chamfered the substrate and added an intermediate layer between the substrate and the transition layer to assess whether these modifications could reduce or eliminate the thermal stress concentration points and extend the service life of the multilayer structure.The results indicate that chamfering and adding the intermediate layer effectively reduce stress discontinuities and mitigate thermal stress concentration points,thereby improving interlayer bonding strength.
基金Supported by the Quzhou Science and Technology Plan Project,No.2022K69.
文摘Familial androgen insensitivity syndrome (AIS), resulting from inherited mutations in the androgen receptor (AR)gene, has traditionally been examined within the framework of disorders of sex development. However, growingevidence indicates that AR dysfunction also disrupts systemic metabolic homeostasis, predisposing affectedindividuals to insulin resistance and type 2 diabetes mellitus. This article synthesizes recent advances in genetics,transcriptomics, and physiology to elucidate how AR mutations drive tissue-specific metabolic reprogramming inkey organs, including pancreatic β-cells, skeletal muscle, liver, and adipose tissue. Particular attention is given to anewly identified familial AR variant (c.2117A>G;p.Asn706Ser), which not only broadens the known mutationalspectrum of AIS but also underscores the clinical importance of early metabolic risk screening in this population.We further examine how pubertal stage, hormone replacement therapy, and sex-specific signaling pathwaysinteract to influence long-term metabolic outcomes. Lastly, we propose an integrative management framework thatincorporates genetic diagnosis, endocrine surveillance, and personalized pharmacological strategies aimed atreducing the risk of type 2 diabetes mellitus and cardiometabolic complications in individuals with AIS. Distinctfrom previous AIS-centered reviews, this work integrates metabolic and endocrine perspectives into the traditionaldevelopmental paradigm, offering a more comprehensive understanding of disease risk and translational management.
基金Supported by The National Natural Science Foundation of China,No.82470632.
文摘BACKGROUND Whether rtS106C+H126Y+D134E/rtS106C+H126Y+D134E+L269I(rtCYE/rtCYEI)mutations in the hepatitis B virus(HBV)reverse-transcriptase(RT)region are associated with tenofovir disoproxil fumarate(TDF)resistance is controversial.AIM To evaluate the presence of the rtCYE/rtCYEI mutations in a large cohort of Chinese patients with chronic HBV infection.METHODS A total of 28236 patients who underwent drug resistance testing at the Fifth Medical Center of Chinese PLA General Hospital from 2007 to 2019 were enrolled.All patients received nucleoside/nucleotide analogues(NAs)therapy,and serum samples were collected for sequence analysis of the HBV RT domain with mutation analysis.RESULTS The detection rates of a single mutation of rtS106C,rtH126Y,rtD134E,and rtL269I were 8.21%,3.20%,2.55%and 61.49%in 23718 genotype C patients,and 1.31%,1.76%,0.21%,and 92.33%in 4266 genotype B patients,respectively.The combined mutations of rtCYE/rtCYEI were only detected in 12 genotype C patients,accounting for 0.042%of all patients.These 12 patients had received NA treatments except TDF before testing.Among them,6 patients had coexisting rtCYE/rtCYEI and lamivudine-resistance mutations,and 2 patients had coexisting rtCYE/rtCYEI and adefovir-resistance mutations.Compared with the wild-type(WT)strain,the replication capacity of rtCYE/rtCYEI mutants from representative patients decreased by 41.1%-71.8%,and TDF susceptibility reduced by less than 2-fold,but rtCYEI+rtA181V/N236T mutants exhibited a 6.2-/9.9-fold decrease in TDF susceptibility.Molecular modeling showed that rtCYE/rtCYEI mutants had a slight decrease in binding energy to TDF compared to the WT strain.In the clinic,emergence of the rtCYE/rtCYEI mutations was not specifically associated with TDF treatment.CONCLUSION HBV rtCYE/rtCYEI mutations have a limited effect on TDF susceptibility and are not sufficient to cause TDF resistance.
基金Supported by the National Natural Science Foundation of China(no.82303057)Natural Science Foundation of Hubei Province of China(no.2023AFB521)“Chutian Scholars Program”of Hubei Province of China.
