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
The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are imm...The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are immunological,and others associated as idiopathic,are undiagnosed by all possible means.Some of the rare diseases are congenital in nature,passing from the parent to the child.Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent.There is a search for newer treatments for such diseases,which is called genomic medicine.Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual.This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use.In the developing era of precision medicine,genomics,epigenomics,environmental exposure,and other data would be used to more accurately guide individual diagnosis and treatment.Genomic medicine is already making an impact in the fields of oncology,pharmacology,rare,infectious and many undiagnosed diseases.It is beginning to fuel new approaches in certain medical specialties.Oncology is at the leading edge of incorporating genomics,as diagnostics for genetic and genomic markers are increasingly included in cancer screening,and to guide tailored treatment strategies.Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways,including genetic testing(hereditary pancreatitis and hereditary gastrointestinal cancer syndromes).Genetic testing can also help subtype diseases,such as classifying pancreatitis as idiopathic or hereditary.Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries.Gene therapy strategies include gene addition,gene editing,messenger RNA therapy,and gene silencing.Understanding genetic determinants,advances in genetics,have led to a better understanding of the genetic factors that contribute to human disease.Family-member risk stratification and genetic diagnosis can help identify family members who are at risk,which can lead to preventive treatments,lifestyle recommendations,and routine follow ups.Selecting target genes helps identify the gene targets associated with each gastrointestinal disease.Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease,gastroesophageal reflux disease,non-alcoholic fatty liver disease,and irritable bowel syndrome.With advancing tools and technology,research in the search of newer and individualized treatment,genes and genetic medicines are expected to play a significant role in human health and gastroenterology.展开更多
BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to th...BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.展开更多
Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations...Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.展开更多
BACKGROUND Early renal artery thrombosis after kidney transplantation is rare but often leads to graft loss.Prompt diagnosis and intervention are essential,particularly in patients with inherited thrombophilias such a...BACKGROUND Early renal artery thrombosis after kidney transplantation is rare but often leads to graft loss.Prompt diagnosis and intervention are essential,particularly in patients with inherited thrombophilias such as factor V Leiden(FVL)mutation.CASE SUMMARY A kidney transplant recipient with FVL mutation developed an acute transplant renal artery thrombosis.The immediate post-operative Doppler ultrasonography revealed thrombosis of the main and inferior polar renal arteries.Emergent thrombectomy and separate arterial re-anastomoses were performed after cold perfusion with heparinized saline and vasodilator solution.Reperfusion was successful with immediate urine output and gradual improvement in renal function.The patient was discharged on direct oral anticoagulation therapy.CONCLUSION Early detection and surgical intervention can preserve graft function in posttransplant renal artery thrombosis even in patients at high risk.展开更多
The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response...The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.展开更多
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
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
Preserving genetic diversity is crucial for the long-term survival of wild plant species,yet many remain at risk of genetic erosion due to small population sizes and habitat fragmentation.Here,we present a comparative...Preserving genetic diversity is crucial for the long-term survival of wild plant species,yet many remain at risk of genetic erosion due to small population sizes and habitat fragmentation.Here,we present a comparative genomic study of the critically endangered Oreocharis esquirolii(Gesneriaceae)and its widespread congener O.maximowiczii.We assembled and annotated chromosome-level reference genomes for both species and generated whole-genome resequencing data from 28 O.esquirolii and 79 O.maximowiczii individuals.Our analyses reveal substantially lower genetic diversity and higher inbreeding in