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Citrus canker disease, caused by Xanthomonas citri subsp. citri, poses a significant threat to global citrus production. The control of the disease in the field relies mainly on the use of conventional tools such as copper compounds, which are harmful to the environment and could lead to bacterial resistance. This scenario stresses the need for new and sustainable technologies to control phytopathogens, representing a key challenge in developing studies that translate basic into applied knowledge. During infection, X. citri subsp. citri secretes a transcriptional activator-like effector that enters the nucleus of plant cells, activating the expression of the canker susceptibility gene LATERAL ORGAN BOUNDARIES 1 (LOB1). In this study, we explored the use of antisense oligonucleotides (ASOs) with phosphorothioate modifications to transiently inhibit the gene expression of CsLOB1 in Citrus sinensis. We designed and validated three potential ASO sequences, which led to a significant reduction in disease symptoms compared with the control. The selected ASO3-CsLOB1 significantly decreased the expression level of CsLOB1 when delivered through two distinct delivery methods, and the reduction of the symptoms ranged from approximately 15 to 83%. Notably, plants treated with ASO3 did not exhibit an increase in symptom development over the evaluation period. This study highlights the efficacy of ASO technology, based on short oligonucleotide chemically modified sequences, as a promising tool for controlling phytopathogens without the need for genetic transformation or plant regeneration. Our results demonstrate the potential of ASOs as a biotechnological tool for the management of citrus canker disease. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the leading sight-threatening disease in developed countries. On the other hand, recent studies indicated an ethnic variation in the phenotype of AMD. For example, several reports demonstrated that the incidence of drusen in AMD patients is less in Asians compared to Caucasians though the reason has not been clarified yet. In the last decades, several genome association studies have disclosed many susceptible genes of AMD and revealed that the association strength of some genes was different among races and AMD phenotypes. In this review article, the essential findings of the clinical studies and genome association studies for the most significant genes CFH and ARMS2/HTRA1 in AMD of different races are summarized, and theoretical hypotheses about the molecular mechanisms underlying the ethnic variation in the AMD manifestation mainly focused on those genes between Caucasians and Asians are discussed. [ABSTRACT FROM AUTHOR]

The predominant genetic defense mechanism against soybean cyst nematode (SCN) in 95% of the North America market is under threat by virulent SCN populations. Usovsky et al. identified GmSNAP02 as an SCN susceptibility gene through fine-mapping of unique bi-parental populations. Loss-of-function of GmSNAP02 confers enhanced resistance to more virulent SCN. [ABSTRACT FROM AUTHOR]

The most prevalent hip disease in neonates is developmental dysplasia of the hip (DDH). A timely and accurate diagnosis is required to provide the most effective treatment for pediatric patients with DDH. Heredity and gene variation have been the subject of increased attention and research worldwide as one of the factors contributing to the pathogenesis of DDH. Genome-wide association studies (GWAS), genome-wide linkage analyses (GWLA), and exome sequencing (ES) have identified variants in numerous genes and single-nucleotide polymorphisms (SNPs) as being associated with susceptibility to DDH in sporadic and DDH family patients. Furthermore, the DDH phenotype can be observed in animal models that exhibit susceptibility genes or loci, including variants in CX3CR1, KANSL1, and GDF5. The dentification of noncoding RNAs and de novo gene variants in patients with DDH-related syndrome has enhanced our understanding of the genes implicated in DDH. This article reviews the most recent molecular mechanisms and genetic factors that contribute to DDH. [ABSTRACT FROM AUTHOR]

Chronic pancreatitis (CP) is a progressive fibrotic pancreatic disease influenced by multiple factors such as genetic and environmental factors. Currently, the genetic pathogenic mechanisms of CP are mainly divided into three pathways: the trypsin-dependent pathway, the protein misfolding pathway, and the ductal pathway. Pancreatic ductal epithelial cells, as an important cell type in the exocrine pancreas, are capable of producing H2O and HCO-3, and are responsible for the alkalization, dilution, and transportation of digestive enzymes. When genes related to the ductal pathway are functionally impaired, it will lead to an imbalance in the ion concentration within the duct and a disturbance in the transport of digestive enzymes, promoting the occurrence and development of CP. In the past, genes related to the ductal pathway were relatively rare, but in recent years, our understanding of the ductal pathway has gradually deepened, and new susceptibility genes have been continuously discovered. This article mainly discusses the genes related to the ductal pathway and their main pathogenic mechanisms to deepen our understanding of the pathogenesis of CP.

Throughout the history of crop domestication, desirable traits have been selected in agricultural products. However, such selection often leads to crops and vegetables with weaker vitality and viability than their wild ancestors when exposed to adverse environmental conditions. Considering the increasing human population and climate change challenges, it is crucial to enhance crop quality and quantity. Accordingly, the identification and utilization of diverse genetic resources are imperative for developing disease‐resistant plants that can withstand unexpected epidemics of plant diseases. In this review, we provide a brief overview of recent progress in genome‐editing technologies, including zinc‐finger nucleases (ZFNs), transcription activator‐like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)‐associated protein 9 (Cas9) technologies. In particular, we classify disease‐resistant mutants of Arabidopsis thaliana and several crop plants based on the roles or functions of the mutated genes in plant immunity and suggest potential target genes for molecular breeding of genome‐edited disease‐resistant plants. Genome‐editing technologies are resilient tools for sustainable development and promising solutions for coping with climate change and population increases. [ABSTRACT FROM AUTHOR]

Aims: Aimed to identify a new susceptibility gene associated with primary biliary cholangitis (PBC) in Chinese Han and investigate the possible mechanism of that gene in PBC. Methods: A total of 466 PBC and 694 healthy controls (HC) were included in our study, and genotyping GTF2I gene variants by Sequenom. CD19 + B cells were isolated for Chromatin immunoprecipitation sequencing (ChIP-seq). Additionally, MEME-ChIP was utilized to perform searches for known motifs and de novo motif discovery. The GTF2I ChIP-seq of hematopoietic cell line (K562) results were obtained from ENCODE (GSE176987, GSE177691). The Genomic HyperBrowser was used to determine overlap and hierarchal clustering between ours and ENCODE datasets. Results: The frequency of the rs117026326 variant T allele was significantly higher in PBC patients than that in HC (20.26% compared with 13.89%, Pc = 1.09E-04). Furthermore, we observed an elevated proportion of GTF2I binding site located in the upstream and 5ʹ UTR of genes in PBC in comparison with HC. Additionally, an in-depth analysis of IL21R region revealed that GTF2I might bind to the IL21R promoter to regulate the expression of the IL21R, with four peaks of GTF2I binding sites, including three increased binding sites in upstream, one increased binding site in 5' UTR. Motif analysis by MEME-ChIP uncovered five significant motifs. A significant overlap between our ChIP and GSE176987, GSE17769 were found by the Genomic HyperBroswer. Conclusions: Our study confirmed that GTF2I was associated with PBC in Chinese Han. Furthermore, our gene function analysis indicated that IL21R may be the target gene regulated by GTF2I. [ABSTRACT FROM AUTHOR]

