The autophagy-lysosome pathway:a potential target in the chemical and gene therapeutic strategies for Parkinson’s disease

Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.

A Study on the Association Between Siglec-1 Gene Polymorphism and Susceptibility in Patients with Chronic Obstructive Pulmonary Disease in Luohe Area

Objective:To analyze the association between Siglec-1 gene polymorphism and susceptibility to chronic obstructive pulmonary disease(COPD)in the population of the Luohe area.Methods:A case-control study(150 COPD patients and 150 healthy controls)was conducted to analyze the Siglec-1 allele in two groups of individuals using single nucleotide polymorphism(SNP)high-throughput detection technology,and the frequencies of each allele were compared.Results:The frequency of rs611847 heterozygous A/G genotype in COPD patients was significantly lower in females than in healthy controls(OR=0.282,95%CI=0.085-0.938,P=0.039);among smokers,the frequency of rs3859664 and rs6084444 genotypes in COPD patients was significantly higher than that in the healthy control group(OR=2.028,95%CI=1.111-3.704,P=0.021;OR=1.836,95%CI=1.033-3.262,P=0.038).Conclusion:Among the COPD population in the Luohe area,there is a significant correlation between the genotypes of three SNPs loci,rs3859664,rs6084444,and rs611847 and susceptibility to COPD in different subgroups of the population.The rs3859664 A/G-A/A and rs6084444 A/G-G/G genotypes can increase the risk of COPD in smokers;the rs611847 heterozygous A/G genotype can reduce the risk of COPD in both female and smoking populations.

Nanotechnology-based gene therapy as a credible tool in the treatment of Alzheimer’s disease

Toxic aggregated amyloid-βaccumulation is a key pathogenic event in Alzheimer’s disease.Treatment approaches have focused on the suppression,deferral,or dispersion of amyloid-βfibers and plaques.Gene therapy has evolved as a potential therapeutic option for treating Alzheimer’s disease,owing to its rapid advancement over the recent decade.Small interfering ribonucleic acid has recently garnered considerable attention in gene therapy owing to its ability to down-regulate genes with high sequence specificity and an almost limitless number of therapeutic targets,including those that were once considered undruggable.However,lackluster cellular uptake and the destabilization of small interfering ribonucleic acid in its biological environment restrict its therapeutic application,necessitating the development of a vector that can safeguard the genetic material from early destruction within the bloodstream while effectively delivering therapeutic genes across the bloodbrain barrier.Nanotechnology has emerged as a possible solution,and several delivery systems utilizing nanoparticles have been shown to bypass key challenges regarding small interfering ribonucleic acid delivery.By reducing the enzymatic breakdown of genetic components,nanomaterials as gene carriers have considerably enhanced the efficiency of gene therapy.Liposomes,polymeric nanoparticles,magnetic nanoparticles,dendrimers,and micelles are examples of nanocarriers that have been designed,and each has its own set of features.Furthermore,recent advances in the specific delivery of neurotrophic compounds via gene therapy have provided promising results in relation to augmenting cognitive abilities.In this paper,we highlight the use of different nanocarriers in targeted gene delivery and small interfering ribonucleic acid-mediated gene silencing as a potential platform for treating Alzheimer’s disease.

The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3 inflammasome activation

Triggering receptor expressed on myeloid cells-like 2(TREML2)is a newly identified susceptibility gene for Alzheimer's disease(AD).It encodes a microglial inflammation-associated receptor.To date,the potential role of mic roglial TREML2 in neuroinflammation in the context of AD remains unclear.In this study,APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression.In addition,lipopolysaccharide(LPS)stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD.Our res ults show that TREML2 levels gradually increased in the brains of AP P/PS1 mice during disease progression.LPS stimulation of primary microglia led to the release of inflammato ry cytokines including interleukin-1β,inte rleukin-6,and tumor necrosis factor-a in the culture medium.The LPS-induced mic roglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knoc kdown.LPS increased the levels of mic roglial M1-type polarization marker inducible nitric oxide synthase.This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown.Furthermore,the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown.LPS stimulation increased the levels of NLRP3 in primary microglia.The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown.In summary,this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation.These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.

