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
Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apopt...Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.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
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
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
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
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 Patients with BRAF V600E mutant metastatic colorectal cancer(mCRC)have a low incidence rate,poor biological activity,suboptimal response to conventional treatments,and a poor prognosis.In the previous cohor...BACKGROUND Patients with BRAF V600E mutant metastatic colorectal cancer(mCRC)have a low incidence rate,poor biological activity,suboptimal response to conventional treatments,and a poor prognosis.In the previous cohort study on mCRC conducted by our team,it was observed that integrated Chinese and Western medicine treatment could significantly prolong the overall survival(OS)of patients with colorectal cancer.Therefore,we further explored the survival benefits in the population with BRAF V600E mutant mCRC.AIM To evaluate the efficacy of integrated Chinese and Western medicine in the treatment of BRAF V600E mutant metastatic colorectal cancer.METHODS A cohort study was conducted on patients with BRAF V600E mutant metastatic colorectal cancer admitted to Xiyuan Hospital of China Academy of Chinese Medical Sciences and Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region from January 2016 to December 2022.The patients were divided into two cohorts.RESULTS A total of 34 cases were included,with 23 in Chinese-Western medicine cohort(cohort A)and 11 in Western medicine cohort(cohort B).The median overall survival was 19.9 months in cohort A and 14.2 months in cohort B,with a statistically significant difference(P=0.038,hazard ratio=0.46).The 1-3-year survival rates were 95.65%(22/23),39.13%(9/23),and 26.09%(6/23)in cohort A,and 63.64%(7/11),18.18%(2/11),and 9.09%(1/11)in cohort B,respectively.Subgroup analysis showed statistically significant differences in median OS between the two cohorts in the right colon,liver metastasis,chemotherapy,and first-line treatment subgroups(P<0.05).CONCLUSION Integrated Chinese and Western medicine can prolong the survival and reduce the risk of death in patients with BRAF V600E mutant metastatic colorectal cancer,with more pronounced benefits observed in patients with right colon involvement,liver metastasis,combined chemotherapy,and first-line treatment.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
Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular ta...Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular targets.Kirsten rat sarcoma viral oncogene homolog mutations,present in up to 90%of cases,drive aggressive biology,though most variants remain undruggable;allele-specific inhibitors and exosome-based RNA interference are under exploration.Breast cancer susceptibility gene 1/2 mutations occur in 4%-7%of patients,con-ferring sensitivity to platinum agents and poly(ADP-ribose)polymerase inhi-bitors.Other rare but actionable alterations-such as v-raf murine sarcoma viral oncogene homolog B1(V600),neurotrophic tyrosine receptor kinase,fibroblast growth factor receptor 2,and RET fusions-show benefit in tumor-agnostic trials,broadening options for selected subgroups.Immunotherapy is limited,as high tumor mutational burden and mismatch repair deficiency are uncommon in PDAC,though predictive when present.Co-mutations in tumor protein p53,cyclin-dependent kinase inhibitor 2A,and SMAD4 further stratify prognosis and influence therapy response.Cross-cancer analyses underscore the necessity of PDAC-specific strategies despite shared genomic drivers.Collectively,these insights support routine germline and somatic testing,enrollment in biomarker-matched trials,and rational combination strategies,establishing molecular profiling as central to advancing precision treatment in pancreatic cancer.展开更多