文摘Background:Strong sex disparities have been observed among patients with bladder cancer(BCa).FGFR3 is one of the most frequently mutated genes in bladder cancer,and there are inconsistencies in its frequency in male and female patients.Methods:Here,we conducted a meta-analysis comparing the FGFR3 somatic mutation frequency in men and women among 7351 patients with BCa from 18 cohorts.Results:We showed that female patients had a 1.32 times higher risk of having FGFR3 somatic mutations than males.This difference was attributed to mutations occurring at the 2 most frequently mutated sites,S249 and Y375.Additionally,nonsense mutations were more likely to be found in women,whereas indel/frameshift mutations were almost exclusively found in men;however,no difference was noted for missense mutations.Conclusions:A female sex bias in FGFR3 somatic mutationswas observed in BCa.Well-powered individual participant data analyses addressing the possible confounding effects of other factors(eg,age,ethnicity,smoking status,muscle invasiveness,and molecular subtype),as well as analyses integrating omics and functional investigations,are warranted to further validate and explain the mechanisms of the current findings.
基金Supported by The Science and Technology Department of Sichuan Province,No.2021JDKP0015.
文摘BACKGROUND The aim of this study was to investigate the complex heterozygous mutations of ANK1 and SPTA1 in the same individual and improve our understanding of hereditary spherocytosis(HS)in children.We also hope to promote the application of gene detection technology in children with HS,with the goals of identifying more related gene mutations,supporting the acquisition of improved molecular genetic information to further reveal the pathogenesis of HS in children,and providing important guidance for the diagnosis,treatment,and prevention of HS in children.CASE SUMMARY A 1-year and 5-month-old patient presented jaundice during the neonatal period,mild anemia 8 months later,splenic enlargement at 1 year and 5 months,and brittle red blood cell permeability.Genetic testing was performed on the patient,their parents,and sister.Swiss Model software was used to predict the protein structure of complex heterozygous mutations in ANK1 and SPTA1.Genetic testing revealed that the patient harbored a new mutation in the ANK1 gene from the father and a mutation in the SPTA1 gene from the mother.Combined with the clinical symptoms of the children,it is suggested that the newly discovered complex heterozygous mutations of ANK1 and SPTA1 may be the cause,providing important guidance for revealing the pathogenesis,diagnosis,treatment,and promotion of gene detection technology in children with HS.CONCLUSION This case involves an unreported complex heterozygous mutation of ANK1 and SPTA1,which provides a reference for exploring HS.
基金National Natural Science Foundation of China(No.81873396)Capital Health Development Research Project(No.2018-2-4065)Project of China-Japan Friendship Hospital(No.2018-HX-26)。
文摘Owing to significantly prolonged survival,targeted therapy has become standardized recommendation for advanced non-small cell lung cancer patients with mutated driver genes.However,the genetic status of lung cancer patients is dynamic.By dynamically monitoring the evolution of genes status,differential genes and concomitant genes related to progressive disease could be confirmed early,so as to achieve a more accurate and comprehensive insight of the whole process management of targeted therapy for lung cancer patients.Under the guidance of accurate genetic testing results,it is helpful to provide patients with more effective,long-term,and stable individualized targeted therapy.
文摘In Senegal in particular, ovarian cancer, which is one of the most common gynecological cancers, accounts for 2.8% of deaths. The most important risk factor is genetic, with 10% of cases occurring in a context of genetic predisposition. The sequencing of the human genome, which has led to the discovery of millions of sequence variations, makes it possible to study variations within sequences. These variations are limited to Single Nucleotide Polymorphisms (SNPs) and this common form of polymorphism occurs approximately every 1000 bases in the human genome and 1.8 million SNPs are currently listed according to [1]. The aim of this study is to gain a better understanding of the impact of mutations in the D-loop region of mtDNA on ovarian cancer in Senegalese women. This study involved searching for mutations in our study population after DNA extraction and sequencing. Mutations were found after a comparison of our sequences with the Cambridge reference sequence (NC_012920). The mutations found in the DNA studied extend from position 7 to position 16568 and most of these mutations are located in the hypervariate zones (HV1 and HV2). Heteroplasmy with three mutant alleles was also found in certain variants. Common mutations were found in both healthy and cancerous tissues, with almost identical frequencies in both types of tissue. This enabled us to understand the spread of tumor cells throughout the ovary.
