In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next ...In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next generation.This results in an effective increase of de novo mutation rate for CES drivers5-8.CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5.Here,we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation.Our analysis of 54,715 trios ascertained for rare conditions9-13,6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment.We propose 23 genes hypermutable at loss-of-function(LoF)sites as candidate CES drivers.An extra 17 genes feature hypermutable missense mutations at individual positions,suggesting CES acting through gain of function.CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21.Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels,masking the effect of negative selection in human populations.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
BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have ...BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.展开更多
Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopme...Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopment and psychiatric disorder in childhood.Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD.Magnetic resonance imaging(MRI)has been used to assess medical images in Sotos syndrome and ADHD.The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial.In the future,genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.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
BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.A...BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.展开更多
Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(...Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.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
Objective:To investigate the clinical and molecular genetic characteristics of Chinese adolescents with maturity-onset diabetes of the young type 2(MODY 2)and the safety and efficacy of recombinant human growth hormon...Objective:To investigate the clinical and molecular genetic characteristics of Chinese adolescents with maturity-onset diabetes of the young type 2(MODY 2)and the safety and efficacy of recombinant human growth hormone(r-hGH).Methods:The clinical features and laboratory data of a family with MODY 2 combined with partial growth hormone deficiency(pGHD),diagnosed at the Fourth Clinical Medical College of Xinjiang Medical University,were analyzed.DNA was extracted from peripheral blood using the column method,and Sanger sequencing was conducted to analyze the glucokinase(GCK),hepatocyte nuclear factor 1α(HNF1α),and hepatocyte nuclear factor 4α(HNF4α)in the proband and relevant family members.Results:A heterozygous mutation in GCK(Reference sequence:NM_000162,location:Exon 10)c.1340G>A(p.R447Q)was detected in three family members(the proband,the proband’s younger brother,and their mother).The proband also had pGHD.Conclusion:GCK mutations causing MODY 2 exist in the Chinese population,and the combined treatment with r-hGH is safe and effective.展开更多
Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies.Among the genetic contri...Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies.Among the genetic contributors to CP,the carboxypeptidase A1 p.Ser282Pro(CPA1^(S282P))variant has been proposed to promote disease through misfolding-induced endoplasmic reticulum stress(ERS),although the broader pathogenic landscape remains incompletely defined.This study generated a rabbit model mimicking the human CPA1S282P mutation using the SpRY-ABE-8.17 system.Homozygous CPA1^(S282P)rabbits exhibited characteristic human CP phenotypes following alcohol induction,including visceral pain,elevated serum lipase and amylase,inflammatory cell infiltration,and extensive pancreatic fibrosis.Biochemical analyses confirmed that the p.S282P mutation induced CPA1 misfolding and elevated the expression of ERS markers GRP78 and CHOP in both transfected HEK293T cells and homozygous mutant rabbits.Notably,the CPA1^(S282P)mutation markedly disrupted intra-pancreatic lipid homeostasis,contributing to the development of CP in mutant rabbits.This study successfully established the first rabbit model of CP that accurately recapitulates CP caused by a defined human point mutation.Additionally,this study provides insights into a previously unrecognized link between CPA1 and intra-pancreatic lipid metabolism,offering a foundation for identifying novel therapeutic targets for human CP.展开更多
Starch biosynthesis is a complex process that relies on the coordinated action of multiple enzymes.Resistant starch is not digested in the small intestine,thus preventing a rapid rise in the glycemic index.Starch synt...Starch biosynthesis is a complex process that relies on the coordinated action of multiple enzymes.Resistant starch is not digested in the small intestine,thus preventing a rapid rise in the glycemic index.Starch synthase 2a(SS2a)is a key enzyme in amylopectin biosynthesis that has significant effects on starch structure and properties.In this study,we identified an ss2a null mutant(M3-1413)with a single base mutation from an ethyl methane sulfonate(EMS)-mutagenized population of barley.The mutation was located at the 3'end of the first intron of the RNA splicing receptor(AG)site,and resulted in abnormal RNA splicing and two abnormal transcripts of ss2a,which caused the inactivation of the SS2a gene.The starch structure and properties were significantly altered in the mutant,with M3-1413 containing lower total starch and higher amylose and resistant starch levels.This study sheds light on the effect of barley ss2a null mutations on starch properties and will help to guide new applications of barley starch in the development of nutritious food products.展开更多