Gerbera,a popular commercial cut flower with vibrant and striking colors has gained immense popularity in the floriculture industry.They are widely cultivated in various regions,making them available throughout the ye...Gerbera,a popular commercial cut flower with vibrant and striking colors has gained immense popularity in the floriculture industry.They are widely cultivated in various regions,making them available throughout the year.As a better alternative to conventional propagation methods(via seeds and rhizomes),plant tissue culture serves as way to avail large-scale,uniform,disease-free plantlets for commercial cultivation as well as to develop novel genotypes.In addition,it ensures production of healthy plantlets throughout the year in limited space.Based on the plant tissue culture techniques,the in vitro polyploidization,mutagenesis,and genetic transformation pave a path for creation of variation and eventually enhancing the ornamental traits to address the consumers’preferences and also facilitates in developing stress tolerant lines thereby minimizing the losses during cultivation,maintaining the quality of the flowers.This comprehensive review article presents an overview of the recent advancements on genetic improvement of gerbera via various cutting-edge plant tissue culture-based tools and techniques that contribute in enhancing the quality and efficiency of gerbera cultivation,meeting the demands of the floriculture industry while addressing the challenges of changing environment and resource limitations.展开更多
Abiotic stresses,particularly salinity,pose a major threat to rice productivity,highlighting the need to identify novel genetic resources to improve stress tolerance.Gamma irradiation remains one of the most widely us...Abiotic stresses,particularly salinity,pose a major threat to rice productivity,highlighting the need to identify novel genetic resources to improve stress tolerance.Gamma irradiation remains one of the most widely used tools breeding stress-tolerant plant varieties.In this study,we identified a salt-tolerant rice mutant,salt-insensitive TILLING line 4(sitl4),generated via gamma irradiation and linked its enhanced tolerance to a loss-of-function mutation in Oryza sativa protein acyltransferase for ABA response 1(OsPATA1),which encodes a DHHC-type palmitoyl acyltransferase.Functional analyses using both sitl4 and a CRISPR/Cas9-mediated OsPATA1-knockout line(ospata1)revealed that disruption of OsPATA1 leads to increased abscisic acid(ABA)accumulation and upregulation of ABA-responsive genes under salt stress conditions.We identified OsEULD1b,a previously uncharacterized Euonymus lectin(EUL)domaincontaining protein,as an interactor of OsPATA1.In sitl4 and ospata1,OsEULD1b displayed cytosolic retention,suggesting that its subcellular redistribution enhances its role in ABA-mediated stress signaling.Taken together,our findings demonstrate that OsPATA1 and OsEULD1b form a regulatory module that modulates the ABA-dependent salt stress responses in rice.These results provide new insights into the molecular mechanisms underlying abiotic stress tolerance and will help to identify potential genetic targets for developing stress-tolerant rice cultivars through molecular breeding or genome editing.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
This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer(NSCLC),specifically lung adenocarcinoma,featuring reactive oxygen species proto-oncogene 1-receptor(ROS1)co-muta...This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer(NSCLC),specifically lung adenocarcinoma,featuring reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation.The case involves a 64-year-old patient who exhibited both epidermal growth factor receptor(EGFR)L858R mutation and ROS1 rearrangement,achieving significant disease stabilization following treatment with crizotinib.This rare EGFR/ROS1 co-mutation poses distinct challenges for clinical management and highlights the necessity of personalized treatment strategies.While third-generation EGFR tyrosine kinase inhibitors(TKIs),such as osimertinib,are commonly regarded as first-line therapies,recent studies indicate that crizotinib may offer superior disease control in certain EGFR-mutant patients,particularly those who exhibit poor responses to EGFR TKIs.The case also examines the influence of tumor cell genetic heterogeneity on treatment response,underscoring the importance of evaluating tumor characteristics.In patients with EGFR/ROS1 co-mutation,gefitinib is generally effective as a first-line treatment;however,its efficacy can be limited,whereas crizotinib has demonstrated improved disease control.Future research should focus on identifying optimal treatment strategies for patients with EGFR/ROS1 co-mutation to enhance patient outcomes.In conclusion,this case report not only illustrates the effectiveness of crizotinib in managing patients with EGFR/ROS1 co-mutation but also underscores the importance of personalized treatment approaches,offering valuable insights for improving clinical outcomes in NSCLC patients with complex genetic profiles.TO THE EDITOR I read with great interest the case report by Peng et al[1],titled“Concomitant Epidermal Growth Factor Receptor Mutation/C-ROS Oncogene 1 Rearrangement in Non-Small Cell Lung Cancer”,published in the World Journal of Clinical Oncology[1].This report presents a compelling case of the exceedingly rare epidermal growth factor receptor(EGFR)/reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation in non-small cell lung cancer(NSCLC),specifically in a patient with lung adenocarcinoma.The authors describe a 64-year-old woman with an EGFR L858R mutation and ROS1 rearrangement,who achieved notable disease stability with prolonged crizotinib treatment.This case,with its distinct clinical features and challenges inherent to EGFR/ROS1 co-mutations,provides valuable insights for the oncology community and underscores the potential efficacy of ROS1-targeted therapies in treating co-mutated NSCLC.展开更多