Since the leprosy cases have fallen dramatically, the incidence of leprosy has remained stable over the past years, indicating that multidrug therapy seems unable to eradicate leprosy. More seriously, the emergence of rifampicinresistant strains also affects the effectiveness of treatment. Immunoprophylaxis was mainly carried out through vaccination with the BCG but also included vaccines such as LepVax and MiP. Meanwhile, it is well known that the infection and pathogenesis largely depend on the host's genetic background and immunity, with the onset of the disease being genetically regulated. The immune process heavily influences the clinical course of the disease. However, the impact of immune processes and genetic regulation of leprosy on pathogenesis and immunological levels is largely unknown. Therefore, we summarize the latest research progress in leprosy treatment, prevention, immunity and gene function. The comprehensive research in these areas will help elucidate the pathogenesis of leprosy and provide a basis for developing leprosy elimination strategies. [ABSTRACT FROM AUTHOR]

ABSTRACT Stripe rust of wheat is caused by the fungal pathogen Puccinia striiformis f. sp. tritici (Pst). Breeding durably resistant wheat varieties by disrupting the susceptibility (S) gene has an important impact on the control of wheat stripe rust. Mingxian169 (MX169) showed strong stripe rust susceptibility to all the races of Pst. However, molecular mechanisms and responsive genes underlying susceptibility of the wheat variety MX169 to Pst have not been elucidated. Here, we utilized next-generation sequencing technology to analyze transcriptomics data of “MX169” and high-resistance wheat “Zhong4” at 24, 48, and 120 h post-inoculation (hpi) with Pst. Comparative transcriptome analysis revealed 3,494, 2,831, and 2,700 differentially expressed genes (DEGs) at different time points. We observed an upregulation of DEGs involved in photosynthesis, flavonoid biosynthesis, pyruvate metabolism, thiamine metabolism, and other biological processes, suggesting their involvement in MX169’s response to Pst. DEGs encoding transcription factors were also identified. Our study suggested the potential susceptibility gene resources in MX169 related to stripe rust response could be valuable for understanding the mechanisms involved in stripe rust susceptibility and for improving wheat resistance to Pst.IMPORTANCEOur study suggests the potential susceptibility gene resources in MX169 related to stripe rust response could be valuable for understanding the mechanisms involved in stripe rust susceptibility and for improving wheat resistance to Pst.

Abstract Background Gestational diabetes mellitus (GDM) affects the metabolism of both the mother and fetus during and after pregnancy. Genetic factors are important in the pathogenesis of GDM, and associations vary by ethnicity. However, related studies about the relationship between the susceptibility genes and glucose traits remain limited in China. This study aimed to identify genes associated with GDM susceptibility in Chinese Han women and validate those findings using clinical data during pregnancy and postpartum period. Methods A genome-wide association study (GWAS) of 398 Chinese Han women (199 each with and without GDM) was conducted and associations between single nucleotide polymorphisms (SNPs) and glucose metabolism were identified by searching public databases. Relationships between filtered differential SNPs and glucose metabolism were verified using clinical data during pregnancy. The GDM group were followed up postpartum to evaluate the progression of glucose metabolism. Results We identified five novel SNPs with genome-wide significant associations with GDM: rs62069863 in TRPV3 gene and rs2232016 in PRMT6 gene were positive correlated with 1 h plasma glucose (1hPG) and 2 h plasma glucose (2hPG), rs1112718 in HHEX/EXOC6 gene and rs10460009 in LPIN2 gene were positive associated with fasting plasma glucose, 1hPG and 2hPG, rs927316 in GLIS3 gene was negative correlated with 2hPG. Of the 166 GDM women followed up postpartum, rs62069863 in TRPV3 gene was positively associated with fasting insulin, homoeostasis model assessment of insulin resistance. Conclusions The variants of rs62069863 in TRPV3 gene, rs2232016 in PRMT6 gene, rs1112718 in HHEX/EXOC6 gene, rs927316 in GLIS3 gene, and rs10460009 in LPIN2 gene were newly-identified susceptibility loci for GDM in the Chinese Han population. TRPV3 was associated with worse insulin resistance postpartum. Trial registration This study was registered in the Chinese Clinical Trial Registry. Trial registration number: ChiCTR2100043762. Date of first registration: 28/02/2021.

Individuals with schizophrenia (SCZ) have, on average, a 10- to 20-year shorter expected life span than the rest of the population, primarily due to cardiovascular disease comorbidity. Genome-wide association studies (GWAS) have previously been used to separately identify common variants in SCZ and cardiometabolic traits. However, genetic variants jointly influencing both traits remain to be fully characterised. To assess overlaps (if any) between the genetic architecture of SCZ and cardiometabolic traits, we used conditional false discovery rate (FDR) and local genetic correlation statistical framework analyses. A conjunctional FDR was used to identify shared genetic traits between SCZ and cardiometabolic risk factors. We identified 144 genetic variants which were shared between SCZ and body mass index (BMI), and 15 variants shared between SCZ and triglycerides (TG). Furthermore, we discovered four novel single nucleotide polymorphisms (SNPs) (rs3865350, rs9860913, rs13307 and rs9614186) and four proximate genes (DERL2, SNX4, LY75 and EFCAB6) which were shared by SCZ and BMI. We observed that the novel genetic variant rs13307 and the most proximate gene LY75 exerted potential effects on SCZ and BMI comorbidity. Also, we observed a mixture of concordant and opposite direction associations with shared genetic variants. We demonstrated a moderate to high genetic overlap between SCZ and cardiometabolic traits associated with a pattern of bidirectional associations. Our data suggested a complex interplay between metabolism-related gene pathways in SCZ pathophysiology.