The CRISPR/Cas9 system has shown great promise in engineering targeted mutations in a genome.The efficiency of Cas9-mediated genome editing is temperature sensitive.A high-temperature regime can increase the mutation ...The CRISPR/Cas9 system has shown great promise in engineering targeted mutations in a genome.The efficiency of Cas9-mediated genome editing is temperature sensitive.A high-temperature regime can increase the mutation efficiency induced by the CRISPR/Cas9 system in many plant species.However,a heat stress treatment has not been applied during the tissue culture process in citrus.To develop an efficient heat stress regime to improve the efficiency of CRISPR/Cas9-mediated targeted mutagenesis,three and five cycles of heat stress treatments were used during callus induction in citrus.The results showed that the heat stress treatment with three cycles of 24 h at 37℃,followed by 24 h at 26℃,increased the mutation efficiency by 11.6%compared with no heat stress treatment,and that five cycles of heat stress treatment were optimal,from which 50%mutants had a 100%mutation rate.The mutation profiles of Cas9 at 28℃ for 10 d and 37℃ for three or five cycles were similar,indicating that heat stress treatment did not affect the non-homologous end joining repair pathway.No detectable off-target mutation was detected in the potential off-target sites with four nucleotide mismatches compared with the designed on-target site.This study demonstrated that five cycles of heat stress treatment during callus induction could efficiently increase the mutation efficiency mediated by the CRISPR/Cas9 system without observable negative effects,and provided an efficient Cas9-mediated citrus genome editing system to produce mutants with a high mutation rate.展开更多
BACKGROUND Familial adenomatous polyposis(FAP)is an autosomal dominant syndrome that results from a germline mutation in the adenomatous polyposis coli gene.It is characterized by the early development of hundreds of ...BACKGROUND Familial adenomatous polyposis(FAP)is an autosomal dominant syndrome that results from a germline mutation in the adenomatous polyposis coli gene.It is characterized by the early development of hundreds of adenomas in the colon during the second decade of life.If prophylactic colectomy is not performed,most patients eventually develop colorectal cancer(CRC).CASE SUMMARY We present the mutational profile of a case of FAP that progressed to CRC.A 45-year-old Saudi man presented with intestinal obstruction and underwent a total colectomy.The colon showed hundreds of polyps and two infiltrative ulcerative lesions,which proved to be adenocarcinoma according to histopathology.We performed next-generation sequencing and found mutations in the TP53,NRAS,EGFR PDGFR,MET,KIT,ERBB2,and GUSP genes.CONCLUSION To the best of our knowledge,this case report is the first to sheds the light on the mutation profile of FAP that progressed to CRC in Saudi Arabia.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
AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia...AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.展开更多
BACKGROUND Hypertrophic cardiomyopathy(HCM)is one of the most prevalent inherited myocardial disorders and is charac-terized by considerable genetic and phenotypic heterogeneity.A subset of patients with HCM progress ...BACKGROUND Hypertrophic cardiomyopathy(HCM)is one of the most prevalent inherited myocardial disorders and is charac-terized by considerable genetic and phenotypic heterogeneity.A subset of patients with HCM progress to a dilated phase of HCM(DPHCM),which is associated with a poor prognosis;however,the underlying pathogenesis remains inadequately understood.CASE SUMMARY In this study,we present a case involving a pedigree with familial DPHCM and conduct a retrospective review of patients with DPHCM with identified gene mutations.Through panel sequencing targeting the coding regions of 312 genes associated with inherited cardiomyopathy,a heterozygous missense mutation(c.746G>A,p.Arg249Glu)in the MYH7 gene was identified in the proband(III-5).Sanger sequencing subsequently confirmed this pathogenic mutation in three additional family members(II-4,III-4,and IV-3).A total of 26 well-documented patients with DPHCM were identified in the literature.Patients with DPHCM are commonly middle-aged and male.The mean age of patients with DPHCM was 53.43±12.79 years.Heart failure,dyspnoea,and atrial fibrillation were the most prevalent symptoms observed,accompanied by an average left ventricular end-diastolic size of 58.62 mm.CONCLUSION Our findings corroborate the pathogenicity of the MYH7(c.746G>A,p.Arg249Glu)mutation for DPHCM and suggest that the Arg249Gln mutation may be responsible for high mortality.展开更多
BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old femal...BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.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
BACKGROUND Colorectal cancer(CRC)remains a major global health burden due to its high incidence and mortality,with treatment efficacy often hindered by tumor hetero-geneity,drug resistance,and a complex tumor microenv...BACKGROUND Colorectal cancer(CRC)remains a major global health burden due to its high incidence and mortality,with treatment efficacy often hindered by tumor hetero-geneity,drug resistance,and a complex tumor microenvironment(TME).Lactate metabolism plays a pivotal role in reshaping the TME,promoting immune eva-sion and epithelial-mesenchymal transition,making it a promising target for novel therapeutic strategies and prognostic modeling in CRC.AIM To offer an in-depth analysis of the role of lactate metabolism in CRC,high-lighting its significance in the TME and therapeutic response.METHODS Utilizing single-cell and transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas,we identified key lactate metabolic activities,particularly in the monocyte/macrophage subpopulation.RESULTS Seven lactate metabolism-associated genes were significantly linked to CRC prognosis and used to construct a predictive model.This model accurately forecasts patient outcomes and reveals notable distinct patterns of immune infiltration and transcriptomic profiles mutation profiles between high-and low-risk groups.High-risk patients demonstrated elevated immune cell infiltration,increased mutation frequencies,and heightened sensitivity to specific drugs(AZD6482,tozasertib,and SB216763),providing a foundation for personalized treatment approaches.Additionally,a nomogram integrating clinical and metabolic data effectively predicted 1-,3-,and 5-year survival rates.CONCLUSION This report underscored the pivotal mechanism of lactate metabolism in CRC prognosis and suggest novel avenues for therapeutic intervention.展开更多
文摘In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next generation.This results in an effective increase of de novo mutation rate for CES drivers5-8.CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5.Here,we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation.Our analysis of 54,715 trios ascertained for rare conditions9-13,6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment.We propose 23 genes hypermutable at loss-of-function(LoF)sites as candidate CES drivers.An extra 17 genes feature hypermutable missense mutations at individual positions,suggesting CES acting through gain of function.CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21.Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels,masking the effect of negative selection in human populations.
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.
文摘BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.
基金Supported by Natural Science Foundation of Shanghai,No.17ZR1431400National Key R and D Program of China,No.2017YFA0103902.
文摘Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopment and psychiatric disorder in childhood.Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD.Magnetic resonance imaging(MRI)has been used to assess medical images in Sotos syndrome and ADHD.The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial.In the future,genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.
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Supported by the Medical Education Collaborative Innovation Fund of Jiangsu University,No.JDY2022015。
文摘BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.
基金supported by grants from the National Natural Science Foundation of China(32170238,32400191)Guangdong Basic and Applied Basic Research Foundation(2023A1515111029)+2 种基金the Science,Technology and Innovation Commission of Shenzhen Municipality(RCYX20200714114538196)the Chinese Academy of Agricultural Sciences Elite Youth Program(grant 110243160001007)the Guangdong Pearl River Talent Program(2021QN02N792)。
文摘Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.
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.
文摘Objective:To investigate the clinical and molecular genetic characteristics of Chinese adolescents with maturity-onset diabetes of the young type 2(MODY 2)and the safety and efficacy of recombinant human growth hormone(r-hGH).Methods:The clinical features and laboratory data of a family with MODY 2 combined with partial growth hormone deficiency(pGHD),diagnosed at the Fourth Clinical Medical College of Xinjiang Medical University,were analyzed.DNA was extracted from peripheral blood using the column method,and Sanger sequencing was conducted to analyze the glucokinase(GCK),hepatocyte nuclear factor 1α(HNF1α),and hepatocyte nuclear factor 4α(HNF4α)in the proband and relevant family members.Results:A heterozygous mutation in GCK(Reference sequence:NM_000162,location:Exon 10)c.1340G>A(p.R447Q)was detected in three family members(the proband,the proband’s younger brother,and their mother).The proband also had pGHD.Conclusion:GCK mutations causing MODY 2 exist in the Chinese population,and the combined treatment with r-hGH is safe and effective.
