ヒトキンガタ ホスホグリセレートムターゼ ノ コッカクキン シンキン トクイテキ ハツゲン ハ MEF-2 site ニヨッテ チョウセツ サレテイル

YUJI, NAKATSUJI; KYOKO, HIDAKA; SEIICHI, TSUJINO; YOICHI, YAMAMOTO; TSUNEHIRO, MUKAI; TAKEHIKO, YANAGlHARA; TADAMITSU, KISHIMOTO; SABURO, SAKODA. A single MEF-2 site Is a Major Positive Regulatory Element Required for Transcription of the Muscle-Specific Subunit of the Human Phosphoglycerate Mutase Gene in Skeletal and Cardiac Muscle Cells. Molecular and Cellular Biology. 1992. 12(10). p.4384-4390

Goblet Cell Hyperplasia and Muscular Layer Thickening in the Small Intestine of a Cynomolgus Monkey

We report here the interesting case of a 5-year-old male cynomolgus monkey with goblet cell hyperplasia and thickening of the muscular layer throughout the small intestine without exhibiting any clinical symptoms. Necropsy examination showed diffuse thickening of the intestinal wall from the jejunum to the ileum, with an appearance likened to a rubber tube. Histopathologically, marked thickening was observed in both the mucosal and muscular layers in the jejunum and ileum, and slight thickening was observed in the duodenum. Goblet cell hyperplasia with extension of the circular folds and villi was prominently observed. The mucosal surface was covered with a thick mucus layer containing desquamated mucosal epithelial cells, and both the inner and outer muscular layers were markedly thickened due to smooth muscle hypertrophy. Neither macroscopic nor histopathological examination identified any causative factors, such as infection, enteritis and intestinal stenosis, or obstruction that may have caused development of this lesion. Given these observations, this case may simply be considered of spontaneous goblet cell hyperplasia and muscular layer thickening in the small intestine of a cynomolgus monkey

The Lactic Acid Bacterium Pediococcus acidilactici Suppresses Autoimmune Encephalomyelitis by Inducing IL-10-Producing Regulatory T Cells

BACKGROUND: Certain intestinal microflora are thought to regulate the systemic immune response. Lactic acid bacteria are one of the most studied bacteria in terms of their beneficial effects on health and autoimmune diseases; one of which is Multiple sclerosis (MS) which affects the central nervous system. We investigated whether the lactic acid bacterium Pediococcus acidilactici, which comprises human commensal bacteria, has beneficial effects on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. METHODOLOGY/PRINCIPAL FINDINGS: P. acidilactici R037 was orally administered to EAE mice to investigate the effects of R037. R037 treatment suppressed clinical EAE severity as prophylaxis and therapy. The antigen-specific production of inflammatory cytokines was inhibited in R037-treated mice. A significant increase in the number of CD4(+) Interleukin (IL)-10-producing cells was observed in the mesenteric lymph nodes (MLNs) and spleens isolated from R037-treated naive mice, while no increase was observed in the number of these cells in the lamina propria. Because only a slight increase in the CD4(+)Foxp3(+) cells was observed in MLNs, R037 may primarily induce Foxp3(-) IL10-producing T regulatory type 1 (Tr1) cells in MLNs, which contribute to the beneficial effect of R037 on EAE. CONCLUSIONS/SIGNIFICANCE: An orally administered single strain of P. acidilactici R037 ameliorates EAE by inducing IL10-producing Tr1 cells. Our findings indicate the therapeutic potential of the oral administration of R037 for treating multiple sclerosis

Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis

BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1(G93A) mice). FINDINGS: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1(G93A) mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1β, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1(G93A) mice. CONCLUSIONS: JAK2 inhibitor was not effective against ALS symptoms in mSOD1(G93A) mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-014-0179-2) contains supplementary material, which is available to authorized users

Disease-Association Analysis of an Inflammation-Related Feedback Loop

SummaryThe IL-6-triggered positive feedback loop for NFκB signaling (or the IL-6 amplifier/Inflammation amplifier) was originally discovered as a synergistic-activation signal that follows IL-17/IL-6 stimulation in nonimmune cells. Subsequent results from animal models have shown that the amplifier is activated by stimulation of NFκB and STAT3 and induces chemokines and inflammation via an NFκB loop. However, its role in human diseases is unclear. Here, we combined two genome-wide mouse screens with SNP-based disease association studies, revealing 1,700 genes related to the IL-6 amplifier, 202 of which showed 492 indications of association with ailments beyond autoimmune diseases. We followed up on ErbB1 from our list. Blocking ErbB1 signaling suppressed the IL-6 amplifier, whereas the expression of epiregulin, an ErbB1 ligand, was higher in patients with inflammatory diseases. These results indicate that the IL-6 amplifier is indeed associated with human diseases and disorders and that the identified genes may make for potential therapeutic targets

Effects of Transcranial Direct Current Stimulation (tDCS) Over the Frontal Polar Area on Motor and Executive Functions in Parkinson’s Disease; A Pilot Study