This paper introduces a novel optimization approach called Recuperated Seed Search Optimization(RSSO),designed to address challenges in solving mechanical engineering design problems.Many optimization techniques strug...This paper introduces a novel optimization approach called Recuperated Seed Search Optimization(RSSO),designed to address challenges in solving mechanical engineering design problems.Many optimization techniques struggle with slow convergence and suboptimal solutions due to complex,nonlinear natures.The Sperm Swarm Optimization(SSO)algorithm,which mimics the sperm’s movement to reach an egg,is one such technique.To improve SSO,researchers combined it with three strategies:opposition-based learning(OBL),Cauchy mutation(CM),and position clamping.OBL introduces diversity to SSO by exploring opposite solutions,speeding up convergence.CM enhances both exploration and exploitation capabilities throughout the optimization process.This combined approach,RSSO,has been rigorously tested on standard benchmark functions,real-world engineering problems,and through statistical analysis(Wilcoxon test).The results demonstrate that RSSO significantly outperforms other optimization algorithms,achieving faster convergence and better solutions.The paper details the RSSO algorithm,discusses its implementation,and presents comparative results that validate its effectiveness in solving complex engineering design challenges.展开更多
Base editors are essential tools for precise genome editing in plants.However,achieving high efficiency in C-to-G editing while minimizing byproduct and offtarget mutations remains challenging.In this study,we present...Base editors are essential tools for precise genome editing in plants.However,achieving high efficiency in C-to-G editing while minimizing byproduct and offtarget mutations remains challenging.In this study,we present the development and evaluation of a novel glycosylase-based cytosine base editor(gCBE)for efficient C-to-G editing in rice.Unlike traditional cytosine base editors,which rely on cytosine deamination,gCBE directly excises cytosine to generate an apurinic/apyrimidinic(AP)site,thus circumventing the deamination step and reducing the production of C-to-T byproducts.We constructed several gCBE variants,including N-gCBE,M-gCBE,and C-gCBE,by fusing engineered human UDG2(UNG*)to SpCas9 nickase(nSpCas9,D10A)and tested their editing efficiency and specificity in rice.Our results demonstrate that M-gCBE achieved efficient C-to-G editing(6.3%to 37.5%)similar to OsCGBE(9.4%to 28.1%)at most targets,though with site-dependent variations.Notably,gCBE tools showed a marked reduction in C-to-T byproducts,with average C-to-T mutation rates of 12.5%for N-gCBE and 16.7%for M-gCBE,compared to 53.1%for OsCGBE.Notably,both N-gCBE and M-gCBE were capable of generating homozygous C-to-G mutations in the T_(0)generation,a key advantage over OsCGBE,which predominantly generated C-to-T mutations.Off-target analysis revealed minimal off-target effects with M-gCBE,highlighting its potential for high-precision genome editing.These findings suggest that gCBE tools,particularly M-gCBE,are highly efficient and precise,providing an advanced solution for C-to-G editing in plants and offering promising applications for crop improvement.展开更多
This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors(GISTs).We read with great interest this article concerning the diagnosis,treatment,and post-treatment management of patient...This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors(GISTs).We read with great interest this article concerning the diagnosis,treatment,and post-treatment management of patients with familial GISTs.The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs.The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha(PDGFRA)genes.A subset of GISTs without these mutations known as wild-type GISTs,may harbor other rare mutations,impacting their response to targeted therapies.Clinically,patients with GISTs present with nonspecific symptoms,often leading to delayed diagnosis.Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs.Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors.The management of GISTs,especially in familial cases,requires a multidisciplinary approach.Cases of different gene mutations were reported in the same family,suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.展开更多
Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibi...Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.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
Southern corn leaf blight(SCLB)caused by Cochliobolus heterostrophus,is a widespread foliar disease that has a substantial impact on maize yield in the Huang-Huai-Hai Region of China.Pydiflumetofen(Pyd),a new succinat...Southern corn leaf blight(SCLB)caused by Cochliobolus heterostrophus,is a widespread foliar disease that has a substantial impact on maize yield in the Huang-Huai-Hai Region of China.Pydiflumetofen(Pyd),a new succinate dehydrogenase inhibitor(SDHI),has been found as a promising fungicide for the efficient control of SCLB,however,resistance of C.heterostrophus to Pyd has not been studied well.Here,five Pyd-resistant mutants were generated through fungicide adaptation.Sequence alignment analysis revealed that these mutants primarily mutated in ChSdhB and ChSdhD,with three genotypes:ChSdhB^(H277Y),ChSdhB^(I279T)and ChSdhD^(H133Y),exhibiting two distinct categories of resistance:high resistance(HR)and moderate resistance(MR),among which the resistance factors were 214.22 and 44.33-53.67,respectively.These mutants were more pathogenic than the wild-type parental strains,but there was a significant reduction in mycelial growth rate and sporulation in the resistant mutants,indicating a significant fitness cost associated with resistance to Pyd.In addition,this study revealed a positive cross-resistance between Pyd and another SDHI fungicide cyclobutrifluram.However,no cross-resistance was found between Pyd and other classes of fungicides,including prochloraz,fludioxonil,iprodione or pyraclostrobin.Homology modeling and molecular docking further confirmed that point mutations of ChSdhB^(H277Y),ChSdhB^(I279T),and ChSdhD^(H133Y)could reduce binding affinity between Pyd and its target subunits from-74.07,-74.07,-152.52 kcal mol^(-1)to-3.90,-4.95,-9.93 kcal mol^(-1),respectively.These findings not only provided valuable insights for managing SCLB caused by C.heterostrophus,but also enhanced our understanding of molecular mechanism underlying plant pathogen resistance to Pyd.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 National Natural Science Foundation of China,Nos.32271043(to ZW)and 82171047(to YM)the both Science and Technology Major Project of Shanghai,No.2018SHZDZX01 and ZJLabShanghai Center for Brain Science and Brain-Inspired Technology(to ZW)。
文摘Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells,which is involved in retinal ganglion cell apoptosis in glaucoma.Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma.In this study,we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation.Following this,we treated Müller glial cells in vitro and in vivo with the m Glu R I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr^(9)Asp overexpression.We found that both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited activation of Müller glial cells.Subsequently,we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr^(9)Asp in the eye,and observed similar results in Müller cells in vivo as those seen in vitro.Both Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression inhibited Müller cell activation,regulated the balance of Bax/Bcl-2,and reduced the m RNA and protein levels of pro-inflammatory factors,including interleukin-1βand tumor necrosis factor-α.Furthermore,we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia.In this co-culture system,we observed elevated adenosine triphosphate concentrations in activated Müller cells,increased levels of translocator protein(a marker of microglial activation),and elevated interleukin-1βm RNA and protein levels in microglia induced by activated Müller cells.These changes could be reversed by Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression in Müller cells.Kir4.1 overexpression,but not Kir4.1 Tyr^(9)Asp overexpression,reduced the number of proliferative and migratory microglia induced by activated Müller cells.Collectively,these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma.Kir4.1 and Kir4.1 Tyr^(9)Asp overexpression attenuated Müller cell activation,reduced ATP/P2X receptor–mediated interactions between glial cells,inhibited microglial activation,and decreased the synthesis and release of pro-inflammatory factors,consequently ameliorating retinal ganglion cell apoptosis in glaucoma.