基金supported by the Jilin Provincial Department of Education Science and Technology Research Project(JJKH20231141K)Natural Science Foundation of Jilin Province of China(20230101154JC)Young Elite Scientists Sponsorship Program by CAST(2022QNRC001)。
文摘Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies.Among the genetic contributors to CP,the carboxypeptidase A1 p.Ser282Pro(CPA1^(S282P))variant has been proposed to promote disease through misfolding-induced endoplasmic reticulum stress(ERS),although the broader pathogenic landscape remains incompletely defined.This study generated a rabbit model mimicking the human CPA1S282P mutation using the SpRY-ABE-8.17 system.Homozygous CPA1^(S282P)rabbits exhibited characteristic human CP phenotypes following alcohol induction,including visceral pain,elevated serum lipase and amylase,inflammatory cell infiltration,and extensive pancreatic fibrosis.Biochemical analyses confirmed that the p.S282P mutation induced CPA1 misfolding and elevated the expression of ERS markers GRP78 and CHOP in both transfected HEK293T cells and homozygous mutant rabbits.Notably,the CPA1^(S282P)mutation markedly disrupted intra-pancreatic lipid homeostasis,contributing to the development of CP in mutant rabbits.This study successfully established the first rabbit model of CP that accurately recapitulates CP caused by a defined human point mutation.Additionally,this study provides insights into a previously unrecognized link between CPA1 and intra-pancreatic lipid metabolism,offering a foundation for identifying novel therapeutic targets for human CP.
基金supported by the Major Program of National Agricultural Science and Technology of China(NK20220607)the Sichuan Science and Technology Program,China(2023YFH0041)。
文摘Starch biosynthesis is a complex process that relies on the coordinated action of multiple enzymes.Resistant starch is not digested in the small intestine,thus preventing a rapid rise in the glycemic index.Starch synthase 2a(SS2a)is a key enzyme in amylopectin biosynthesis that has significant effects on starch structure and properties.In this study,we identified an ss2a null mutant(M3-1413)with a single base mutation from an ethyl methane sulfonate(EMS)-mutagenized population of barley.The mutation was located at the 3'end of the first intron of the RNA splicing receptor(AG)site,and resulted in abnormal RNA splicing and two abnormal transcripts of ss2a,which caused the inactivation of the SS2a gene.The starch structure and properties were significantly altered in the mutant,with M3-1413 containing lower total starch and higher amylose and resistant starch levels.This study sheds light on the effect of barley ss2a null mutations on starch properties and will help to guide new applications of barley starch in the development of nutritious food products.
基金supported by the National Key Research and Development Program of China(Grant No.2022YFD1201600)Earmarked Fund for China Agriculture Research System(Grant No.CARS-26)+1 种基金Chongqing Natural Science Foundation Project(Grant No.CSTB2023NSCQ-MSX1085)Cultivar Improvement of Nanfeng Orange.
文摘The CRISPR/Cas9 system has shown great promise in engineering targeted mutations in a genome.The efficiency of Cas9-mediated genome editing is temperature sensitive.A high-temperature regime can increase the mutation efficiency induced by the CRISPR/Cas9 system in many plant species.However,a heat stress treatment has not been applied during the tissue culture process in citrus.To develop an efficient heat stress regime to improve the efficiency of CRISPR/Cas9-mediated targeted mutagenesis,three and five cycles of heat stress treatments were used during callus induction in citrus.The results showed that the heat stress treatment with three cycles of 24 h at 37℃,followed by 24 h at 26℃,increased the mutation efficiency by 11.6%compared with no heat stress treatment,and that five cycles of heat stress treatment were optimal,from which 50%mutants had a 100%mutation rate.The mutation profiles of Cas9 at 28℃ for 10 d and 37℃ for three or five cycles were similar,indicating that heat stress treatment did not affect the non-homologous end joining repair pathway.No detectable off-target mutation was detected in the potential off-target sites with four nucleotide mismatches compared with the designed on-target site.This study demonstrated that five cycles of heat stress treatment during callus induction could efficiently increase the mutation efficiency mediated by the CRISPR/Cas9 system without observable negative effects,and provided an efficient Cas9-mediated citrus genome editing system to produce mutants with a high mutation rate.
文摘BACKGROUND Familial adenomatous polyposis(FAP)is an autosomal dominant syndrome that results from a germline mutation in the adenomatous polyposis coli gene.It is characterized by the early development of hundreds of adenomas in the colon during the second decade of life.If prophylactic colectomy is not performed,most patients eventually develop colorectal cancer(CRC).CASE SUMMARY We present the mutational profile of a case of FAP that progressed to CRC.A 45-year-old Saudi man presented with intestinal obstruction and underwent a total colectomy.The colon showed hundreds of polyps and two infiltrative ulcerative lesions,which proved to be adenocarcinoma according to histopathology.We performed next-generation sequencing and found mutations in the TP53,NRAS,EGFR PDGFR,MET,KIT,ERBB2,and GUSP genes.CONCLUSION To the best of our knowledge,this case report is the first to sheds the light on the mutation profile of FAP that progressed to CRC in Saudi Arabia.