O.esquirolii,despite its overall reduced mutational burden.Notably,O.esquirolii exhibits an elevated proportion of strongly deleterious mutations relative to O.maximowiczii,suggesting that limited opportunities for purging have allowed these variants to accumulate.These contrasting genomic profileslikely reflectdivergent demographic histories,with O.esquirolii having experienced severe bottlenecks and protracted population decline.Collectively,our findingshighlight the critically endangered status of O.esquirolii,characterized by diminished genetic diversity,pronounced inbreeding,and reduced ability to eliminate deleterious alleles.This study provides valuable genomic resources for the Gesneriaceae family and underscores the urgent need for targeted conservation measures,including habitat protection and ex situ preservation efforts,to mitigate the extinction risk facing O.esquirolii and potentially other threatened congeners.展开更多
The stability and fracture behavior of a goaf roof beneath an open-pit bench are critical concerns,especially under impact loading.However,the effect of the thickness-to-span ratio on dynamic failure modes remains lar...The stability and fracture behavior of a goaf roof beneath an open-pit bench are critical concerns,especially under impact loading.However,the effect of the thickness-to-span ratio on dynamic failure modes remains largely unexplored,as existing research focuses mainly on static stability.Energy dissipation and instability evolution under impact loading require further study.To address this gap,this study conducts drop-weight impact experiments on specimens with circular perforations,complemented by numerical simulations.By integrating dimensional analysis,cusp catastrophe theory,and strength reduction techniques,the dynamic instability mechanism of goaf roofs with varying thickness-to-span ratios is revealed.Results show that the thickness-to-span ratio significantly influences energy accumulation and dissipation during roof failure.A higher ratio increases both the magnitude and rate of energy dissipation,particularly during crack initiation and stable propagation,while its impact diminishes in the final failure stage.Optimizing the thickness-to-span ratio within a critical range enhances structural stability,improving the safety factor by up to 83%.However,beyond a certain threshold,additional thickness yields diminishing benefits.This study provides new insights into the energy-based instability mechanism of goaf roofs under impact loads,establishing a theoretical foundation for early warning systems and optimized safety design.展开更多
Climate change and anthropogenic activities have driven significant terrestrial water storage changes(TWSC)in the Three Rivers Source Region(TRSR),exerting profound impacts on freshwater availability across China and ...Climate change and anthropogenic activities have driven significant terrestrial water storage changes(TWSC)in the Three Rivers Source Region(TRSR),exerting profound impacts on freshwater availability across China and broader Asia.However,long-term TWSC characterization remains challenging due to limited observational data in this alpine region.Here,we integrate GRACE observations(2002-2020),ERA5-Land reanalysis,and GLDAS data to reconstruct TWSC using two methods:(1)the water balance method(PER)and(2)the component summation method(SS),applied to three input datasets(ERA5-Land,GLDAS,and their average,GLER).Comparative analysis reveals that the SS method applied to GL-ER yields the highest consistency with GRACE-derived TWSC.Using this optimal approach,we extend the analysis to 1951~2020,uncovering spatiotemporal TWSC patterns.Although annual TWSC trends appear negligible due to strong seasonality,we introduce the intra-year TWSC fluctuation(TWSCF)index to quantify cumulative variability.A significant(p<0.05)transition occurred in 1980,with TWSCF shifting from a declining trend(-0.39 mm/yr)to an increasing trend(0.56 mm/yr),primarily driven by soil moisture changes.However,Hurst exponent analysis suggests this upward trend may not persist.Drought and vegetation assessments indicate concurrent wetting and greening in the TRSR.TWSC correlates strongly with meteorological drought,acting as a reliable drought indicator while its linkage with vegetation dynamics suggests a potential contribution to greening.Our findings provide a robust framework for understanding long-term TWSC evolution and its hydrological-ecological interactions under climate change.展开更多