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 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 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 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 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 National Natural Science Foundation of China,No.82174461Hospital Capability Enhancement Project of Xiyuan Hospital,CACMS,No.XYZX0201-22Technology Innovation Project of China Academy of Chinese Medical Sciences,No.CI2021A01811.
文摘BACKGROUND Patients with BRAF V600E mutant metastatic colorectal cancer(mCRC)have a low incidence rate,poor biological activity,suboptimal response to conventional treatments,and a poor prognosis.In the previous cohort study on mCRC conducted by our team,it was observed that integrated Chinese and Western medicine treatment could significantly prolong the overall survival(OS)of patients with colorectal cancer.Therefore,we further explored the survival benefits in the population with BRAF V600E mutant mCRC.AIM To evaluate the efficacy of integrated Chinese and Western medicine in the treatment of BRAF V600E mutant metastatic colorectal cancer.METHODS A cohort study was conducted on patients with BRAF V600E mutant metastatic colorectal cancer admitted to Xiyuan Hospital of China Academy of Chinese Medical Sciences and Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region from January 2016 to December 2022.The patients were divided into two cohorts.RESULTS A total of 34 cases were included,with 23 in Chinese-Western medicine cohort(cohort A)and 11 in Western medicine cohort(cohort B).The median overall survival was 19.9 months in cohort A and 14.2 months in cohort B,with a statistically significant difference(P=0.038,hazard ratio=0.46).The 1-3-year survival rates were 95.65%(22/23),39.13%(9/23),and 26.09%(6/23)in cohort A,and 63.64%(7/11),18.18%(2/11),and 9.09%(1/11)in cohort B,respectively.Subgroup analysis showed statistically significant differences in median OS between the two cohorts in the right colon,liver metastasis,chemotherapy,and first-line treatment subgroups(P<0.05).CONCLUSION Integrated Chinese and Western medicine can prolong the survival and reduce the risk of death in patients with BRAF V600E mutant metastatic colorectal cancer,with more pronounced benefits observed in patients with right colon involvement,liver metastasis,combined chemotherapy,and first-line treatment.
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.
文摘Pancreatic ductal adenocarcinoma(PDAC)remains one of the most lethal ma-lignancies with limited treatment efficacy.Advances in precision oncology,enabled by next-generation sequencing,have highlighted key molecular targets.Kirsten rat sarcoma viral oncogene homolog mutations,present in up to 90%of cases,drive aggressive biology,though most variants remain undruggable;allele-specific inhibitors and exosome-based RNA interference are under exploration.Breast cancer susceptibility gene 1/2 mutations occur in 4%-7%of patients,con-ferring sensitivity to platinum agents and poly(ADP-ribose)polymerase inhi-bitors.Other rare but actionable alterations-such as v-raf murine sarcoma viral oncogene homolog B1(V600),neurotrophic tyrosine receptor kinase,fibroblast growth factor receptor 2,and RET fusions-show benefit in tumor-agnostic trials,broadening options for selected subgroups.Immunotherapy is limited,as high tumor mutational burden and mismatch repair deficiency are uncommon in PDAC,though predictive when present.Co-mutations in tumor protein p53,cyclin-dependent kinase inhibitor 2A,and SMAD4 further stratify prognosis and influence therapy response.Cross-cancer analyses underscore the necessity of PDAC-specific strategies despite shared genomic drivers.Collectively,these insights support routine germline and somatic testing,enrollment in biomarker-matched trials,and rational combination strategies,establishing molecular profiling as central to advancing precision treatment in pancreatic cancer.