Research progress on the relationship between Paneth cellssusceptibility genes,intestinal microecology and inflammatory bowel disease

Inflammatory bowel disease(IBD)is a disorder of the immune system and intestinal microecosystem caused by environmental factors in genetically susceptible people.Paneth cells(PCs)play a central role in IBD pathogenesis,especially in Crohn's disease development,and their morphology,number and function are regulated by susceptibility genes.In the intestine,PCs participate in the formation of the stem cell microenvironment by secreting antibacterial particles and play a role in helping maintain the intestinal microecology and intestinal mucosal homeostasis.Moreover,PC proliferation and maturation depend on symbiotic flora in the intestine.This paper describes the interactions among susceptibility genes,PCs and intestinal microecology and their effects on IBD occurrence and development.

Neurologic orphan diseases:Emerging innovations and role for genetic treatments

Orphan diseases are rare diseases that affect less than 200000 individuals within the United States.Most orphan diseases are of neurologic and genetic origin.With the current advances in technology,more funding has been devoted to developing therapeutic agents for patients with these conditions.In our review,we highlight emerging options for patients with neurologic orphan diseases,specifically including diseases resulting in muscular deterioration,epilepsy,seizures,neurodegenerative movement disorders,inhibited cognitive development,neuron deterioration,and tumors.After extensive literature review,gene therapy offers a promising route for the treatment of neurologic orphan diseases.The use of clustered regularly interspaced palindromic repeats/Cas9 has demonstrated positive results in experiments investigating its role in several diseases.Additionally,the use of adeno-associated viral vectors has shown improvement in survival,motor function,and developmental milestones,while also demonstrating reversal of sensory ataxia and cardiomyopathy in Friedreich ataxia patients.Antisense oligonucleotides have also been used in some neurologic orphan diseases with positive outcomes.Mammalian target of rapamycin inhibitors are currently being investigated and have reduced abnormal cell growth,proliferation,and angiogenesis.Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.

Meta-QTL analysis for mining of candidate genes and constitutive gene network development for fungal disease resistance in maize(Zea mays L.)

The development of resistant maize cultivars is the most effective and sustainable approach to combat fungal diseases.Over the last three decades,many quantitative trait loci(QTL)mapping studies reported numerous QTL for fungal disease resistance(FDR)in maize.However,different genetic backgrounds of germplasm and differing QTL analysis algorithms limit the use of identified QTL for comparative studies.The meta-QTL(MQTL)analysis is the meta-analysis of multiple QTL experiments,which entails broader allelic coverage and helps in the combined analysis of diverse QTL mapping studies revealing common genomic regions for target traits.In the present study,128(33.59%)out of 381 reported QTL(from 82 studies)for FDR could be projected on the maize genome through MQTL analysis.It revealed 38 MQTL for FDR(12 diseases)on all chromosomes except chromosome 10.Five MQTL namely 1_4,2_4,3_2,3_4,and 5_4 were linked with multiple FDR.Total of 1910 candidate genes were identified for all the MQTL regions,with protein kinase gene families,TFs,pathogenesis-related,and disease-responsive proteins directly or indirectly associated with FDR.The comparison of physical positions of marker-traits association(MTAs)from genome-wide association studies with genes underlying MQTL interval verified the presence of QTL/candidate genes for particular diseases.The linked markers to MQTL and putative candidate genes underlying identified MQTL can be further validated in the germplasm through marker screening and expression studies.The study also attempted to unravel the underlying mechanism for FDR resistance by analyzing the constitutive gene network,which will be a useful resource to understand the molecular mechanism of defense-response of a particular disease and multiple FDR in maize.