Influenza,a highly contagious respiratory infectious disease caused by an influenza virus,is a threat to public health worldwide.Avian influenza viruses(AIVs)have the potential to cause the next pandemic by crossing t...Influenza,a highly contagious respiratory infectious disease caused by an influenza virus,is a threat to public health worldwide.Avian influenza viruses(AIVs)have the potential to cause the next pandemic by crossing the species barrier through mutation of viral genome.Here,we investigated the pathogenicity of AIVs obtained from South Korea and Mongolia during 2018–2019 by measuring viral titers in the lungs and extrapulmonary organs of mouse models.In addition,we assessed the pathogenicity of AIVs in ferret models.Moreover,we compared the ability of viruses to replicate in mammalian cells,as well as the receptor-binding preferences of AIV isolates.Genetic analyses were finally performed to identify the genetic relationships and amino acid substitutions between viral proteins during mammalian adaptation.Of the 24 AIV isolates tested,A/Mallard/South Korea/KNU2019-34/2019(KNU19-34;H1N1)caused severe bodyweight loss and high mortality in mice.The virus replicated in the lungs,kidneys,and heart.Importantly,KNU19-34-infected ferrets showed high viral loads in both nasal washes and lungs.KNU19-34 replicated rapidly in A549 and bound preferentially to human likeα2,6-linked sialic acids rather than to avian-likeα2,3-linked sialic acids,similar to the pandemic A/California/04/2009(H1N1)strain.Gene segments of KNU19-34 were distributed in Egypt and Asia lineages from 2015 to 2018,and the virus had several amino acid substitutions compared to H1N1 AIV isolates that were non-pathogenic in mice.Collectively,the data suggest that KNU19-34 has zoonotic potential and the possibility of new mutations responsible for mammalian adaptation.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
BACKGROUND Kirsten rat sarcoma viral oncogene homolog(KRAS),neuroblastoma RAS viral oncogene homolog(NRAS),and v-raf murine sarcoma viral oncogene homolog B1(BRAF)nucleotide variants may generate quantitatively or qua...BACKGROUND Kirsten rat sarcoma viral oncogene homolog(KRAS),neuroblastoma RAS viral oncogene homolog(NRAS),and v-raf murine sarcoma viral oncogene homolog B1(BRAF)nucleotide variants may generate quantitatively or qualitatively various protein activities,which may be reflected in their differential association with tumor characteristics.AIM To examine the association between these mutations and colorectal cancer(CRC)progression stages.METHODS A retrospective analysis was conducted on 799 patients with CRC,whose tumor samples were examined for mutations in the hot-spots of the KRAS,NRAS,and BRAF genes at the University of Texas Medical Branch,spanning from January 2016 to July 2023.Statistical analyses were performed to assess the association of spe-cific nucleotide changes with tumor,nodes,and metastasis stages.RESULTS KRAS mutations were found in 39.5%of cases,NRAS mutations in 4.4%,and BRAF mutations in 6.0%.The KRAS p.Gly12Val and p.Gly13Asp mutations were positively associated with pathological stage 4 tumors.Additionally,the KRAS p.Gly12Asp and p.Gly12Val mutations were linked to an increased risk of distant metastasis.Meanwhile,the BRAF Val600Glu mutation was associated with a higher likelihood of lymph node involvement.CONCLUSION Our findings support the potential prognostic utility of specific KRAS(p.Gly12Val,p.Gly12Asp,and p.Gly13Asp)and BRAF p.Val600Glu mutations in CRC.These results are preliminary and require validation through larger,multi-center studies before they can be considered reliable in clinical practice.展开更多
BACKGROUND Primary ciliary dyskinesia(PCD)is a rare genetic disorder caused by motile cilia dysfunction.Identifying pathogenic variants is essential for diagnosis and personalized care,especially in consanguineous pop...BACKGROUND Primary ciliary dyskinesia(PCD)is a rare genetic disorder caused by motile cilia dysfunction.Identifying pathogenic variants is essential for diagnosis and personalized care,especially in consanguineous populations like Saudi Arabia.CASE SUMMARY This report presents a Saudi pediatric patient diagnosed with PCD who exhibited persistent neonatal tachypnea,chronic productive cough,and recurrent otitis media.Whole-exome sequencing revealed a novel homozygous nonsense variant in the C3orf67 gene(NM_198463.2:c.508C>T),resulting in a truncated,nonfunctional protein.This mutation likely impairs ciliary motility due to the production of a truncated,non-functional protein.The clinical findings were supported by multiple positive sputum cultures and a significant family history of similar symptoms,suggesting a genetic etiology consistent with autosomal recessive inheritance.CONCLUSION This case highlights the importance of genetic studies in diagnosing PCD,particularly in communities with a high rate of consanguinity.The identification of a novel homozygous variant in the C3orf67 gene expands the known genetic landscape of the disease.Further research is essential to clarify the functional role of C3orf67 in ciliary biology and its contribution to PCD pathogenesis.展开更多