基金funded by Department of Science&Technology and Biotechnology,Govt.of West Bengal,India[Sanction No.565(Sanc.)/STBT-13015/15/11/2021-ST SEC]。
文摘Gerbera,a popular commercial cut flower with vibrant and striking colors has gained immense popularity in the floriculture industry.They are widely cultivated in various regions,making them available throughout the year.As a better alternative to conventional propagation methods(via seeds and rhizomes),plant tissue culture serves as way to avail large-scale,uniform,disease-free plantlets for commercial cultivation as well as to develop novel genotypes.In addition,it ensures production of healthy plantlets throughout the year in limited space.Based on the plant tissue culture techniques,the in vitro polyploidization,mutagenesis,and genetic transformation pave a path for creation of variation and eventually enhancing the ornamental traits to address the consumers’preferences and also facilitates in developing stress tolerant lines thereby minimizing the losses during cultivation,maintaining the quality of the flowers.This comprehensive review article presents an overview of the recent advancements on genetic improvement of gerbera via various cutting-edge plant tissue culture-based tools and techniques that contribute in enhancing the quality and efficiency of gerbera cultivation,meeting the demands of the floriculture industry while addressing the challenges of changing environment and resource limitations.
基金supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF)Ministry of Education(RS-2021-NR060130,00355529).
文摘Abiotic stresses,particularly salinity,pose a major threat to rice productivity,highlighting the need to identify novel genetic resources to improve stress tolerance.Gamma irradiation remains one of the most widely used tools breeding stress-tolerant plant varieties.In this study,we identified a salt-tolerant rice mutant,salt-insensitive TILLING line 4(sitl4),generated via gamma irradiation and linked its enhanced tolerance to a loss-of-function mutation in Oryza sativa protein acyltransferase for ABA response 1(OsPATA1),which encodes a DHHC-type palmitoyl acyltransferase.Functional analyses using both sitl4 and a CRISPR/Cas9-mediated OsPATA1-knockout line(ospata1)revealed that disruption of OsPATA1 leads to increased abscisic acid(ABA)accumulation and upregulation of ABA-responsive genes under salt stress conditions.We identified OsEULD1b,a previously uncharacterized Euonymus lectin(EUL)domaincontaining protein,as an interactor of OsPATA1.In sitl4 and ospata1,OsEULD1b displayed cytosolic retention,suggesting that its subcellular redistribution enhances its role in ABA-mediated stress signaling.Taken together,our findings demonstrate that OsPATA1 and OsEULD1b form a regulatory module that modulates the ABA-dependent salt stress responses in rice.These results provide new insights into the molecular mechanisms underlying abiotic stress tolerance and will help to identify potential genetic targets for developing stress-tolerant rice cultivars through molecular breeding or genome editing.
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.