Identification and expression analysis of sugar transporter family genes reveal the role of ZmSTP2 and ZmSTP20 in maize disease resistance

Sugar is an indispensable source of energy for plant growth and development, and it requires the participation of sugar transporter proteins(STPs) for crossing the hydrophobic barrier in plants. Here, we systematically identified the genes encoding sugar transporters in the genome of maize(Zea mays L.), analyzed their expression patterns under different conditions, and determined their functions in disease resistance. The results showed that the mazie sugar transporter family contained 24 members, all of which were predicted to be distributed on the cell membrane and had a highly conserved transmembrane transport domain. The tissue-specific expression of the maize sugar transporter genes was analyzed, and the expression level of these genes was found to be significantly different in different tissues. The analysis of biotic and abiotic stress data showed that the expression levels of the sugar transporter genes changed significantly under different stress factors. The expression levels of Zm STP2 and Zm STP20 continued to increase following Fusarium graminearum infection. By performing disease resistance analysis of zmstp2 and zmstp20 mutants, we found that after inoculation with Cochliobolus carbonum, Setosphaeria turcica, Cochliobolus heterostrophus, and F. graminearum, the lesion area of the mutants was significantly higher than that of the wild-type B73 plant. In this study, the genes encoding sugar transporters in maize were systematically identified and analyzed at the whole genome level. The expression patterns of the sugar transporter-encoding genes in different tissues of maize and under biotic and abiotic stresses were revealed, which laid an important theoretical foundation for further elucidation of their functions.

Hybrid Feature Selection Method for Predicting Alzheimer’s Disease Using Gene Expression Data

Gene expression(GE)classification is a research trend as it has been used to diagnose and prognosis many diseases.Employing machine learning(ML)in the prediction of many diseases based on GE data has been a flourishing research area.However,some diseases,like Alzheimer’s disease(AD),have not received considerable attention,probably owing to data scarcity obstacles.In this work,we shed light on the prediction of AD from GE data accurately using ML.Our approach consists of four phases:preprocessing,gene selection(GS),classification,and performance validation.In the preprocessing phase,gene columns are preprocessed identically.In the GS phase,a hybrid filtering method and embedded method are used.In the classification phase,three ML models are implemented using the bare minimum of the chosen genes obtained from the previous phase.The final phase is to validate the performance of these classifiers using different metrics.The crux of this article is to select the most informative genes from the hybrid method,and the best ML technique to predict AD using this minimal set of genes.Five different datasets are used to achieve our goal.We predict AD with impressive values forMultiLayer Perceptron(MLP)classifier which has the best performance metrics in four datasets,and the Support Vector Machine(SVM)achieves the highest performance values in only one dataset.We assessed the classifiers using sevenmetrics;and received impressive results,allowing for a credible performance rating.The metrics values we obtain in our study lie in the range[.97,.99]for the accuracy(Acc),[.97,.99]for F1-score,[.94,.98]for kappa index,[.97,.99]for area under curve(AUC),[.95,1]for precision,[.98,.99]for sensitivity(recall),and[.98,1]for specificity.With these results,the proposed approach outperforms recent interesting results.With these results,the proposed approach outperforms recent interesting results.

Presymptomatic Diagnosis and Gene Therapy for Alzheimer’s Disease: Genomic, Therapeutic, and Ethical Aspects—A Systematic Review

Over the past three decades, genomic and epigenetic sciences have identified more than 70 genes involved in the molecular pathophysiology of Alzheimer’s disease (AD). DNA methylation, abnormal histone and chromatin regulation and the action of various miRNAs induce AD. The identification of mutated genes has paved the way for the development of diagnostic kits and the initiation of gene therapy trials. However, despite major advances in neuroscience research, there is yet no suitable treatment for AD. Therefore, the early diagnosis of this neurodegenerative disease raises several ethical questions, including the balance between the principle of non-maleficence and the principle of beneficence. The aims of this research were to present the genomic and ethical aspects of AD, and to highlight the ethical principles involved in its presymptomatic diagnosis and therapy. A systematic review of the literature in PubMed, Google Scholar and Science Direct was carried out to outline the genomic aspects and ethical principles relating not only to the presymptomatic diagnosis of AD, but also to its gene therapy. A total of 16 publications were selected. AD is a multifactorial disease that can be genetically classified into Sporadic Alzheimer’s Disease and Familial Alzheimer’s Disease based on family history. Gene therapy targeting specific disease-causing genes is a promising therapeutic strategy. Advancements in artificial intelligence applications may enable the prediction of AD onset several years in advance. While early diagnosis of AD may empower patients with full decision competence for early decision-making, it also carries implications for the patient’s family members, who are at risk of developing the disease, potentially becoming a source of confusion or anxiety. AD has a significant impact on the life of individuals at risk and their families. Given the absence of disease modifying therapy, genetic screening and early diagnosis for this condition raise ethical issues that must be carefully considered in the context of fundamental bioethical principles, including autonomy, beneficence, non-maleficence, and justice.