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The etiopathogenesis of gastrointestinal diseases is varied in nature.Various etiogenic factors described are infective,inflammatory,viral,bacterial,parasitic,dietary and lifestyle change.Rare causative agents are immunological,and others associated as idiopathic,are undiagnosed by all possible means.Some of the rare diseases are congenital in nature,passing from the parent to the child.Many of the undiagnosed diseases are now being diagnosed as genetic and the genes have been implicated as a causative agent.There is a search for newer treatments for such diseases,which is called genomic medicine.Genomic medicine is an emerging medical discipline that involves the use of genomic information about an individual.This is used both for diagnostic as well as therapeutic decisions to improve the current health domain and pave the way for policymakers for its clinical use.In the developing era of precision medicine,genomics,epigenomics,environmental exposure,and other data would be used to more accurately guide individual diagnosis and treatment.Genomic medicine is already making an impact in the fields of oncology,pharmacology,rare,infectious and many undiagnosed diseases.It is beginning to fuel new approaches in certain medical specialties.Oncology is at the leading edge of incorporating genomics,as diagnostics for genetic and genomic markers are increasingly included in cancer screening,and to guide tailored treatment strategies.Genetics and genetic medicine have been reported to play a role in gastroenterology in several ways,including genetic testing(hereditary pancreatitis and hereditary gastrointestinal cancer syndromes).Genetic testing can also help subtype diseases,such as classifying pancreatitis as idiopathic or hereditary.Gene therapy is a promising approach for treating gastrointestinal diseases that are not effectively treated by conventional pharmaceuticals and surgeries.Gene therapy strategies include gene addition,gene editing,messenger RNA therapy,and gene silencing.Understanding genetic determinants,advances in genetics,have led to a better understanding of the genetic factors that contribute to human disease.Family-member risk stratification and genetic diagnosis can help identify family members who are at risk,which can lead to preventive treatments,lifestyle recommendations,and routine follow ups.Selecting target genes helps identify the gene targets associated with each gastrointestinal disease.Common gastrointestinal diseases associated with genetic abnormalities include-inflammatory bowel disease,gastroesophageal reflux disease,non-alcoholic fatty liver disease,and irritable bowel syndrome.With advancing tools and technology,research in the search of newer and individualized treatment,genes and genetic medicines are expected to play a significant role in human health and gastroenterology.
基金Supported by the Research Grants of the National Research,Development and Innovation Office,No.K125377,No.K134863 and No.K143549New National Excellence Program of the Ministry of Human Capacities,No.UNKP-20-5-SZTE-161,No.UNKP-22-3-SZTE-233,No.UNKP-23-5-SZTE-719,No.UNKP-22-4-SZTE-296 and No.UNKP-22-3-SZTE-278+1 种基金Janos Bolyai Research Grant,No.BO/00723/22the Géza Hetényi Research Grant by Albert Szent-Györgyi Medical School,University of Szeged.
文摘BACKGROUND Familial adenomatous polyposis(FAP)is a disorder of autosomal dominant inheritance that is responsible for around 1%of colorectal cancer(CRC)cases.AIM To determine the mutation profile of FAP-specific to the Hungarian population.METHODS This prospective single-center study enrolled patients with clinically suspected FAP or attenuated FAP(aFAP).Whole-exome next-generation sequencing was performed to detect variants of 50 FAP priority genes and 173 CRC predisposing genes or other CRC disease-associated genes.To identify larger deletions and insertions,a multiplex amplifiable probe hybridization technique was used.The identified genes were then classified according to the American College of Medical Genetics and Genomics guidelines.RESULTS A total of 26 index patients with clinically suspected FAP(n=21)and aFAP(n=5)were enrolled.APC gene alterations were confirmed in 92.31%of the cases(region 1B deletion,n=2;whole-gene deletion,n=4;frameshift mutation,n=2;nonsense mutation,n=5,and splice mutation,n=1),with the remaining two cases having CHEK2 and MSH3 gene alterations.According to pathogenicity,21 cases had pathogenic mutations,6 cases had likely pathogenic mutations,and 16 cases had variants of unknown significance(VUS).The most frequent of the latter were the POLE(n=5)and PIEZO1(n=4)gene variants.CONCLUSION Germline mutations in the APC gene were confirmed in more than 90%of Hungarian patients with clinically suspected FAP.Although the role of VUS genes is unclear,they are highly likely to play a role in the development of CRC.