文摘This letter provides a review of the report by Peng et al on a unique case of non-small cell lung cancer(NSCLC),specifically lung adenocarcinoma,featuring reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation.The case involves a 64-year-old patient who exhibited both epidermal growth factor receptor(EGFR)L858R mutation and ROS1 rearrangement,achieving significant disease stabilization following treatment with crizotinib.This rare EGFR/ROS1 co-mutation poses distinct challenges for clinical management and highlights the necessity of personalized treatment strategies.While third-generation EGFR tyrosine kinase inhibitors(TKIs),such as osimertinib,are commonly regarded as first-line therapies,recent studies indicate that crizotinib may offer superior disease control in certain EGFR-mutant patients,particularly those who exhibit poor responses to EGFR TKIs.The case also examines the influence of tumor cell genetic heterogeneity on treatment response,underscoring the importance of evaluating tumor characteristics.In patients with EGFR/ROS1 co-mutation,gefitinib is generally effective as a first-line treatment;however,its efficacy can be limited,whereas crizotinib has demonstrated improved disease control.Future research should focus on identifying optimal treatment strategies for patients with EGFR/ROS1 co-mutation to enhance patient outcomes.In conclusion,this case report not only illustrates the effectiveness of crizotinib in managing patients with EGFR/ROS1 co-mutation but also underscores the importance of personalized treatment approaches,offering valuable insights for improving clinical outcomes in NSCLC patients with complex genetic profiles.TO THE EDITOR I read with great interest the case report by Peng et al[1],titled“Concomitant Epidermal Growth Factor Receptor Mutation/C-ROS Oncogene 1 Rearrangement in Non-Small Cell Lung Cancer”,published in the World Journal of Clinical Oncology[1].This report presents a compelling case of the exceedingly rare epidermal growth factor receptor(EGFR)/reactive oxygen species proto-oncogene 1-receptor(ROS1)co-mutation in non-small cell lung cancer(NSCLC),specifically in a patient with lung adenocarcinoma.The authors describe a 64-year-old woman with an EGFR L858R mutation and ROS1 rearrangement,who achieved notable disease stability with prolonged crizotinib treatment.This case,with its distinct clinical features and challenges inherent to EGFR/ROS1 co-mutations,provides valuable insights for the oncology community and underscores the potential efficacy of ROS1-targeted therapies in treating co-mutated NSCLC.
文摘This paper introduces a novel optimization approach called Recuperated Seed Search Optimization(RSSO),designed to address challenges in solving mechanical engineering design problems.Many optimization techniques struggle with slow convergence and suboptimal solutions due to complex,nonlinear natures.The Sperm Swarm Optimization(SSO)algorithm,which mimics the sperm’s movement to reach an egg,is one such technique.To improve SSO,researchers combined it with three strategies:opposition-based learning(OBL),Cauchy mutation(CM),and position clamping.OBL introduces diversity to SSO by exploring opposite solutions,speeding up convergence.CM enhances both exploration and exploitation capabilities throughout the optimization process.This combined approach,RSSO,has been rigorously tested on standard benchmark functions,real-world engineering problems,and through statistical analysis(Wilcoxon test).The results demonstrate that RSSO significantly outperforms other optimization algorithms,achieving faster convergence and better solutions.The paper details the RSSO algorithm,discusses its implementation,and presents comparative results that validate its effectiveness in solving complex engineering design challenges.
基金supported by the National Natural Science Foundation of China(82404798)the Natural Science Foundation of Sichuan Province(2024NSFSC1831)+1 种基金the National Key Laboratory for Tropical Crop Breeding(NKLTCB-RC202403,NKLTCBZRJJ4)the Hainan Seed Industrial Laboratory(B22C1000P).
文摘Base editors are essential tools for precise genome editing in plants.However,achieving high efficiency in C-to-G editing while minimizing byproduct and offtarget mutations remains challenging.In this study,we present the development and evaluation of a novel glycosylase-based cytosine base editor(gCBE)for efficient C-to-G editing in rice.Unlike traditional cytosine base editors,which rely on cytosine deamination,gCBE directly excises cytosine to generate an apurinic/apyrimidinic(AP)site,thus circumventing the deamination step and reducing the production of C-to-T byproducts.We constructed several gCBE variants,including N-gCBE,M-gCBE,and C-gCBE,by fusing engineered human UDG2(UNG*)to SpCas9 nickase(nSpCas9,D10A)and tested their editing efficiency and specificity in rice.Our results demonstrate that M-gCBE achieved efficient C-to-G editing(6.3%to 37.5%)similar to OsCGBE(9.4%to 28.1%)at most targets,though with site-dependent variations.Notably,gCBE tools showed a marked reduction in C-to-T byproducts,with average C-to-T mutation rates of 12.5%for N-gCBE and 16.7%for M-gCBE,compared to 53.1%for OsCGBE.Notably,both N-gCBE and M-gCBE were capable of generating homozygous C-to-G mutations in the T_(0)generation,a key advantage over OsCGBE,which predominantly generated C-to-T mutations.Off-target analysis revealed minimal off-target effects with M-gCBE,highlighting its potential for high-precision genome editing.These findings suggest that gCBE tools,particularly M-gCBE,are highly efficient and precise,providing an advanced solution for C-to-G editing in plants and offering promising applications for crop improvement.
