ARG098, a novel anti-human Fas antibody, suppresses synovial hyperplasia and prevents cartilage destruction in a severe combined immunodeficient-HuRAg mouse model

<p>Abstract</p> <p>Background</p> <p>The anti-human Fas/APO-1/CD95 (Fas) mouse/human chimeric monoclonal IgM antibody ARG098 (ARG098) targets the human Fas molecule. The cytotoxic effects of ARG098 on cells isolated from RA patients, on normal cells <it>in vitro</it>, and on RA synovial tissue and cartilage <it>in vivo </it>using implanted rheumatoid tissues in an SCID mouse model (SCID-HuRAg) were investigated to examine the potential of ARG098 as a therapy for RA.</p> <p>Methods</p> <p>ARG098 binding to each cell was analyzed by cytometry. The effects of ARG098 on several cells were assessed by a cell viability assay <it>in vitro</it>. Effects on the RA synovium, lymphocytes, and cartilage were assessed <it>in vivo </it>using the SCID-HuRAg mouse model.</p> <p>Results</p> <p>ARG098 bound to cell surface Fas molecules, and induced apoptosis in Fas-expressing RA synoviocytes and infiltrating lymphocytes in the RA synovium in a dose-dependent manner. However, ARG098 did not affect the cell viability of peripheral blood mononuclear cells of RA patients or normal chondrocytes. ARG098 also induced apoptosis in RA synoviocytes and infiltrating lymphocytes in the RA synovium <it>in vivo</it>. The destruction of cartilage due to synovial invasion was inhibited by ARG098 injection in the modified SCID-HuRAg mouse model.</p> <p>Conclusions</p> <p>ARG098 treatment suppressed RA synovial hyperplasia through the induction of apoptosis and prevented cartilage destruction <it>in vivo</it>. These results suggest that ARG098 might become a new therapy for RA.</p

Ionotropic Glutamate Receptor AMPA 1 Is Associated with Ovulation Rate

Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system by opening ion channels upon the binding of glutamate. Despite the essential roles of glutamate in the control of reproduction and anterior pituitary hormone secretion, there is a limited understanding of how glutamate receptors control ovulation. Here we reveal the function of the ionotropic glutamate receptor AMPA-1 (GRIA1) in ovulation. Based on a genome-wide association study in Bos taurus, we found that ovulation rate is influenced by a variation in the N-terminal leucine/isoleucine/valine-binding protein (LIVBP) domain of GRIA1, in which serine is replaced by asparagine. GRIA1Asn has a weaker affinity to glutamate than GRIA1Ser, both in Xenopus oocytes and in the membrane fraction of bovine brain. This single amino acid substitution leads to the decreased release of gonadotropin-releasing hormone (GnRH) in immortalized hypothalamic GT1-7 cells. Cows with GRIA1Asn have a slower luteinizing hormone (LH) surge than cows with GRIA1Ser. In addition, cows with GRIA1Asn possess fewer immature ovarian follicles before superovulation and have a lower response to hormone treatment than cows with GRIA1Ser. Our work identified that GRIA1 is a critical mediator of ovulation and that GRIA1 might be a useful target for reproductive therapy

A genome-wide association study identifying the SNPs predictive of rapid joint destruction in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a common chronic autoimmune disease leading to joint destruction. The aim of the present study was to identify the genomic factors predictive of susceptibility to joint destruction in patients with RA by performing a genome‑wide association study of genetic variants, including single nucleotide polymorphisms (SNPs). The study sample included 228 patients with a diagnosis of RA in the past 5 years. Patients were classified into rapid (total Sharp score/years of RA, ≥50) and slow (total Sharp score/years of RA, <50) joint destruction groups for analysis. The association between the genome‑wide SNP analysis and joint destruction was evaluated. The following SNPs were strongly associated with rapid radiographic joint destruction: rs2295926 (P<1x10(‑7)), belonging to the N‑acetylgalactosaminyltransferase 12 (GALNT12) gene and rs11958855 (P<1x10(‑6)), belonging to the KCNN2 gene (associated with the potassium calcium‑activated channel subfamily). The identification of genetic predictors of rapid joint destruction in RA (GALNT12 and KCNN2) may provide information regarding potential therapeutic targets, and this information may be used to assist in the management RA disease progression, thereby improving the functional outcomes for patients

A pilot study on the construction of a full text date base of documents of atomic bomb damages

There have been various efforts made to compile bibliographies and directories of documents of Atomic bomb damages in Hiroshima and Nagasaki, such as hibakusha's memoirs, testimonies, or so-called 'A-bomb literature.' There have been, however, few serious attempts to analyze these documents in full detail and make clear specifically human aspects of the damages caused by the Atomic boms. The present study is an initial attempt at such an academic effort. It aims to create a full text data base of the documents and, on the basis of such a text data base, develop ways to analyze aspects of the damages in full detail. In this initial study, we first created machine-readable texts mainly of early documents. The machine-readable texts includes The City of Corpses (Shikabane no Machi) by Yoko Ota, Atomic Bomb Peoms (Genbaku Shishu) by Sankichi Toge, Expen'ences of Atomic Bomb (Genbaku Taikenki), Voice from Heaven (Ten yori no Koe). Moreover, several others such as Hiroshima Diary (Hiroshima Nikki) by Michihiko Hachiya, Collection of Tanka by Shinoe Shoda, Nagasaki - Records of Twenty Persons' A-bomb Eeeriences (Nagasaki - 22 nin no Genbaku Taiken Kiroku) and so on are now in preparation. Secondly, to use these texts on a microcomputer, a simple concording and word counting program was developed. It easily and speedily retrieves parts of the text where a given word or string occurs and outputs the results in KWIC or other formats. It also counts the occurrences of given words or strings and shows their distributions among parts or subtexts