Aim: Genome‐wide association studies (GWAS) have identified multiple susceptibility loci associated with insulin resistance (IR)‐relevant phenotypes. However, the genes responsible for these associations remain largely unknown. We aim to identify susceptibility genes for IR‐relevant phenotypes via a transcriptome‐wide association study. Materials and Methods: We conducted a large‐scale multi‐tissue transcriptome‐wide association study for IR (Insulin Sensitivity Index, homeostasis model assessment‐IR, fasting insulin) and lipid‐relevant traits (high‐density lipoprotein cholesterol, triglycerides, low‐density lipoprotein cholesterol and total cholesterol) using the largest GWAS summary statistics and precomputed gene expression weights of 49 human tissues. Conditional and joint analyses were implemented to identify significantly independent genes. Furthermore, we estimated the causal effects of independent genes by Mendelian randomization causal inference analysis. Results: We identified 1190 susceptibility genes causally associated with IR‐relevant phenotypes, including 58 genes that were not implicated in the original GWAS. Among them, 11 genes were further supported in differential expression analyses or a gene knockout mice database, such as KRIT1 showed both significantly differential expression and IR‐related phenotypic effects in knockout mice. Meanwhile, seven proteins encoded by susceptibility genes were targeted by clinically approved drugs, and three of these genes (H6PD, CACNB2 and DRD2) have been served as drug targets for IR‐related diseases/traits. Moreover, drug repurposing analysis identified four compounds with profiles opposing the expression of genes associated with IR risk. Conclusions: Our study provided new insights into IR aetiology and avenues for therapeutic development. [ABSTRACT FROM AUTHOR]

Summary: Vascular wilt diseases caused by Fusarium oxysporum are a major threat to many agriculturally important crops. Genetic resistance is rare and inevitably overcome by the emergence of new races. To identify potentially durable and non‐race‐specific genetic resistance against Fusarium wilt diseases, we set out to identify effector targets in tomato that mediate susceptibility to the fungus. For this purpose, we used the SIX8 effector protein, an important and conserved virulence factor present in many pathogenic F. oxysporum isolates. Using protein pull‐downs and yeast two‐hybrid assays, SIX8 was found to interact specifically with two members of the tomato TOPLESS family: TPL1 and TPL2. Loss‐of‐function mutations in TPL1 strongly reduced disease susceptibility to Fusarium wilt and a tpl1;tpl2 double mutant exerted an even higher level of resistance. Similarly, Arabidopsis tpl;tpr1 mutants became significantly less diseased upon F. oxysporum inoculation as compared to wildtype plants. We conclude that TPLs encode susceptibility genes whose mutation can confer resistance to F. oxysporum. [ABSTRACT FROM AUTHOR]

The susceptibility to autoimmune diseases is conditioned by the association of modest genetic alterations which altogether weaken self-tolerance. The mechanism whereby these genetic interactions modulate T-cell pathogenicity remains largely uncovered. Here, we investigated the epistatic interaction of two interacting proteins involved in T Cell Receptor signaling and which were previously associated with the development of Multiple Sclerosis. To this aim, we used mice expressing an hypomorphic variant of Vav1 (Vav1R63W), combined with a T cell-conditional deletion of Themis. We show that the combined mutations in Vav1 and Themis induce a strong attenuation of the severity of Experimental Autoimmune Encephalomyelitis (EAE), contrasting with the moderate effect of the single mutation in each of those two proteins. This genotype-dependent gradual decrease of EAE severity correlates with decreased quantity of phosphorylated Vav1 in CD4 T cells, establishing that Themis promotes the development of encephalitogenic Tconv response by enhancing Vav1 activity. We also show that the cooperative effect of Themis and Vav1 on EAE severity is independent of regulatory T cells and unrelated to the impact of Themis on thymic selection. Rather, it results from decreased production of pro-inflammatory cytokines (IFN-γ, IL-17, TNF and GM-CSF) and reduced T cell infiltration in the CNS. Together, our results provide a rationale to study combination of related genes, in addition to single gene association, to better understand the genetic bases of human diseases. [ABSTRACT FROM AUTHOR]

Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future. [ABSTRACT FROM AUTHOR]

Abstract Objective The comorbidities of coronary artery disease (CAD) and rheumatoid arthritis (RA) are mutual risk factors, which lead to higher mortality, but the biological mechanisms connecting the two remain unclear. Here, we aimed to identify the risk genes for the comorbid presence of these two complex diseases using a network modularization approach, to offer insights into clinical therapy and drug development for these diseases. Method The expression profile data of patients CAD with and without RA were obtained from the GEO database (GSE110008). Based on the differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) was used to construct a gene network, detect co-expression modules, and explore their relation to clinical traits. The Zsummary index, gene significance (GS), and module membership (MM) were utilized to screen the important differentiated modules and hub genes. The GO and KEGG pathway enrichment analysis were applied to analyze potential mechanisms. Result Based on the 278 DEGs obtained, 41 modules were identified, of which 17 and 24 modules were positively and negatively correlated with the comorbid occurrence of CAD and RA (CAD&RA), respectively. Thirteen modules with Zsummary < 2 were found to be the underlying modules, which may be related to CAD&RA. With GS ≥ 0.5 and MM ≥ 0.8, 49 hub genes were identified, such as ADO, ABCA11P, POT1, ZNF141, GPATCH8, ATF6 and MIA3, etc. The area under the curve values of the representative seven hub genes under the three models (LR, KNN, SVM) were greater than 0.88. Enrichment analysis revealed that the biological functions of the targeted modules were mainly involved in cAMP-dependent protein kinase activity, demethylase activity, regulation of calcium ion import, positive regulation of tyrosine, phosphorylation of STAT protein, and tissue migration, etc. Conclusion Thirteen characteristic modules and 49 susceptibility hub genes were identified, and their corresponding molecular functions may reflect the underlying mechanism of CAD&RA, hence providing insights into the development of clinical therapies against these diseases.

Graves' disease(GD)is an organ-specific autoimmune disease with genetic background. The core pathogenesis of GD is immune factors, but genetic factors also play an important role in it. The susceptibility genes of GD are mainly divided into immunoregulatory gene and thyroid specific gene. The polymorphism of immunoregulatory gene may have some impact on the susceptibility of GD through various mechanisms, which may provide new ideas for the further study of the susceptibility genes and pathogenesis of GD.

Abstract The genetic generalized epilepsies (GGEs) have been proved to generate from genetic impact by twin studies and family studies. The genetic mechanisms of generalized epilepsies are always updating over time. Although the genetics of GGE is complex, there are always new susceptibility genes coming up as well as copy number variations which can lead to important breakthroughs in exploring the problem. At the same time, the development of ClinGen fades out some of the candidate genes. This means we have to figure out what accounts for a reliable gene for GGE, in another word, which gene has sufficient evidence for GGE. This will improve our understanding of the genetic mechanisms of GGE. In this review, important up-to-date genetic mechanisms of GGE were discussed.

