A Mutation in the Gene Encoding Mitochondrial Mg2+ Channel MRS2 Results in Demyelination in the Rat

The rat demyelination (dmy) mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system (CNS) after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2 (MRS2 magnesium homeostasis factor (Saccharomyces cerevisiae)) gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg2+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg2+ homeostasis in CNS mitochondria is essential for the maintenance of myelin

ウンドウ シッチョウ groggy ラット ワ デンイ イソンガタ P Q タイプ カルシウム チャネル アルファ1A サブユニット イデンシ ニ ミスセンス ヘンイ オ ユウシ ケッシン ホッサ オ シメス

京都大学0048新制・課程博士博士(医学)甲第12886号医博第3046号新制||医||939(附属図書館)UT51-2007-H159京都大学大学院医学研究科病理系専攻(主査)教授 髙橋 良輔, 教授 大森 治紀, 教授 金子 武嗣学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

The ring finger protein 213 gene (Rnf213) contributes to Rift Valley fever resistance in mice

International audienceRift Valley fever (RVF) is an emerging viral zoonosis that primarily affects ruminants and humans. We have previously shown that wild-derived MBT/Pas mice are highly susceptible to RVF virus and that part of this phenotype is controlled by a locus located on distal Chromosome 11. Using congenic strains, we narrowed down the critical interval to a 530 kb region containing five protein-coding genes among which Rnf213 emerged as a potential candidate. We generated Rnf213-deficient mice by CRISPR/CAS9 on the C57BL/6J background and showed that they were significantly more susceptible to RVF than control mice, with an average survival time post-infection reduced from 7 to 4 days. The human RNF213 gene had been associated with the cerebrovascular Moyamoya disease (MMD or MYMY) but the inactivation of this gene in the mouse resulted only in mild anomalies of the neovascularization. This study provides the first evidence that the Rnf213 gene may also impact the resistance to infectious diseases such as RVF

Biomarkers for Allergen Immunotherapy in Cedar Pollinosis

To initiate, monitor, and complete effective immunotherapy, biomarkers to predict and visualize the immune responses are needed. First, we need to identify the right candidate for immunotherapy. Secondly, the immune responses induced by immunotherapy should be monitored. For the first objective, analysis of polymorphisms of candidate genes may be helpful, but still be in development. Regarding biomarkers for immune responsese, there are numerous reports that evaluate immunotherapy-induced immune changes such as suppression of effector cells, deviation to Th1 cytokine production, and induction of regulatory T cells. No standardized methods, however, have been established. Among them, a functional assay of blocking IgG activity, the IgE-facilitated allergen binding assay, may be useful. We quantitated induced expression of an activation marker, CD203c, on basophils and found that the assay efficiently predicts sensitivity to particular allergen and severity of the allergen-induced symptoms. In patients who received rush immunotherapy for Japanese cedar pollinosis, reduction in CD203c expression after the therapy was observed, suggesting the utility of the test for monitoring immunotherapy

Genetic dissection of Rift Valley fever pathogenesis: Rvfs2 locus on mouse chromosome 11 enables survival to early-onset hepatitis

International audienceInfection of mice with Rift Valley fever virus (RVFV) reproduces major pathological features of severe human disease, notably the early-onset hepatitis and delayed-onset encephalitis. We previously reported that the Rvfs2 locus from the susceptible MBT/Pas strain reduces survival time after RVFV infection. Here, we used BALB/cByJ (BALB) mice congenic for Rvfs2 (C.MBT-Rvfs2) to investigate the pathophysiological mechanisms impacted by Rvfs2. Clinical, biochemical and histopathological features indicated similar liver damage in BALB and C.MBT-Rvfs2 mice until day 5 after infection. However, while C.MBT-Rvfs2 mice succumbed from acute liver injury, most BALB mice recovered and died later of encephalitis. Hepatocytes of BALB infected liver proliferated actively on day 6, promoting organ regeneration and recovery from liver damage. By comparison with C.MBT-Rvfs2, BALB mice had up to 100-fold lower production of infectious virions in the peripheral blood and liver, strongly decreased RVFV protein in liver and reduced viral replication in primary cultured hepatocytes, suggesting that the BALB Rvfs2 haplotype limits RVFV pathogenicity through decreased virus replication. Moreover, bone marrow chimera experiments showed that both hematopoietic and non-hematopoietic cells are required for the protective effect of the BALB Rvfs2 haplotype. Altogether, these results indicate that Rvfs2 controls critical events which allow survival to RVFV-induced hepatitis

Effect of blastocyst shrinkage on assisted reproductive outcomes: a retrospective cohort study describing a new morphological evaluation of blastocyst pre-vitrification and post-warming

Abstract Background The failure of frozen-thawed blastocysts to re-expand adequately within a few hours after warming has been reported to have a negative impact on assisted reproductive technology (ART) outcomes. However, the extent to which this failure truly affects ART outcomes has not yet been presented in a manner that is easily understandable to medical practitioners and patients. This study aimed to assess the effects of blastocyst shrinkage on ART outcomes and determine a more effective morphological evaluation approach for use in clinical settings. Methods This retrospective observational cohort study of frozen-thawed blastocyst transfer cycles was conducted from April 2017 to March 2022. Overall, 1,331 cycles were eligible for inclusion, of which 999 were good-quality blastocysts (GQB) and 332 were non-good-quality blastocysts (non-GQB). All frozen-thawed blastocyst transfer cycles performed during the specified study period were included in the study. Exclusion criteria were established to mitigate potential sources of bias as these cycles could impact implantations. We calculated rates and age-adjusted odds ratios of implantation, clinical pregnancy, ongoing pregnancy, and live birth of the re-expansion group, which showed sufficient expansion, and shrinkage group, which showed insufficient expansion. We also calculated the implantation, clinical pregnancy, ongoing pregnancy, and live birth rates of the re-expansion and shrinkage groups for each morphological scoring system parameter. Results A reduced ART outcome was observed with use of blastocysts with shrinkage after vitrification/warming. The age-adjusted odds ratios for implantation, clinical pregnancy, ongoing pregnancy, and live birth were lower in the shrinkage group than in the re-expansion group. Conclusions This study examined the adverse effect of blastocyst shrinkage after warming and recovery culturing on reproductive outcomes in a clinically useful manner by retrospectively examining a substantial number of frozen-thawed embryo transfer cycles. The study findings can possibly reduce concerns regarding over- or under-estimation of blastocyst implantation by allowing providers and patients to refer to the data

Additional file 1: of The balance between Foxp3 and Ror-Îłt expression in peripheral blood is altered by tocilizumab and abatacept in patients with rheumatoid arthritis

The expression levels of master regulator genes and clinical responses to ABT or TCZ. (XLSX 47 kb

Tuberculosis Exposure among Evacuees at a Shelter after Earthquake, Japan, 2011

Tuberculosis was diagnosed in a person who had stayed in a shelter after the 2011 Great East Japan Earthquake. A contact investigation showed that the prevalence of latent tuberculosis infection among other evacuees at the shelter was 20%. Our report underscores the importance of tuberculosis prevention and control after natural disasters