Gene Repair of iPSC Line with GARS (G294R) Mutation of CMT2D Disease by CRISPR/Cas9

Objective Charcot-Marie-Tooth disease(CMT)severely affects patient activity,and may cause disability.However,no clinical treatment is available to reverse the disease course.The combination of CRISPR/Cas9 and iPSCs may have therapeutic potential against nervous diseases,such as CMT.Methods In the present study,the skin fibroblasts of CMT type 2D(CMT2D)patients with the c.880G>A heterozygous nucleotide mutation in the GARS gene were reprogrammed into iPSCs using three plasmids(pCXLE-hSK,pCXLE-hUL and pCXLE-hOCT3/4-shp5-F).Then,CRISPR/Cas9 technology was used to repair the mutated gene sites at the iPSC level.Results An iPSC line derived from the GARS(G294R)family with fibular atrophy was successfully induced,and the mutated gene loci were repaired at the iPSC level using CRISPR/Cas9 technology.These findings lay the foundation for future research on drug screening and cell therapy.Conclusion iPSCs can differentiate into different cell types,and originate from autologous cells.Therefore,they are promising for the development of autologous cell therapies for degenerative diseases.The combination of CRISPR/Cas9 and iPSCs may open a new avenue for the treatment of nervous diseases,such as CMT.

Bioinformatic analysis and in vivo validation of angiogenesis related genes in inflammatory bowel disease

Angiogenesis plays a significant role in the occurrence and development of inflammatory bowel disease(IBD).The aim of this study is to explore potential angiogenesis related genes(ARGs)in IBD through bioinformatics analysis and in vivo experiments.Methods:GSE57945,GSE87466,and GSE36807 were obtained from the Gene Expression Omnibus database.GSE57945 was used as the training set,while GSE87466 and GSE36807 were used as the validation set.The key ARGs associated with IBD were identified using the least absolute shrinkage and selection operator(LASSO)and random forest methods.These identified ARGs were then utilized to construct a diagnostic model for IBD.The Single-Sample Genome Enrichment Analysis,Cibersort,and Xcell methods were used to evaluate the immune infiltration.Expression of amyloid beta precursor protein(APP)was verified in the IBD mouse model induced by dextran sulfate sodium using immunohistochemistry(IHC).Results:The receiver operating curve area of GSE57945 was 0.948.Two distinct clusters were identified using consensus clustering and non-negative matrix factorization clustering.Subsequent analyses revealed significant differences in immune levels and functional enrichment between the two clusters.The successful construction of the animal model for the IBD was evident by hematoxylin and eosin staining,while IHC results showed a high expression of APP in IBD and a low expression in normal tissues.Conclusion:Our findings provide new insights into the diagnosis of IBD by ARGs,and APP could be a potential novel biomarker for IBD and promising therapeutic targets.