The reduction of pesticide treatments is of paramount importance for the sustainability of viticulture, and it can be achieved through a combination of strategies, including the cultivation of vines (Vitis vinifera) that are resistant or tolerant to diseases such as downy mildew (DM). In many crops, the knock-out of Downy Mildew Resistant 6 (DMR6) proved successful in controlling DMresistance, but the effect of mutations in DMR6 genes is not yet known in grapevine. Today, gene editing serves crop improvement with small and specific mutations while maintaining the genetic background of commercially important clones. Moreover, recent technological advances allowed to produce non-transgenic grapevine clones by regeneration of protoplasts edited with the CRISPR/Cas9 ribonucleoprotein. This approach may revolutionize the production of new grapevine varieties and clones, but it requires knowledge about the targets and the impact of editing on plant phenotype and fitness in different cultivars. In this work we generated single and double knock-out mutants by editing DMR6 susceptibility (S) genes using CRISPR/Cas9, and showed that only the combined mutations in VviDMR6-1 and VviDMR6-2 are effective in reducing susceptibility to DM in two table-grape cultivars by increasing the levels of endogenous salicylic acid. Therefore, editing both genes may be necessary for effective DM control in real-world agricultural settings, which could potentially lead to unwanted phenotypes. Additional research, including trials conducted in experimental vineyards, is required to gain a deeper understanding of DMR6- based resistance. [ABSTRACT FROM AUTHOR]

Objective: Acute necrotizing encephalopathy (ANE) is a severe complication of infectious diseases affecting the brain and systemic organs. The main pathogenesis is cytokine storm, in which interleukin-6 (IL-6) and interleukin-10 (IL-10) are candidates for key cytokines. To further elucidate their roles in the etiology and pathogenesis of ANE, we studied polymorphisms in the promotor regions of the IL6 and IL10 genes by genetic and functional analyses. Methods: We first conducted a case--control association study of four IL6 and three IL10 polymorphisms. We genotyped 31 Japanese ANE cases and compared the results with those of approximately 200 Japanese controls. For the two polymorphisms showing a possible association, we next studied whether the polymorphisms alter the production of IL-6 or IL-10 by lymphoblasts upon phorbol 12-myristate 13-acetate (PMA) stimulation. Results: The frequencies of IL6 rs1800796G allele and IL10 rs1800871/rs1800872 CC/CC diplotype were significantly higher in ANE cases than in controls. The IL10 CC/CC diplotype was associated with low IL-10 production, whereas the IL6 GG genotype was not associated with IL-6 production. Conclusion: IL10 rs1800871/rs1800872 CC/CC diplotype may predispose Japanese children to ANE by altering IL-10 production in the early phase of infection. Etio-pathogenetic significance of IL6 rs1800796G remains to be elucidated. [ABSTRACT FROM AUTHOR]

Objective: The comorbidities of coronary artery disease (CAD) and rheumatoid arthritis (RA) are mutual risk factors, which lead to higher mortality, but the biological mechanisms connecting the two remain unclear. Here, we aimed to identify the risk genes for the comorbid presence of these two complex diseases using a network modularization approach, to offer insights into clinical therapy and drug development for these diseases. Method: The expression profile data of patients CAD with and without RA were obtained from the GEO database (GSE110008). Based on the differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) was used to construct a gene network, detect co-expression modules, and explore their relation to clinical traits. The Zsummary index, gene significance (GS), and module membership (MM) were utilized to screen the important differentiated modules and hub genes. The GO and KEGG pathway enrichment analysis were applied to analyze potential mechanisms. Result: Based on the 278 DEGs obtained, 41 modules were identified, of which 17 and 24 modules were positively and negatively correlated with the comorbid occurrence of CAD and RA (CAD&RA), respectively. Thirteen modules with Zsummary < 2 were found to be the underlying modules, which may be related to CAD&RA. With GS ≥ 0.5 and MM ≥ 0.8, 49 hub genes were identified, such as ADO, ABCA11P, POT1, ZNF141, GPATCH8, ATF6 and MIA3, etc. The area under the curve values of the representative seven hub genes under the three models (LR, KNN, SVM) were greater than 0.88. Enrichment analysis revealed that the biological functions of the targeted modules were mainly involved in cAMP-dependent protein kinase activity, demethylase activity, regulation of calcium ion import, positive regulation of tyrosine, phosphorylation of STAT protein, and tissue migration, etc. Conclusion: Thirteen characteristic modules and 49 susceptibility hub genes were identified, and their corresponding molecular functions may reflect the underlying mechanism of CAD&RA, hence providing insights into the development of clinical therapies against these diseases. [ABSTRACT FROM AUTHOR]

Transcription activator-like effectors are key virulence factors of Xanthomonas. They are secreted into host plant cells and mimic transcription factors inducing the expression of host susceptibility (S) genes. In citrus, CsLOBl is a direct target of PthA4, the primary effector associated with citrus canker symptoms. CsLOBl is a transcription factor, and its expression is required for canker symptoms induced by Xanthomonas citri subsp. citri. Several genes are up-regulated by PthA4; however, only CsLOBl was described as an S gene induced by PthA4. Here, we investigated whether other up-regulated genes could be direct targets of PthA4 or CsLOB 1. Seven up-regulated genes by PthA4 were investigated; however, an expansin-coding gene was more induced than CsLOBl. In Nicotiana benthamiana transient expression experiments, we demonstrate that the expansin-coding gene, referred here to as CsLOBl-INDUCED EXPANSIN 1 (CsLIEXPl), is not a direct target of PthA4, but CsLOB 1. Interestingly, CsLIEXPl was induced by CsLOBl even without the predicted CsLOBl binding site, which suggested that CsLOB 1 has other unknown binding sites. We also investigated the minimum promoter regulated by CsLOBl, and this region and LOB1 domain were conserved among citrus species and relatives, which suggests that the interaction PthM-CsLOB 1'-CsLIEXPl is conserved in citrus species and relatives. This is the first study that experimentally demonstrated a CsLOBl downstream target and lays the foundation to identify other new targets. In addition, we demonstrated that the CsLIEXPl is a putative S gene indirectly induced by PthA4, which may serve as the target for genome editing to generate citrus canker-resistant varieties. [ABSTRACT FROM AUTHOR]