Parkinson’s disease (PD) is a neurodegenerative disorder with motor and non-motor symptoms due to degeneration of dopaminergic neurons. The current pharmacological treatments induce complications associated with long-term use. However, current stimulation techniques for PD treatment, such as deep brain stimulation (DBS), are too invasive. In this context, non-invasive brain stimulation including transcranial direct current stimulation (tDCS) may be a safe and effective alternative treatment for PD. We previously reported that anodal tDCS over the frontal polar area (FPA) improved motor functions in heathy subjects. Therefore, in the present study, effects of tDCS over the FPA on motor and cognitive functions of PD patients were analyzed. Nine PD patients (3 men and 6 women) participated in this cross over study with three tDCS protocols; anodal, cathodal or sham tDCS over the FPA. Each tDCS protocol was applied for 1 week (5 times/week). Before and after each protocol, motor and cognitive functions of the patients were assessed using Unified PD Rating Scale [UPDRS (part III: motor examination)], Fugl Meyer Assessment set (FMA), Simple Test for Evaluating hand Function (STEF) and Trail Making Test A (TMT-A). The results indicated that anodal stimulation significantly decreased scores of motor disability in UPDRS-III compared with sham and cathodal stimulation, and significantly increased scores of motor functions in FMA compared with sham stimulation. Furthermore, anodal stimulation significantly decreased time to complete a motor task requiring high dexterity in STEF compared with those requiring low and medium levels of dexterity. In addition, anodal stimulation significantly decreased time to complete the TMT-A task, which requires executive functions, compared with sham stimulation. To the best of our knowledge, this is the first clinical research reporting that tDCS over the FPA successfully improved the motor and non-motor functions in PD patients. These findings suggest that tDCS over the FPA might be a useful alternative for the treatment of PD patients

Efficient integration of transgenes into a defined locus in human embryonic stem cells

Random integration is one of the more straightforward methods to introduce a transgene into human embryonic stem (ES) cells. However, random integration may result in transgene silencing and altered cell phenotype due to insertional mutagenesis in undefined gene regions. Moreover, reliability of data may be compromised by differences in transgene integration sites when comparing multiple transgenic cell lines. To address these issues, we developed a genetic manipulation strategy based on homologous recombination and Cre recombinase-mediated site-specific integration. First, we performed gene targeting of the hypoxanthine phosphoribosyltransferase 1 (HPRT) locus of the human ES cell line KhES-1. Next, a gene-replacement system was created so that a circular vector specifically integrates into the targeted HPRT locus via Cre recombinase activity. We demonstrate the application of this strategy through the creation of a tetracycline-inducible reporter system at the HPRT locus. We show that reporter gene expression was responsive to doxycycline and that the resulting transgenic human ES cells retain their self-renewal capacity and pluripotency

NBRP databases: databases of biological resources in Japan

The National BioResource Project (NBRP) is a Japanese project that aims to establish a system for collecting, preserving and providing bioresources for use as experimental materials for life science research. It is promoted by 27 core resource facilities, each concerned with a particular group of organisms, and by one information center. The NBRP database is a product of this project. Thirty databases and an integrated database-retrieval system (BioResource World: BRW) have been created and made available through the NBRP home page (http://www.nbrp.jp). The 30 independent databases have individual features which directly reflect the data maintained by each resource facility. The BRW is designed for users who need to search across several resources without moving from one database to another. BRW provides access to a collection of 4.5-million records on bioresources including wild species, inbred lines, mutants, genetically engineered lines, DNA clones and so on. BRW supports summary browsing, keyword searching, and searching by DNA sequences or gene ontology. The results of searches provide links to online requests for distribution of research materials. A circulation system allows users to submit details of papers published on research conducted using NBRP resources

Human Pluripotent Stem Cell-Derived Cardiac Tissue-like Constructs for Repairing the Infarcted Myocardium.

High-purity cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are promising for drug development and myocardial regeneration. However, most hiPSC-derived CMs morphologically and functionally resemble immature rather than adult CMs, which could hamper their application. Here, we obtained high-quality cardiac tissue-like constructs (CTLCs) by cultivating hiPSC-CMs on low-thickness aligned nanofibers made of biodegradable poly(D,L-lactic-co-glycolic acid) polymer. We show that multilayered and elongated CMs could be organized at high density along aligned nanofibers in a simple one-step seeding process, resulting in upregulated cardiac biomarkers and enhanced cardiac functions. When used for drug assessment, CTLCs were much more robust than the 2D conventional control. We also demonstrated the potential of CTLCs for modeling engraftments in vitro and treating myocardial infarction in vivo. Thus, we established a handy framework for cardiac tissue engineering, which holds high potential for pharmaceutical and clinical applications

Where Do AQP4 Antibodies Fit in the Pathogenesis of NMO?

Recent advances in the field of neuromyelitis optica (NMO) research provided convincing evidence that anti-AQP4 antibody (AQP4-Ab) not only serves as a highly specific disease marker, but also plays an essential role in the pathogenesis of the disease. Although it is now widely recognized that AQP4-Ab induces astrocytic necrosis in a complement-dependent manner, additional triggers are also suspected as a prerequisite for the development of the disease. Unraveling these unresolved aspects of the disease will provide substantial insight into still controversial issues in the pathogenesis of NMO