Gene therapy for Parkinson’s Disease and Ethical Challenges: A Systematic Review

Background: Parkinson’s disease (PD) is a complex, multifactorial neurodegenerative disorder with a pathophysiology deriving from the synergy of abnormal aggregation of neuroinflammation, synuclein and dysfunction of lysosomes, mitochondria and synaptic transport difficulties influenced by genetic and idiopathic factors. Worldwide, PD has a prevalence of 2-3% in people over the age of 65. To date, there is no certified, effective treatment for PD. Aim: The aims of this research were: (i) to present, on the basis of recent advances in molecular genetics and epigenetics, the genomic aspects and challenges of gene therapy trials for PD;(ii) to outline the ethical principles applicable to therapeutic trials for PD. Method: A systematic literature review was carried out to identify relevant articles reporting on genomic aspects and gene therapy in PD from 2001 to October 2023. The search was conducted in French and/or English in three databases: PubMed, Google Scholar and Science Direct. PRISMA guidelines were used in this systematic review. Results: A total of thirty-three publications were selected. An inductive thematic analysis revealed that numerous genetic mutations (SNCA, Parkin, PINK1, DJ-1, LRRK2, ATP13A2, VPS35, Parkin/PRKN, PINK1, DJ1/PARK7) and epigenetic events such as the action of certain miRNAs (miR-7, miR-153, miR-133b, miR-124, miR-137) are responsible for the onset of PD, and that genetic therapy for this pathology raises ethical questions that need to be elucidated in the light of the bioethical principles of autonomy, beneficence, non-maleficence and justice. Conclusion: There is no zero risk in biotechnology. Then, it will be necessary to assess all the potential risks of Parkinson disease’s gene therapy to make the right decision. It is therefore essential to pursue research and, with the guidance of ethics, to advance treatment options and meet the challenges of brain manipulation and its impact on human identity. The golden rule of medicine remains: “Primum non nocere”.

Treatment of refractory anti-melanoma differentiation-associated gene 5 anbibody-positive dermatomyositis complicated by rapidly progressing interstitial pulmonary disease:Two case reports

BACKGROUND Anti-melanoma differentiation-associated gene 5 antibody-positive(anti-MDA5 Ab+)dermatomyositis complicated with rapidly progressive interstitial lung disease(anti-MDA5 Ab+DM-RP-ILD)has an unclear underlying mechanism with no recommended unified treatment plan.Herein,one of the cases that we report(Case 2)was successfully treated with tocilizumab despite having lung infection.CASE SUMMARY Case 1 was a 30-year-old woman who was admitted due to recurrent rash for 5 mo,fever and cough for 1 mo,and chest tightness for 3 d.She was diagnosed with non-myopathic dermatomyositis(anti-MDA5 Ab+)and interstitial pneumonia,and was treated with the combination of hormone therapy and cyclophosphamide followed by oral tacrolimus.Case 2 was a 31-year-old man admitted due to systemic rash accompanied by muscle weakness of limbs for more than 1 mo,and chest tightness and dry cough for 4 d.He was diagnosed with dermatomyositis(anti-MDA5 Ab+)and acute interstitial pneumonia with Pneumocystis jirovecii and Aspergillus fumigatus infections and was treated with hormone therapy(without cyclophosphamide)and the combination of tocilizumab and tacrolimus.The condition of both patients eventually improved and they were discharged and showed clinically stable condition at the latest follow-up.CONCLUSION Tocilizumab could be a salvage treatment for patients with anti-MDA5 Ab+DMRP-ILD who are refractory to intensive immunosuppression.

Creutzfeldt-Jakob disease presenting as Korsakoff syndrome caused by E196A mutation in PRNP gene:A case report

BACKGROUND Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations.In humans,prion diseases result from mutations in the prion protein gene(PRNP).Only a limited number of cases involving a specific PRNP mutation at codon 196(E196A)have been reported.The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease(CJD)caused by E196A mutation has not been documented in the existing literature.CASE SUMMARY A 61-year-old Chinese man initially presented with Korsakoff syndrome,followed by rapid-onset dementia,visual hallucinations,akinetic mutism,myoclonus,and hyperthermia.The patient had no significant personal or familial medical history.Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex,while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism.Routine biochemical and microorganism testing of the cerebrospinal fluid(CSF)yielded normal results.Tests for thyroid function,human immunodeficiency virus,syphilis,vitamin B1 and B12 levels,and autoimmune rheumatic disorders were normal.Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results.A test for 14-3-3 protein in the CSF yielded negative results.Whole-genome sequencing revealed a diseasecausing mutation in PRNP.The patient succumbed to the illness 11 months after the initial symptom onset.CONCLUSION Korsakoff syndrome,typically associated with alcohol intoxication,also manifests in CJD patients.Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.