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=0.015 8), ApoE gene (P=0.012 6), FGB gene (P=0.005), GNB gene (P=0.015 1), MTFHR gene (P=0.011 9), SEL gene (P=0.005), TNF gene (P=0.029 8) were significantly overexpressed in the non-coronary heart disease group. The expression of NOS3 gene (P=0.304 7), IL6 gene (P=0.723 9), ACE gene (P=0.785 2)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. [ABSTRACT FROM AUTHOR]

Abstract Aim Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood, with genetic susceptibility and pathological processes such as autoimmunity and autoinflammation, but its pathogenesis is unclear. We conducted a transcriptome-wide association study (TWAS) using expression interpolation from a large-scale genome-wide association study (GWAS) dataset to identify genes, biological pathways, and environmental chemicals associated with JIA. Methods We obtained published GWAS data on JIA for TWAS and used mRNA expression profiling to validate the genes identified by TWAS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. A protein–protein interaction (PPI) network was generated, and central genes were obtained using Molecular Complex Detection (MCODE). Finally, chemical gene expression datasets were obtained from the Comparative Toxicogenomics database for chemical genome enrichment analysis. Results TWAS identified 1481 genes associated with JIA, and 154 differentially expressed genes were identified based on mRNA expression profiles. After comparing the results of TWAS and mRNA expression profiles, we obtained eight overlapping genes. GO and KEGG enrichment analyses of the genes identified by TWAS yielded 163 pathways, and PPI network analysis as well as MCODE resolution identified a total of eight clusters. Through chemical gene set enrichment analysis, 287 environmental chemicals associated with JIA were identified. Conclusion By integrating TWAS and mRNA expression profiles, genes, biological pathways, and environmental chemicals associated with JIA were identified. Our findings provide new insights into the pathogenesis of JIA, including candidate genetic and environmental factors contributing to its onset and progression.

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 microglial 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 results show that TREML2 levels gradually increased in the brains of APP/PS1 mice during disease progression. LPS stimulation of primary microglia led to the release of inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α in the culture medium. The LPS-induced microglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knockdown. LPS increased the levels of microglial 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.

Summary: Southern leaf blight (SLB), caused by the necrotrophic fungal pathogen Cochliobolus heterostrophus (anamorph Bipolaris maydis), is a major foliar disease which causes significant yield losses in maize worldwide. A major quantitative trait locus, qSLB3.04, conferring recessive resistance to SLB was previously mapped on maize chromosome 3.Using a combination of map‐based cloning, association analysis, ethyl methanesulfonate and transposon mutagenesis, and CRISPR‐Cas9 editing, we demonstrate that a leucine‐rich repeat receptor‐like kinase gene which we have called ChSK1 (Cochliobolus heterostrophus Susceptibility Kinase 1) at qSLB3.04 causes increased susceptibility to SLB. Genes of this type have generally been associated with the defense response.We present evidence that ChSK1 may be associated with suppression of the basal immune response.These findings contribute to our understanding of plant disease susceptibility genes and the potential to use them for engineering durable disease resistance. [ABSTRACT FROM AUTHOR]

Powdery mildew (PM) diseases may severely limit the production of various crops, including members of the family Cucurbitaceae. Successful PM infection relies on the Mildew Resistance Locus O (MLO) plant gene family, which encodes susceptibility factors essential for fungus penetration into the host cell. In cucumber (Cucumis sativus). natural mutations in CsaML08 con ferresistanceto the PM pathogen Podosphaera xanthii. Here, we used CRISPR/Cas9-mediated mutagenesis to generate PM resistance in the susceptible cucumber cultivar Ilan. Two transgene - free Csam!08 CRISPR mutant lines (Csamio- crd and Csamlo - cr-2) were isolated, the first with a 5-bp deletion in exon 1, and the second harboring a 1,280-bp deletion and 10-bp insertion between exons 1 and 5. Both lines showed high resistance to PM under semicommercial growth conditions in the summer growing seasons of 2019 and 2021. These results provide the basis for generating transgene-free powdery mildew resistance in cucumber in any genetic background. This method can directly be employed on commercial cultivars and hybrid parental lines. and thereby substantially shorten and simplify the breeding process for PM resistance in cucumber. [ABSTRACT FROM AUTHOR]

CRISPR crops carrying a mutation in susceptibility (S) genes provide an effective strategy for controlling plant disease, because they could be 'transgene-free' and commonly have more broad-spectrum and durable type of resistance. Despite their importance, CRISPR/Cas9-mediated editing of S genes for engineering resistance to plant-parasitic nematode (PPN) disease has not been reported. In this study, we employed the CRISPR/Cas9 system to specifically induce targeted mutagenesis of the S gene rice copper metallochaperone heavy metal-associated plant protein 04 (OsHPP04), and successfully obtained genetically stable homozygous rice mutants with or without transgenic elements. These mutants confer enhanced resistance to the rice root-knot nematode (Meloidogyne graminicola), a major plant pathogenic nematode in rice agriculture. Moreover, the plant immune responses triggered by flg22, including reactive oxygen species burst, defence-related genes expression and callose deposition, were enhanced in the 'transgene-free' homozygous mutants. Analysis of rice growth and agronomic traits of two independent mutants showed that there are no obvious differences between wild-type plants andmutants. These findings suggest that OsHPP04 may be an S gene as a negative regulator of host immunity and genetic modification of S genes through the CRISPR/Cas9 technology can be used as a powerful tool to generate PPN resistant plant varieties. [ABSTRACT FROM AUTHOR]

The genetic generalized epilepsies (GGEs) have been proved to generate from genetic impact by twin studies and family studies. The genetic mechanisms of generalized epilepsies are always updating over time. Although the genetics of GGE is complex, there are always new susceptibility genes coming up as well as copy number variations which can lead to important breakthroughs in exploring the problem. At the same time, the development of ClinGen fades out some of the candidate genes. This means we have to figure out what accounts for a reliable gene for GGE, in another word, which gene has sufficient evidence for GGE. This will improve our understanding of the genetic mechanisms of GGE. In this review, important up-to-date genetic mechanisms of GGE were discussed. [ABSTRACT FROM AUTHOR]

Graves’ disease (GD )is an organ-specific autoimmune disease with genetic background. The core pathogenesis of GD is immune factors, but genetic factors also play an important role in it. The susceptibility genes of GD are mainly divided into immunoregulatory gene and thyroid specific gene. The polymorphism of immunoregulatory gene may have some impact on the susceptibility of GD through various mechanisms, which may provide new ideas for the further study of the susceptibility genes and pathogenesis of GD. [ABSTRACT FROM AUTHOR]