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.
文摘AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.
基金Supported by National Natural Science Foundation of China,No.81770379.
文摘BACKGROUND Hypertrophic cardiomyopathy(HCM)is one of the most prevalent inherited myocardial disorders and is charac-terized by considerable genetic and phenotypic heterogeneity.A subset of patients with HCM progress to a dilated phase of HCM(DPHCM),which is associated with a poor prognosis;however,the underlying pathogenesis remains inadequately understood.CASE SUMMARY In this study,we present a case involving a pedigree with familial DPHCM and conduct a retrospective review of patients with DPHCM with identified gene mutations.Through panel sequencing targeting the coding regions of 312 genes associated with inherited cardiomyopathy,a heterozygous missense mutation(c.746G>A,p.Arg249Glu)in the MYH7 gene was identified in the proband(III-5).Sanger sequencing subsequently confirmed this pathogenic mutation in three additional family members(II-4,III-4,and IV-3).A total of 26 well-documented patients with DPHCM were identified in the literature.Patients with DPHCM are commonly middle-aged and male.The mean age of patients with DPHCM was 53.43±12.79 years.Heart failure,dyspnoea,and atrial fibrillation were the most prevalent symptoms observed,accompanied by an average left ventricular end-diastolic size of 58.62 mm.CONCLUSION Our findings corroborate the pathogenicity of the MYH7(c.746G>A,p.Arg249Glu)mutation for DPHCM and suggest that the Arg249Gln mutation may be responsible for high mortality.
文摘BACKGROUND Dystrophic epidermolysis bullosa is characterized by fragile ulcerations of the skin caused by mutations in specific genes.However,genetic typing of this con-dition is rare.CASE SUMMARY An 11-year-old female suffered from recurrent fever,visible ulcerations of the entire skin,and severe malnutrition.Genetic testing revealed a frameshift mu-tation in the coding region 4047 of the 35th intron region of COL7A1,and she was diagnosed as malnutrition-type epidermolysis bullosa.Drug therapy(immu-noglobulin,fresh frozen plasma),topical therapy(silver ion dressing),fever redu-ction,cough relief,and promotion of gastrointestinal peristalsis are mainly used for respiratory and gastrointestinal complications.The patient’s condition impro-ved after treatment.CONCLUSION Dystrophic epidermolysis bullosa caused by a new framework shift mutation in COL7A1 should be taken seriously.
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 Henan Province Science and Technology Research Project,No.232102310043Henan Provincial Science and Technology Research and Development Plan Joint Fund,No.222103810047Key Scientific Research Project Plan of Colleges and Universities in Henan Province,No.22A320033.
文摘BACKGROUND Colorectal cancer(CRC)remains a major global health burden due to its high incidence and mortality,with treatment efficacy often hindered by tumor hetero-geneity,drug resistance,and a complex tumor microenvironment(TME).Lactate metabolism plays a pivotal role in reshaping the TME,promoting immune eva-sion and epithelial-mesenchymal transition,making it a promising target for novel therapeutic strategies and prognostic modeling in CRC.AIM To offer an in-depth analysis of the role of lactate metabolism in CRC,high-lighting its significance in the TME and therapeutic response.METHODS Utilizing single-cell and transcriptomic data from the Gene Expression Omnibus and The Cancer Genome Atlas,we identified key lactate metabolic activities,particularly in the monocyte/macrophage subpopulation.RESULTS Seven lactate metabolism-associated genes were significantly linked to CRC prognosis and used to construct a predictive model.This model accurately forecasts patient outcomes and reveals notable distinct patterns of immune infiltration and transcriptomic profiles mutation profiles between high-and low-risk groups.High-risk patients demonstrated elevated immune cell infiltration,increased mutation frequencies,and heightened sensitivity to specific drugs(AZD6482,tozasertib,and SB216763),providing a foundation for personalized treatment approaches.Additionally,a nomogram integrating clinical and metabolic data effectively predicted 1-,3-,and 5-year survival rates.CONCLUSION This report underscored the pivotal mechanism of lactate metabolism in CRC prognosis and suggest novel avenues for therapeutic intervention.