Differential expression analysis of coronary heart disease related genes in Hainan residents

Objective:To explore the correlation between coronary heart disease related genes and coronary heart disease in hospitalized patients in Hainan,and to provide theoretical basis for enriching the screening methods of high-risk groups of coronary heart disease in Hainan,and optimizing the prevention and treatment strategies.Methods:We select hospitalized patients born in Hainan and aged>30 years old from the Second Affiliated Hospital of Hainan Medical Unversity between January 1,2020 and June 30,2022,and divided the patients into the coronary heart disease group and the non-coronary heart disease group.PCR real-time fluorescence was used to measure gene expression,and Spearman correlation analysis was used to explore the correlation between gene expression and coronary heart disease.Results:A total of 55 whole blood samples were collected from non-coronary heart disease patients(including 26 women and 29 men),with a median age of 57 years,and 170 whole blood samples from coronary heart disease patients(including 44 women and 126 men),with a median age of 63.17.Apolipoprotein B gene(ApoB)was highly expressed in patients with coronary heart disease(P<0.001);AGT gene(P=0.0158),ApoE gene(P=0.0126),FGB gene(P=0.005),GNB gene(P=0.0151),MTFHR gene(P=0.0119),SEL gene(P=0.005),TNF gene(P=0.0298)were significantly overexpressed in the non-coronary heart disease group.The expression of NOS3 gene(P=0.3047),IL6 gene(P=0.7239),ACE gene(P=0.7852)was not different between the two groups.Coronary heart disease was negatively correlated with AGT gene(r=-0.163,P=0.011,P<0.05),positively correlated with APOB gene(r=0.75,P=0,P<0.01),negatively correlated with FGB gene(r=-0.163,P=0.011,P<0.05),negatively correlated with GNB gene(r=-0.165,P=0.011,P<0.05),negatively correlated withSEL gene(r=-0.171,P=0.007,P<0.01),negatively correlated with MHTHR gene(r=-0.210,P=0.001,P<0.01)and negatively correlated with TNF gene(r=-0.131,P=0.04,P<0.05),but coronary heart disease was not correlated with APOE,NOS3,ACE,IL6 and other genes(P>0.05).The ApoB gene of coronary heart disease was negatively correlated with triglyceride(r=-0.461,P=0),positively correlated with age(r=0.173,P=0.009),positively correlated with total cholesterol(r=0.499,P=0),negatively correlated with high-density lipoprotein(r=-0.181,P=0.007),and negatively correlated with low-density lipoprotein(r=-0.143,P=0.031).Conclusion:(1)The detection of apolipoprotein B gene expression may be used as an indicator for screening coronary heart disease in the coronary population in Hainan.It may increase the risk of coronary heart disease by affecting the level of total cholesterol.A larger sample of research is still needed.(2)AGT,ApoE,FGB,GNB,MTFHR,SELE,TNF and other genes may be the protective genes of non-coronary heart disease population in Hainan,and the high expression of these genes may reduce the occurrence of coronary heart disease,which still needs further study.

Anti-melanoma differentiation-associated gene 5 and anti-Ro52 antibody-dual positive dermatomyositis accompanied by rapidly lung disease:Three case reports

BACKGROUND Clinically amyopathic deramatomyositis was manifested as the various cutaneous dermatomyositis(DM)manifestations without muscle weakness.Anti-melanoma differentiation-associated gene 5(anti-MDA5)and anti-Ro52 antibody-dual positive clinically amyopathic DM patients are at a high risk of developing rapidly progressive interstitial lung disease,and they exhibit an immensely high half-year mortality.CASE SUMMARY We presented three patients with anti-MDA5 and anti-Ro52 antibody-dual positive DM patients and we reviewed the previous studies on the link between anti-MDA5 and anti-Ro52 antibody-dual positive DM.Although we aggressively treated these patients similarly,but they all exhibited different prognoses.We reviewed the importance of clinical cutaneous rashes as well as the pathogenesis and treatment in the dual positive anti-MDA5 and anti-Ro52 associated DM.CONCLUSION Patients with anti-MDA5 anti-Ro52 antibody-dual positive DM should be accurately diagnosed at an early stage and should be treated aggressively,thus,the patient’s prognosis can be significantly modified.