The reduction of pesticide treatments is of paramount importance for the sustainability of viticulture, and it can be achieved through a combination of strategies, including the cultivation of vines (Vitis vinifera) that are resistant or tolerant to diseases such as downy mildew (DM). In many crops, the knock-out of Downy Mildew Resistant 6 (DMR6) proved successful in controlling DM-resistance, but the effect of mutations in DMR6 genes is not yet known in grapevine.Today, gene editing serves crop improvement with small and specific mutations while maintaining the genetic background of commercially important clones. Moreover, recent technological advances allowed to produce non-transgenic grapevine clones by regeneration of protoplasts edited with the CRISPR/Cas9 ribonucleoprotein. This approach may revolutionize the production of new grapevine varieties and clones, but it requires knowledge about the targets and the impact of editing on plant phenotype and fitness in different cultivars.In this work we generated single and double knock-out mutants by editing DMR6 susceptibility (S) genes using CRISPR/Cas9, and showed that only the combined mutations in VviDMR6-1 and VviDMR6-2 are effective in reducing susceptibility to DM in two table-grape cultivars by increasing the levels of endogenous salicylic acid. Therefore, editing both genes may be necessary for effective DM control in real-world agricultural settings, which could potentially lead to unwanted phenotypes. Additional research, including trials conducted in experimental vineyards, is required to gain a deeper understanding of DMR6-based resistance.

Keywords: tomato; PUB17; susceptibility gene; necrotroph; Botrytis cinerea; Alternaria solani EN tomato PUB17 susceptibility gene necrotroph Botrytis cinerea Alternaria solani 2157 2159 3 10/19/23 20231101 NES 231101 Necrotrophic fungi, such as I Botrytis cinerea i and I Alternaria solani i , cause severe damage in tomato production. H, heterozygous with one WT allele and one mutant allele; IR, intermediate resistant; M, homozygous for the mutant allele; S, susceptible; WT, homozygous for the MT allele. WT, wild-type tomato PUB17 protein; M2042, EMS PUB17 mutant allele; allele 1-4, CRISPR PUB17 mutant alleles. [Extracted from the article]

Keywords: Chinese population; East Asian; inflammatory bowel disease; personalized medicine; susceptibility gene EN Chinese population East Asian inflammatory bowel disease personalized medicine susceptibility gene 1 3 3 10/03/23 20230901 NES 230901 THE CHALLENGE OF GENOME-WIDE ASSOCIATION STUDIES IN INFLAMMATORY BOWEL DISEASE Inflammatory bowel diseases (IBD) are characterized by idiopathic chronic inflammation of the gastrointestinal tract, comprising the two major entities ulcerative colitis (UC) and Crohn's disease (CD). As the variance explained for IBD loci differs across ancestries, the ability to exploit genetic loci and predict an individual's disease risk of IBD also differs greatly. [Extracted from the article]

Abstract Gout is a chronic metabolic disease that seriously affects human health. It is also a major challenge facing the world, which has brought a heavy burden to patients and society. Hyperuricemia (HUA) is the most important risk factor for gout. In recent years, with the improvement of living standards and the change of dietary habits, the incidence of gout in the world has increased dramatically, and gradually tends to be younger. An increasing number of studies have shown that gene mutations may play an important role in the development of HUA and gout. Therefore, we reviewed the existing literature and summarized the susceptibility genes and research status of HUA and gout, in order to provide reference for the early diagnosis, individualized treatment and the development of new targeted drugs of HUA and gout.

Abstract Individuals with schizophrenia (SCZ) have, on average, a 10- to 20-year shorter expected life span than the rest of the population, primarily due to cardiovascular disease comorbidity. Genome-wide association studies (GWAS) have previously been used to separately identify common variants in SCZ and cardiometabolic traits. However, genetic variants jointly influencing both traits remain to be fully characterised. To assess overlaps (if any) between the genetic architecture of SCZ and cardiometabolic traits, we used conditional false discovery rate (FDR) and local genetic correlation statistical framework analyses. A conjunctional FDR was used to identify shared genetic traits between SCZ and cardiometabolic risk factors. We identified 144 genetic variants which were shared between SCZ and body mass index (BMI), and 15 variants shared between SCZ and triglycerides (TG). Furthermore, we discovered four novel single nucleotide polymorphisms (SNPs) (rs3865350, rs9860913, rs13307 and rs9614186) and four proximate genes (DERL2, SNX4, LY75 and EFCAB6) which were shared by SCZ and BMI. We observed that the novel genetic variant rs13307 and the most proximate gene LY75 exerted potential effects on SCZ and BMI comorbidity. Also, we observed a mixture of concordant and opposite direction associations with shared genetic variants. We demonstrated a moderate to high genetic overlap between SCZ and cardiometabolic traits associated with a pattern of bidirectional associations. Our data suggested a complex interplay between metabolism-related gene pathways in SCZ pathophysiology.

Potyviruses are the largest group of plant-infecting RNA viruses that affect a wide range of crop plants. Plant resistance genes against potyviruses are often recessive and encode translation initiation factors eIF4E. The inability of potyviruses to use plant eIF4E factors leads to the development of resistance through a loss-ofsusceptibility mechanism. Plants have a small family of eIF4E genes that encode several isoforms with distinct but overlapping functions in cell metabolism. Potyviruses use distinct eIF4E isoforms as susceptibility factors in different plants. The role of different members of the plant eIF4E family in the interaction with a given potyvirus could differ drastically. An interplay exists between different members of the eIF4E family in the context of plant–potyvirus interactions, allowing different eIF4E isoforms to modulate each other’s availability as susceptibility factors for the virus. In this review, possible molecular mechanisms underlying this interaction are discussed, and approaches to identify the eIF4E isoform that plays a major role in the plant–potyvirus interaction are suggested. The final section of the review discusses how knowledge about the interaction between different eIF4E isoforms can be used to develop plants with durable resistance to potyviruses [ABSTRACT FROM AUTHOR]