基金supported by grants from the Tianjin Health Technology Project(Grant no.2022QN106).
文摘Background:Receptor-interacting protein kinases(RIPKs)regulate cell death,inflammation,and immune responses,yet their roles in cancer are not fully understood.This study investigates the expression,genomic alterations,and functional implications of RIPK family members across various cancers.Methods:We collected multi-omics data from The Cancer Genome Atlas and other public databases,including gene expression,copy number variation(CNV),mutation,methylation,tumor mutation burden(TMB),and microsatellite instability(MSI).Differential expression and survival analyses were performed using DESeq2 and Cox proportional hazards models.CNV and mutation data were analyzed with GISTIC2 and Mutect2,and methylation data with the ChAMP package.Correlations with TMB and MSI were assessed using Pearson coefficients,and gene set enrichment analysis was conducted with the MSigDB Hallmark gene sets.Results:RIPK family members show significant differential expression in various cancers,with RIPK1 and RIPK4 frequently altered.Survival analysis reveals heterogeneous impacts on overall survival.CNV and mutation analyses identify high alteration frequencies for RIPK2 and RIPK7,affecting gene expression.RIPK1 and RIPK7 are hypermethylated in several cancers,inversely correlating with RIPK3 expression.RIPK1,RIPK2,RIPK5,RIPK6,and RIPK7 correlate positively with TMB,while RIPK3 shows negative correlations in some cancers.MSI analysis indicates associations with DNA mismatch repair.G ene set enrichment analysis highlights immune-related pathway enrichment for RIPK1,RIPK2,RIPK3,and RIPK6,and cell proliferation and DNA repair pathways for RIPK4 and RIPK5.RIPK family members showed heterogeneous alterations across cancers:for example,RIPK7 was mutated in up to~15%of u terine c orpus e ndometrial c arcinoma and l ung s quamous c ell c arcinoma cases,and RIPK1 and RIPK7 exhibited frequent promoter hypermethylation in multiple tumor types.Several genes displayed context-dependent associations with overall survival and with TMB/MSI.Conclusion:This pan-cancer analysis of the RIPK family reveals their diverse roles and potential as biomarkers and therapeutic targets.The findings emphasize the importance of RIPK genes in tumorigenesis and suggest context-dependent functions across cancer types.Further studies are needed to explore their mechanisms in cancer development and clinical applications.
文摘BACKGROUND Early renal artery thrombosis after kidney transplantation is rare but often leads to graft loss.Prompt diagnosis and intervention are essential,particularly in patients with inherited thrombophilias such as factor V Leiden(FVL)mutation.CASE SUMMARY A kidney transplant recipient with FVL mutation developed an acute transplant renal artery thrombosis.The immediate post-operative Doppler ultrasonography revealed thrombosis of the main and inferior polar renal arteries.Emergent thrombectomy and separate arterial re-anastomoses were performed after cold perfusion with heparinized saline and vasodilator solution.Reperfusion was successful with immediate urine output and gradual improvement in renal function.The patient was discharged on direct oral anticoagulation therapy.CONCLUSION Early detection and surgical intervention can preserve graft function in posttransplant renal artery thrombosis even in patients at high risk.
基金supported by the Natural Science Foundation of Shaanxi Province(Key Program),No.2021JZ-60(to HZ)。
文摘The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.
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 National Key R&D Program of China(2024YFF1307400)Guangdong S&T Program(2022B1111230001).
文摘Preserving genetic diversity is crucial for the long-term survival of wild plant species,yet many remain at risk of genetic erosion due to small population sizes and habitat fragmentation.Here,we present a comparative genomic study of the critically endangered Oreocharis esquirolii(Gesneriaceae)and its widespread congener O.maximowiczii.We assembled and annotated chromosome-level reference genomes for both species and generated whole-genome resequencing data from 28 O.esquirolii and 79 O.maximowiczii individuals.Our analyses reveal substantially lower genetic diversity and higher inbreeding in O.esquirolii,despite its overall reduced mutational burden.Notably,O.esquirolii exhibits an elevated proportion of strongly deleterious mutations relative to O.maximowiczii,suggesting that limited opportunities for purging have allowed these variants to accumulate.These contrasting genomic profileslikely reflectdivergent demographic histories,with O.esquirolii having experienced severe bottlenecks and protracted population decline.Collectively,our findingshighlight the critically endangered status of O.esquirolii,characterized by diminished genetic diversity,pronounced inbreeding,and reduced ability to eliminate deleterious alleles.This study provides valuable genomic resources for the Gesneriaceae family and underscores the urgent need for targeted conservation measures,including habitat protection and ex situ preservation efforts,to mitigate the extinction risk facing O.esquirolii and potentially other threatened congeners.
