Members of a novel gene family, Gsdm, are expressed exclusively in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner

AbstractGasdermin (Gsdm) was originally identified as a candidate causative gene for several mouse skin mutants. Several Gsdm-related genes sharing a protein domain with DFNA5, the causative gene of human nonsyndromic hearing loss, have been found in the mouse and human genomes, and this group is referred to as the DFNA5–Gasdermin domain family. However, our current comparative genomic analysis identified several novel motifs distinct from the previously reported domain in the Gsdm-related genes. We also identified three new Gsdm genes clustered on mouse chromosome 15. We named these genes collectively the Gsdm family. Extensive expression analysis revealed exclusive expression of Gsdm family genes in the epithelium of the skin and gastrointestinal tract in a highly tissue-specific manner. Further database searching revealed the presence of other related genes with a similar N-terminal motif. These results suggest that the Gsdm family and related genes have evolved divergent epithelial expression profiles

A synthesis method of indole-3-methanamine and/or gramine from indole-3-carboxaldehyde, and its application for the syntheses of brassinin, its 4-substituted analogs, and 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline

金沢大学大学院自然科学研究科生理活性物質科学金沢大学薬学

Identification of a novel uterine leiomyoma GWAS locus in a Japanese population

Uterine leiomyoma is one of the most common gynaecologic benign tumours, but its genetic basis remains largely unknown. Six previous GWAS identified 33 genetic factors in total. Here, we performed a two-staged GWAS using 13,746 cases and 70,316 controls from the Japanese population, followed by a replication analysis using 3,483 cases and 4,795 controls. The analysis identified 9 significant loci, including a novel locus on 12q23.2 (rs17033114, P = 6.12 × 10−25 with an OR of 1.177 (1.141-1.213), LINC00485). Subgroup analysis indicated that 5 loci (3q26.2, 5p15.33, 10q24.33, 11p15.5, 13q14.11) exhibited a statistically significant effect among multiple leiomyomas, and 2 loci (3q26.2, 10q24.33) exhibited a significant effect among submucous leiomyomas. Pleiotropic analysis indicated that all 9 loci were associated with at least one proliferative disease, suggesting the role of these loci in the common neoplastic pathway. Furthermore, the risk T allele of rs2251795 (3q26.2) was associated with longer telomere length in both normal and tumour tissues. Our findings elucidated the significance of genetic factors in the pathogenesis of leiomyoma

ERAL1 is associated with mitochondrial ribosome and elimination of ERAL1 leads to mitochondrial dysfunction and growth retardation

ERAL1, a homologue of Era protein in Escherichia coli, is a member of conserved GTP-binding proteins with RNA-binding activity. Depletion of prokaryotic Era inhibits cell division without affecting chromosome segregation. Previously, we isolated ERAL1 protein as one of proteins which were associated with mitochondrial transcription factor A by using immunoprecipitation. In this study, we analysed the localization and function of ERAL1 in mammalian cells. ERAL1 was localized in mitochondrial matrix and associated with mitoribosomal proteins including the 12S rRNA. siRNA knockdown of ERAL1 decreased mitochondrial translation, caused redistribution of ribosomal small subunits and reduced 12S rRNA. The knockdown of ERAL1 in human HeLa cells elevated mitochondrial superoxide production and slightly decreased mitochondrial membrane potential. The knockdown inhibited the growth of HeLa cells with an accumulation of apoptotic cells. These results suggest that ERAL1 is localized in a small subunit of the mitochondrial ribosome, plays an important role in the small ribosomal constitution, and is also involved in cell viability

Comprehensive Network Analysis of Anther-Expressed Genes in Rice by the Combination of 33 Laser Microdissection and 143 Spatiotemporal Microarrays

Co-expression networks systematically constructed from large-scale transcriptome data reflect the interactions and functions of genes with similar expression patterns and are a powerful tool for the comprehensive understanding of biological events and mining of novel genes. In Arabidopsis (a model dicot plant), high-resolution co-expression networks have been constructed from very large microarray datasets and these are publicly available as online information resources. However, the available transcriptome data of rice (a model monocot plant) have been limited so far, making it difficult for rice researchers to achieve reliable co-expression analysis. In this study, we performed co-expression network analysis by using combined 44 K agilent microarray datasets of rice, which consisted of 33 laser microdissection (LM)-microarray datasets of anthers, and 143 spatiotemporal transcriptome datasets deposited in RicexPro. The entire data of the rice co-expression network, which was generated from the 176 microarray datasets by the Pearson correlation coefficient (PCC) method with the mutual rank (MR)-based cut-off, contained 24,258 genes and 60,441 genes pairs. Using these datasets, we constructed high-resolution co-expression subnetworks of two specific biological events in the anther, “meiosis” and “pollen wall synthesis”. The meiosis network contained many known or putative meiotic genes, including genes related to meiosis initiation and recombination. In the pollen wall synthesis network, several candidate genes involved in the sporopollenin biosynthesis pathway were efficiently identified. Hence, these two subnetworks are important demonstrations of the efficiency of co-expression network analysis in rice. Our co-expression analysis included the separated transcriptomes of pollen and tapetum cells in the anther, which are able to provide precise information on transcriptional regulation during male gametophyte development in rice. The co-expression network data presented here is a useful resource for rice researchers to elucidate important and complex biological events