基金National Natural Science Foundation of China,No.82370569Basic and Applied Basic Research Foundation of Guangdong Province,No.2022A1515012647the Key Program for Science and Technology Projects of Social Development in Zhuhai,No.2220004000249(to Li XF).
文摘This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors(GISTs).We read with great interest this article concerning the diagnosis,treatment,and post-treatment management of patients with familial GISTs.The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs.The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha(PDGFRA)genes.A subset of GISTs without these mutations known as wild-type GISTs,may harbor other rare mutations,impacting their response to targeted therapies.Clinically,patients with GISTs present with nonspecific symptoms,often leading to delayed diagnosis.Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs.Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors.The management of GISTs,especially in familial cases,requires a multidisciplinary approach.Cases of different gene mutations were reported in the same family,suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.
基金supported by grants from the National Key R&D Program of China(2019YFA0801603)the Guangdong High Level Innovation Research Institute(2021B0909050004)+2 种基金the National Natural Science Foundation of China(32330044,32170951,82201615,and 82101393)the Natural Science Foundation of Jiangsu Province(BK20201255 and BK20210008)the Fundamental Research Funds for the Central Universities(021414380533).
文摘Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
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 the National Key Research and Development Program of China(2023YFD1401504)the Open Project of Anhui Province Key Laboratory of Pesticide Resistance Management on Grain and Vegetable Pests,China(PKLPRMGVP202402)+3 种基金the Programs for the Scientific Research Activities of Academic and Technical Leaders of Anhui Province,China(2020D251)the Development Fund for Talent Personnel of Anhui Agricultural University,China(rc342006)the University Synergy Innovation Program of Anhui Province,China(GXXT-2021-059)Anhui Province Agricultural Eco-Environmental Protection and Quality Safety Industry Technology System,China。
文摘Southern corn leaf blight(SCLB)caused by Cochliobolus heterostrophus,is a widespread foliar disease that has a substantial impact on maize yield in the Huang-Huai-Hai Region of China.Pydiflumetofen(Pyd),a new succinate dehydrogenase inhibitor(SDHI),has been found as a promising fungicide for the efficient control of SCLB,however,resistance of C.heterostrophus to Pyd has not been studied well.Here,five Pyd-resistant mutants were generated through fungicide adaptation.Sequence alignment analysis revealed that these mutants primarily mutated in ChSdhB and ChSdhD,with three genotypes:ChSdhB^(H277Y),ChSdhB^(I279T)and ChSdhD^(H133Y),exhibiting two distinct categories of resistance:high resistance(HR)and moderate resistance(MR),among which the resistance factors were 214.22 and 44.33-53.67,respectively.These mutants were more pathogenic than the wild-type parental strains,but there was a significant reduction in mycelial growth rate and sporulation in the resistant mutants,indicating a significant fitness cost associated with resistance to Pyd.In addition,this study revealed a positive cross-resistance between Pyd and another SDHI fungicide cyclobutrifluram.However,no cross-resistance was found between Pyd and other classes of fungicides,including prochloraz,fludioxonil,iprodione or pyraclostrobin.Homology modeling and molecular docking further confirmed that point mutations of ChSdhB^(H277Y),ChSdhB^(I279T),and ChSdhD^(H133Y)could reduce binding affinity between Pyd and its target subunits from-74.07,-74.07,-152.52 kcal mol^(-1)to-3.90,-4.95,-9.93 kcal mol^(-1),respectively.These findings not only provided valuable insights for managing SCLB caused by C.heterostrophus,but also enhanced our understanding of molecular mechanism underlying plant pathogen resistance to Pyd.