Summary: Wheat stripe rust caused by the fungus Puccinia striiformis f. sp. tritici (Pst) is one of the most destructive wheat diseases resulting in significant losses to wheat production worldwide. The development of disease‐resistant varieties is the most economical and effective measure to control diseases. Altering the susceptibility genes that promote pathogen compatibility via CRISPR/Cas9‐mediated gene editing technology has become a new strategy for developing disease‐resistant wheat varieties. Calcineurin B‐like protein (CBL)‐interacting protein kinases (CIPKs) has been demonstrated to be involved in defence responses during plant‐pathogen interactions. However, whether wheat CIPK functions as susceptibility factor is still unclear. Here, we isolated a CIPK homoeologue gene TaCIPK14 from wheat. Knockdown of TaCIPK14 significantly increased wheat resistance to Pst, whereas overexpression of TaCIPK14 resulted in enhanced wheat susceptibility to Pst by decreasing different aspects of the defence response, including accumulation of ROS and expression of pathogenesis‐relative genes. We generated wheat Tacipk14 mutant plants by simultaneous modification of the three homoeologues of wheat TaCIPK14 via CRISPR/Cas9 technology. The Tacipk14 mutant lines expressed race‐nonspecific (RNS) broad‐spectrum resistance (BSR) to Pst. Moreover, no significant difference was found in agronomic yield traits between Tacipk14 mutant plants and Fielder control plants under greenhouse and field conditions. These results demonstrate that TaCIPK14 acts as an important susceptibility factor in wheat response to Pst, and knockout of TaCIPK14 represents a powerful strategy for generating new disease‐resistant wheat varieties with BSR to Pst. [ABSTRACT FROM AUTHOR]

Background: Diabetic kidney disease (DKD) is one of the most common complications of diabetes, with approximately 30–40% of patients with type 1 diabetes mellitus and 20% of patients with type 2 diabetes mellitus eventually developing DKD. If DKD is not controlled in the early clinical stage and proteinuria develops, the disease will progress to end-stage renal disease. The pathogenesis of DKD remains largely unknown and is multifactorial, likely due to interactions between genetic and environmental factors. Familial clustering also supports a critical role of hereditary factors in DKD. The development of gene detection technology has promoted the exploration of DKD susceptibility genes in different cohorts of patients with diabetes. Identifying susceptibility genes can provide insights into the pathogenesis of DKD, as well as a basis for its clinical diagnosis and therapy. Results: Numerous candidate gene loci have been found to be associated with DKD, many of which play critical regulatory roles in the pathogenesis of this disease, including genes involved in glycol-metabolism, lipid metabolism, the renin–angiotensin–aldosterone system, inflammation and oxidative stress. In this review, we summarize the functions of several susceptibility genes involved in the development of DKD. Conclusion: Based on our findings, we recommend that studying susceptibility gene polymorphisms can lead to a better understanding of the pathogenesis of DKD and could help prevent this disease or improve its outcomes. [ABSTRACT FROM AUTHOR]

Acute encephalopathy is a constellation of syndromes in which immune response, metabolism and neuronal excitation are affected in a variable fashion. Most of the syndromes are complex disorders, caused or aggravated by multiple, genetic and environmental risk factors. Environmental factors include pathogenic microorganisms of the antecedent infection such as influenza virus, human herpesvirus-6 and enterohemorrhagic Escherichia coli, and drugs such as nonsteroidal anti-inflammatory drugs, valproate and theophylline. Genetic factors include mutations such as rare variants of the SCN1A and RANBP2 genes, and polymorphisms such as thermolabile CPT2 variants and HLA genotypes. By altering immune response, metabolism or neuronal excitation, these factors complicate the pathologic process. On the other hand, some of them could provide promising targets to prevent or treat acute encephalopathy. [ABSTRACT FROM AUTHOR]

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue tumor in children, and its most common pathological types include embryonal RMS and alveolar RMS. In contrast, spindle cell RMS (SRMS) is a rare type. Moreover, the tongue is a rare primary site of RMS, and infancy is a rare age at onset. Case presentation: Two infants were diagnosed with lingual RMS at 3 and 5 months after birth, respectively, and were admitted to Beijing Children's Hospital. The pathological type in both cases was SRMS. Both were classified as low-risk and were treated with surgery and chemotherapy. Case 1 was in complete remission at the latest follow-up, and Case 2 had a relapse 10 months after stopping chemotherapy, achieving complete remission after the multimodal treatment of chemotherapy, surgery, and radiotherapy. The venous blood gene test of the two infants did not indicate a pathogenic mutation or a possible pathogenic mutation related to RMS. In Case 1, variants of the CDK4 and BRCA1 genes, both with unknown significance and a possible relation to RMS, were detected. In Case 2, three gene variants of unknown significance that were possibly associated with RMS--TRIP13, APC, and RAD54L--were identified. Conclusion: Lingual RMS in infants is rare. Its clinical manifestations lack specificity, and early recognition is complex. The success and timing of local treatment are important prognostic factors. Genetic testing may be helpful for the early detection of tumor susceptibility and the estimation of prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background To explore possible associations between glucose transporter 4 (GLUT4) genetic polymorphisms in the patients with coronary heart disease (CHD) in Han and Uygur Chinese populations in Xinjiang, China. Methods Two GLUT4 polymorphisms (rs5418 and rs5435) were genotyped in 1262 Han (628 CHD patients and 634 healthy controls) and 896 Uyghur (397 CHD patients and 499 healthy controls) Chinese populations. Results In the Han Chinese population, there were no significant differences in allelic or genotypic distribution of rs5418 and rs5435 between the CHD and control groups (all P > 0.05). However, in the Uygur population, there were significant differences in genotype and allele distributions for rs5418 between CHD and the control group (all P

Potyviruses are the largest group of plant-infecting RNA viruses that affect a wide range of crop plants. Plant resistance genes against potyviruses are often recessive and encode translation initiation factors eIF4E. The inability of potyviruses to use plant eIF4E factors leads to the development of resistance through a loss-of-susceptibility mechanism. Plants have a small family of eIF4E genes that encode several isoforms with distinct but overlapping functions in cell metabolism. Potyviruses use distinct eIF4E isoforms as susceptibility factors in different plants. The role of different members of the plant eIF4E family in the interaction with a given potyvirus could differ drastically. An interplay exists between different members of the eIF4E family in the context of plant–potyvirus interactions, allowing different eIF4E isoforms to modulate each other’s availability as susceptibility factors for the virus. In this review, possible molecular mechanisms underlying this interaction are discussed, and approaches to identify the eIF4E isoform that plays a major role in the plant–potyvirus interaction are suggested. The final section of the review discusses how knowledge about the interaction between different eIF4E isoforms can be used to develop plants with durable resistance to potyviruses.