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Hybrid origin of gynogenetic clones and the introgression of their mitochondrial genome into sexual diploids through meiotic hybridogenesis in the loach,Misgurnus anguillicuadatus

In a few Japanese populations of the loach Misgurnus anguillicaudatus (Teleostei: Cobitidae), clonal diploid lineages produce unreduced diploid eggs that normally undergo gynogenetic reproduction; however the origin of these clones remains elusive. Here, we show the presence of two diverse clades, A and B, within this loach species from sequence analyses of two nuclear genes RAG1 (recombination activating gene 1) and IRBP2 (interphotoreceptor retinoid-binding protein, 2) and then demonstrate heterozygous genotypes fixed at the two loci as the evidence of the hybrid nature of clonal lineages. All the clonal individuals were identified by clone-specific mitochondrial DNA haplotypes, microsatellite genotypes, and random amplified polymorphic DNA fingerprints; they commonly showed two alleles, one from clade A and another from clade B, whereas other wild-type diploids possessed alleles from either clade A or B. However, we also found wild-type diploids with clone-specific mitochondrial DNA and nuclear genes from clade B. One possible explanation is an introgression of a clone-specific mitochondrial genome from clonal to these wild-type loaches. These individuals likely arose by a cross between haploid sperm from bisexual B clade males and haploid eggs with clone-specific mtDNA and clade B nuclear genome, produced by meiotic hybridogenesis (elimination of unmatched A genome followed by meiosis after preferential pairing between two matched B genomes) in clone-origin triploid individual (ABB)

Pneumatosis intestinalis with a benign clinical course: a report of two cases

Abstract Background Pneumatosis intestinalis (PI) is a rare condition characterized by the presence of gas within the gastrointestinal tract wall. Most cases of PI have a benign clinical course, although some have serious outcomes. Mechanical stress on or bacterial infection of the gastrointestinal tract wall may be responsible for the onset of PI, but the detailed mechanism of PI pathogenesis is still unclear. Here, we describe two Japanese patients presenting with benign PI. Case presentation Case 1, a 37-year-old previously healthy male patient, had a 1-week history of abdominal pain, and case 2, a 78-year-old female diabetic patient, had a 2-week history of voglibose treatment and abdominal pain. Intramural gas was mainly distributed in the colon in case 1 and in the small intestine in case 2. Interestingly, neither patient showed obvious inflammatory signs upon admission and recovered spontaneously with conservative treatment, including fasting and fluid infusion without antibiotics. Voglibose treatment was terminated in case 2. Recent studies have shown the presence of nonpathogenic bacteria, such as Clostridium spp., in PI lesions, which usually play an important role in modulating the tolerance of the gastrointestinal immune responses. The benign clinical course and spontaneous resolution of PI in these patients, without specific treatment, suggests that nonpathogenic indigenous bacteria in the gastrointestinal tract participate in the pathogenesis of PI. Conclusion In patients with benign PI, the absence of an inflammatory response and the spontaneous resolution of the disease without specific treatment suggest the participation of nonpathogenic indigenous bacteria of the gastrointestinal tract

Influence of overstated abstract conclusions on clinicians: a web-based randomised controlled trial

Objectives: To investigate whether overstatements in abstract conclusions influence primary care physicians’ evaluations when they read reports of randomised controlled trials (RCTs) Design: CT setting: This study was a parallel-group randomised controlled survey, conducted online while masking the study hypothesis. Participants: Volunteers were recruited from members of the Japan Primary Care Association in January 2017. We sent email invitations to 7040 primary care physicians. Among the 787 individuals who accessed the website, 622 were eligible and automatically randomised into ‘without overstatement’ (n=307) and ‘with overstatement’ (n=315) groups. Interventions: We selected five abstracts from published RCTs with at least one non-significant primary outcome and overstatement in the abstract conclusion. To construct a version without overstatement, we rewrote the conclusion sections. The methods and results sections were standardised to provide the necessary information of primary outcome information when it was missing in the original abstract. Participants were randomly assigned to read an abstract either with or without overstatements and asked to evaluate the benefit of the intervention. Outcome measures: The primary outcome was the participants’ evaluation of the benefit of the intervention discussed in the abstract, on a scale from 0 to 10. A secondary outcome was the validity of the conclusion. Results: There was no significant difference between the groups with respect to their evaluation of the benefit of the intervention (mean difference: 0.07, 95% CI −0.28 to 0.42, p=0.69). Participants in the ‘without’ group considered the study conclusion to be more valid than those in the ‘with’ group (mean difference: 0.97, 95% CI 0.59 to 1.36, P<0.001). Conclusion: The overstatements in abstract conclusions did not significantly influence the primary care physicians’ evaluations of the intervention effect when necessary information about the primary outcomes was distinctly reported. Trial registration number: UMIN000025317; Pre-results