基金support from the Natural Science Foundation of Jiangsu Province(Grant No.BK20242059)the Collaborative Innovation Center for Prevention and Control of Mountain Geological Hazards of Zhejiang Province(PCMGH-2023-02)the opening fund of State Key Laboratory of Coal Mine Disaster Dynamics and Control(2011DA105827-FW202209)are gratefully acknowledged.
文摘The stability and fracture behavior of a goaf roof beneath an open-pit bench are critical concerns,especially under impact loading.However,the effect of the thickness-to-span ratio on dynamic failure modes remains largely unexplored,as existing research focuses mainly on static stability.Energy dissipation and instability evolution under impact loading require further study.To address this gap,this study conducts drop-weight impact experiments on specimens with circular perforations,complemented by numerical simulations.By integrating dimensional analysis,cusp catastrophe theory,and strength reduction techniques,the dynamic instability mechanism of goaf roofs with varying thickness-to-span ratios is revealed.Results show that the thickness-to-span ratio significantly influences energy accumulation and dissipation during roof failure.A higher ratio increases both the magnitude and rate of energy dissipation,particularly during crack initiation and stable propagation,while its impact diminishes in the final failure stage.Optimizing the thickness-to-span ratio within a critical range enhances structural stability,improving the safety factor by up to 83%.However,beyond a certain threshold,additional thickness yields diminishing benefits.This study provides new insights into the energy-based instability mechanism of goaf roofs under impact loads,establishing a theoretical foundation for early warning systems and optimized safety design.
基金funded by the Postdoctoral Research Startup Foundation of University of Jinan(Grant No.100389917).
文摘Climate change and anthropogenic activities have driven significant terrestrial water storage changes(TWSC)in the Three Rivers Source Region(TRSR),exerting profound impacts on freshwater availability across China and broader Asia.However,long-term TWSC characterization remains challenging due to limited observational data in this alpine region.Here,we integrate GRACE observations(2002-2020),ERA5-Land reanalysis,and GLDAS data to reconstruct TWSC using two methods:(1)the water balance method(PER)and(2)the component summation method(SS),applied to three input datasets(ERA5-Land,GLDAS,and their average,GLER).Comparative analysis reveals that the SS method applied to GL-ER yields the highest consistency with GRACE-derived TWSC.Using this optimal approach,we extend the analysis to 1951~2020,uncovering spatiotemporal TWSC patterns.Although annual TWSC trends appear negligible due to strong seasonality,we introduce the intra-year TWSC fluctuation(TWSCF)index to quantify cumulative variability.A significant(p<0.05)transition occurred in 1980,with TWSCF shifting from a declining trend(-0.39 mm/yr)to an increasing trend(0.56 mm/yr),primarily driven by soil moisture changes.However,Hurst exponent analysis suggests this upward trend may not persist.Drought and vegetation assessments indicate concurrent wetting and greening in the TRSR.TWSC correlates strongly with meteorological drought,acting as a reliable drought indicator while its linkage with vegetation dynamics suggests a potential contribution to greening.Our findings provide a robust framework for understanding long-term TWSC evolution and its hydrological-ecological interactions under climate change.
基金funded by grants from the National Research Foundation of Korea(NRF)grant funded by the Korea government(2018M3A9H4055203 and 2023R1A2C2003679)from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(HV23C1857)from KRIBB Research Initiative Program(KGM9942421).