Sedentary plant-parasitic cyst nematodes are obligate biotrophs that infect the roots of their host plant. Their parasitism is based on the modification of root cells to form a hypermetabolic syncytium from which the nematodes draw their nutrients. The aim of this study was to identify nematode susceptibility genes in Arabidopsis thaliana and to characterize their roles in supporting the parasitism of Heterodera schachtii. By selecting genes that were most strongly upregulated in response to cyst nematode infection, we identified HIPP27 (HEAVY METAL-ASSOCIATED ISOPRENYLATED PLANT PROTEIN 27) as a host susceptibility factor required for beet cyst nematode infection and development. Detailed expression analysis revealed that HIPP27 is a cytoplasmic protein and that HIPP27 is strongly expressed in leaves, young roots and nematode-induced syncytia. Loss-of-function Arabidopsis hipp27 mutants exhibited severely reduced susceptibility to H. schachtii and abnormal starch accumulation in syncytial and peridermal plastids. Our results suggest that HIPP27 is a susceptibility gene in Arabidopsis whose loss of function reduces plant susceptibility to cyst nematode infection without increasing the susceptibility to other pathogens or negatively affecting the plant phenotype.

Keywords: maize; disease resistance; genome editing; susceptibility gene; NANMT EN maize disease resistance genome editing susceptibility gene NANMT 1525 1527 3 07/26/23 20230801 NES 230801 Maize is one of the most important crops in the world. Recently, it has been proved that generation of genome editing materials using CRISPR/Cas9 by targeting susceptibility (S) genes (e.g. I Mlo i and I DMR6 i ) is a powerful way to confer disease resistance in economically important crops (Tripathi I et al i ., [8]; Wang I et al i ., [9]). [Extracted from the article]

I Fusarium graminearum i is a hemibiotrophic fungal pathogen for wheat Fusarium head blight (FHB) and shares a similar lifestyle with I Magnaporthe oryzae i for rice blast. Keywords: rice blast resistance; histidine-rich calcium-binding protein; loss-of-function mutation; susceptibility gene; wheat FHB EN rice blast resistance histidine-rich calcium-binding protein loss-of-function mutation susceptibility gene wheat FHB 1516 1518 3 07/26/23 20230801 NES 230801 Rice blast, caused by I Magnaporthe oryzae i , is a serious disease in rice ( I Oryzae sativa i L.) worldwide. Rice blast resistance, loss-of-function mutation, histidine-rich calcium-binding protein, wheat FHB, susceptibility gene. [Extracted from the article]

Potato (Solanum tuberosum L.) cultivation is threatened by various environmental stresses, especially disease. Genome editing technologies are effective tools for generating pathogen-resistant potatoes. Here, we established an efficient RNP-mediated CRISPR/Cas9 genome editing protocol in potato to develop Phytophthora infestans resistant mutants by targeting the susceptibility gene, Signal Responsive 4 (SR4), in protoplasts. Mutations in StSR4 were efficiently introduced into the regenerated potato plants, with a maximum efficiency of 34%. High co-expression of StEDS1 and StPAD4 in stsr4 mutants induced the accumulation of salicylic acid (SA), and enhanced the expression of the pathogen resistance marker StPR1. In addition, increased SA content in the stsr4 mutant enhanced its resistance to P. infestans more than that in wild type. However, the growth of stsr4&lowbar;3-19 and stsr4&lowbar;3-698 mutants with significantly high SA was strongly inhibited, and a dwarf phenotype was induced. Therefore, it is important to adequate SA accumulation in order to overcome StSR4 editing-triggered growth inhibition and take full advantages of the improved pathogen resistance of stsr4 mutants. This RNP-mediated CRISPR/Cas9-based potato genome editing protocol will accelerate the development of pathogen-resistant Solanaceae crops via molecular breeding. [ABSTRACT FROM AUTHOR]

Background: The human leukocyte antigen (HLA) susceptibility gene is the main genetic risk factor for primary biliary cholangitis (PBC). The prognosis of patients with PBC is linked to gut microbiota dysbiosis. However, whether the HLA alleles are associated with the gut microbiota distribution and disease severity remains unknown. Methods: A cohort of 964 Chinese patients with PBC was enrolled at Beijing YouAn Hospital, Beijing, China. High-resolution genotyping of the HLA class I and class II loci from 151 of these patients was performed using sequence-based PCR. Stool samples were collected from43 of the 151 fully HLA-typed patients to analyze their microbiota compositions via 16S RNA gene sequencing. Results: Of the 964 patients, the male:female ratio was 114:850, and 342 of these patients (35.5%) had already developed liver cirrhosis (LC) before enrollment. Patients with PBC showed a significantly higher frequency of HLA DRB1*08:03 than did the controls (21.2% vs. 9.0%, P=0.0001). HLA-DRB1*03:01, DRB1*07:01, DRB1*14:05, and DRB1*14:54 frequencies were also increased but did not reach significance after Bonferroni's correction. Conversely, the DQB1*03:01 frequency was significantly lower in patients with PBC than in the controls (24.5% vs. 39.2%, P=0.0010). The patients' gutmicrobiotawere analyzed from four perspectives. The microbial community abundances were significantly lower in FHRAC-positive patients (patients with a combination of five HLA DRB1 high-risk alleles) than in FHRAC-negative patients (P<0.05). Of the top 10 microbial genera, Lachnospiraceae_incertae_sedis was higher in the FHRACpositive patients than in the FHRAC-negative patients (P<0.05). linear discriminant analysis (LDA) effect-size (LEfSe) analysis showed different microbes at different levels in the FHRAC-negative patients but not in the FHRAC-positive patients. DQB1*03:01-positive patients contained mostly Lactobacillaceae at the family level. A comparison of the FHRAC-positive patients with and without liver cirrhosis showed that the abundances of Veillonella were significantly higher in patients with cirrhosis and FHRAC than in those without cirrhosis and are FHRAC-negative. Conclusion: The HLA class II genes may influence the gut microbiota compositions in patients with PBC. Differential gut microbiota were expressed at different taxonomic levels. Some bacterial abundances may be increased in FHRAC-positive patients with PBC and cirrhosis. [ABSTRACT FROM AUTHOR]

Familial intracranial aneurysms (FIAs) are distinguished by significant genetic predisposition, leading to clustering of cases within families and heightening the risk of subarachnoid hemorrhage (SAH) following aneurysm rupture. This review analyzes recent advancements in understanding the genetic and molecular mechanisms underlying FIAs, focusing on key genetic risk factors and environmental influences. We explore cutting-edge genome-wide association studies (GWAS) and next-generation sequencing (NGS) technologies, which have identified susceptibility genes such as ANGPTL6, PPIL4, and NOTCH3 as crucial contributors to FIA pathophysiology. By incorporating findings from multi-omics and gene-editing research, we highlight the potential for improved screening, preventive strategies, and therapeutic approaches. These insights are essential to advancing precision medicine in managing FIAs, paving the way for collaborative research and targeted interventions., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)