Recent Progress in Elucidating the Structure, Function and Evolution of Disease Resistance Genes in Plants

Plants employ multifaceted mechanisms to fight with numerous pathogens in nature. Resistance （R） genes are the most effective weapons against pathogen invasion since they can specifically recognize the corresponding pathogen effectors or associated protein（s） to activate plant immune responses at the site of infection. Up to date, over 70 R genes have been isolated from various plant species. Most R proteins contain conserved motifs such as nucleotide-binding site （NBS）, leucine-rich repeat （LRR）, Toll-interleukin-1 receptor domain （TIR, homologous to cytoplasmic domains of the Drosophila Toll protein and the manamalian intefleukin-1 receptor）, coiled-coil （CC） or leucine zipper （LZ） structure and protein kinase domain （PK）. Recent results indicate that these domains play significant roles in R protein interactions with effector proteins from pathogens and in activating signal transduction pathways involved in innate immunity. This review highlights an overview of the recent progress in elucidating the structure, function and evolution of the isolated R genes in different plant-pathogen interaction systems.

Cloning and Analysis of a Disease Resistance Gene Homolog from Soybean

Conserved domains e.g. nucleotide binding site (NBS) were found in several cloned plant disease resistance genes. Based on the NBS domain, resistance gene analogs (RGAs) have been isolated previously and were used as probes to screen a soybean (Glycine max L. Merr.) cDNA library. A full-length cDNA, KR3, was obtained by screening the library and rapid amplification of cDNA ends (RACE) method. Sequence analysis revealed that the cDNA is 2 353 bp in length and the open reading frame (ORF) codes for a polypeptide of 636 amino acids with a Toll-Interleukin-1 receptor (TIR) and a NBS domain. Sequence alignment showed that it was similar to N gene of tobacco. The phylogenetic tree analysis of R proteins with NBS from higher plants was performed. The KR3 gene has low copies in soybean genome and its expression was induced by exogenous salicylic acid (SA).

Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort

Inflammatory bowel disease(IBD),including Crohn’s disease(CD)and ulcerative colitis(UC),is a chronic inflammatory disease of the digestive tract with increasing prevalence globally.Although venous thromboembolism(VTE)is a major complication in IBD patients,it is often underappreciated with limited tools for risk stratification.AIM To estimate the proportion of VTE among IBD patients and assess genetic risk factors(monogenic and polygenic)for VTE.METHODS Incident VTE was followed for 8465 IBD patients in the UK Biobank(UKB).The associations of VTE with F5 factor V leiden(FVL)mutation,F2 G20210A prothrombin gene mutation(PGM),and polygenic score(PGS003332)were tested using Cox hazards regression analysis,adjusting for age at IBD diagnosis,gender,and genetic background(top 10 principal components).The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve(AUC).RESULTS The overall proportion of incident VTE was 4.70%in IBD patients and was similar for CD(4.46%),UC(4.49%),and unclassified(6.42%),and comparable to that of cancer patients(4.66%)who are well-known at increased risk for VTE.Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers,hazard ratio(HR)was 1.94,95%confidence interval(CI):1.42-2.65.In contrast,patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores(middle 8 deciles),HR was 2.06(95%CI:1.57-2.71).The AUC for differentiating VTE diagnosis was 0.64(95%CI:0.61-0.67),0.68(95%CI:0.66-0.71),and 0.69(95%CI:0.66-0.71),respectively,for F5/F2 mutation carriers,PGS,and combined.CONCLUSION Similar to cancer patients,VTE complications are common in IBD patients.PGS provides more informative risk information than F5/F2 mutations(FVL and PGM)for personalized thromboprophylaxis.