文摘Influenza,a highly contagious respiratory infectious disease caused by an influenza virus,is a threat to public health worldwide.Avian influenza viruses(AIVs)have the potential to cause the next pandemic by crossing the species barrier through mutation of viral genome.Here,we investigated the pathogenicity of AIVs obtained from South Korea and Mongolia during 2018–2019 by measuring viral titers in the lungs and extrapulmonary organs of mouse models.In addition,we assessed the pathogenicity of AIVs in ferret models.Moreover,we compared the ability of viruses to replicate in mammalian cells,as well as the receptor-binding preferences of AIV isolates.Genetic analyses were finally performed to identify the genetic relationships and amino acid substitutions between viral proteins during mammalian adaptation.Of the 24 AIV isolates tested,A/Mallard/South Korea/KNU2019-34/2019(KNU19-34;H1N1)caused severe bodyweight loss and high mortality in mice.The virus replicated in the lungs,kidneys,and heart.Importantly,KNU19-34-infected ferrets showed high viral loads in both nasal washes and lungs.KNU19-34 replicated rapidly in A549 and bound preferentially to human likeα2,6-linked sialic acids rather than to avian-likeα2,3-linked sialic acids,similar to the pandemic A/California/04/2009(H1N1)strain.Gene segments of KNU19-34 were distributed in Egypt and Asia lineages from 2015 to 2018,and the virus had several amino acid substitutions compared to H1N1 AIV isolates that were non-pathogenic in mice.Collectively,the data suggest that KNU19-34 has zoonotic potential and the possibility of new mutations responsible for mammalian adaptation.
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.
文摘BACKGROUND Kirsten rat sarcoma viral oncogene homolog(KRAS),neuroblastoma RAS viral oncogene homolog(NRAS),and v-raf murine sarcoma viral oncogene homolog B1(BRAF)nucleotide variants may generate quantitatively or qualitatively various protein activities,which may be reflected in their differential association with tumor characteristics.AIM To examine the association between these mutations and colorectal cancer(CRC)progression stages.METHODS A retrospective analysis was conducted on 799 patients with CRC,whose tumor samples were examined for mutations in the hot-spots of the KRAS,NRAS,and BRAF genes at the University of Texas Medical Branch,spanning from January 2016 to July 2023.Statistical analyses were performed to assess the association of spe-cific nucleotide changes with tumor,nodes,and metastasis stages.RESULTS KRAS mutations were found in 39.5%of cases,NRAS mutations in 4.4%,and BRAF mutations in 6.0%.The KRAS p.Gly12Val and p.Gly13Asp mutations were positively associated with pathological stage 4 tumors.Additionally,the KRAS p.Gly12Asp and p.Gly12Val mutations were linked to an increased risk of distant metastasis.Meanwhile,the BRAF Val600Glu mutation was associated with a higher likelihood of lymph node involvement.CONCLUSION Our findings support the potential prognostic utility of specific KRAS(p.Gly12Val,p.Gly12Asp,and p.Gly13Asp)and BRAF p.Val600Glu mutations in CRC.These results are preliminary and require validation through larger,multi-center studies before they can be considered reliable in clinical practice.
文摘BACKGROUND Primary ciliary dyskinesia(PCD)is a rare genetic disorder caused by motile cilia dysfunction.Identifying pathogenic variants is essential for diagnosis and personalized care,especially in consanguineous populations like Saudi Arabia.CASE SUMMARY This report presents a Saudi pediatric patient diagnosed with PCD who exhibited persistent neonatal tachypnea,chronic productive cough,and recurrent otitis media.Whole-exome sequencing revealed a novel homozygous nonsense variant in the C3orf67 gene(NM_198463.2:c.508C>T),resulting in a truncated,nonfunctional protein.This mutation likely impairs ciliary motility due to the production of a truncated,non-functional protein.The clinical findings were supported by multiple positive sputum cultures and a significant family history of similar symptoms,suggesting a genetic etiology consistent with autosomal recessive inheritance.CONCLUSION This case highlights the importance of genetic studies in diagnosing PCD,particularly in communities with a high rate of consanguinity.The identification of a novel homozygous variant in the C3orf67 gene expands the known genetic landscape of the disease.Further research is essential to clarify the functional role of C3orf67 in ciliary biology and its contribution to PCD pathogenesis.
