Optineurin with amyotrophic lateral sclerosis-related mutations abrogates inhibition of interferon regulatory factor-3 activation

Optineurin has been shown to be involved in primary open-angle glaucoma. We recently found that optineurin is involved in familial amyotrophic lateral sclerosis (ALS). On the other hand, optineurin has been shown to inhibit transcription factors related to innate immunity such as NF-kappa B and interferon regulatory factor-3 (IRF3). In the present study, the effect of ALS-associated optineurin mutations on IRF3 activation was investigated. Optineurin inhibited IRF3 activation induced by melanoma differentiation-associated gene 5 or Toll-IL-1 receptor domain-containing adaptor-inducing interferon-beta. The inhibition was abrogated by mutations related to ALS but not by a mutation related to glaucoma. Reporter assay indicated that the JAK-STAT signaling pathway was not affected by optineurin. These results show that ALS-related optineurin is involved in the IRF3 activation pathway. Pathogenesis of ALS may be associated with some kind of innate immunity, especially that against virus infection, through IRF3 activation

Factors responsible for elevated plasma B-type natriuretic peptide levels in severe aortic stenosis: Comparison between elderly and younger patients

AbstractBackgroundElevated plasma B-type natriuretic peptide (BNP) is a predictor of outcome and helpful for risk stratification in aortic stenosis (AS). However, left ventricular (LV) diastolic dysfunction progresses with aging and may also influence plasma BNP levels in elderly patients. We hypothesized that plasma BNP levels may be influenced by age in severe AS, and that factors that affect the elevation of plasma BNP levels may be different between elderly and younger patients with AS.MethodsWe performed echocardiography in 341 patients with severe AS [aortic valve area (AVA)<1.0cm2] and classified them into two groups by age (elderly ≥75 years old, n=201; younger patients <75 years old, n=140). We used multivariate linear regression analysis to assess the factors that determine plasma BNP levels in both groups.ResultsAge was found to be one of the independent determinants of plasma BNP levels in all patients (β=0.135, p=0.005). Although AVA was similar in the two groups, plasma BNP levels and E/e′ were significantly higher in elderly than younger patients [133.0 (IQR, 73.3–329.7)pg/dl vs 92.8 (IQR, 40.6–171.8)pg/dl, p<0.01; 20±8 vs 16±6, p<0.01, respectively). In multivariate stepwise linear regression analysis, AVA index, LV ejection fraction, mass index, E/e′, estimated systolic pulmonary artery pressure (eSPAS), and the presence of atrial fibrillation were independent determinants of plasma BNP levels in younger patients. In contrast, the independent determinants of plasma BNP levels in elderly patients were LV ejection fraction, mass index, E/e′, eSPAS, the presence of atrial fibrillation, age, and hemoglobin levels, but not AVA index.ConclusionsThere may be differences in the factors that influence plasma BNP levels between elderly and younger patients with severe AS. In elderly patients, plasma BNP levels may be influenced more by these factors than AS severity compared with younger patients

Applicability of Permanent Mold Casting for Lead Free Bronze with Sulfide Dispersion (Post-Print Version)

The leaded bronze, the leaded brass, the lead free bronze including bismuth and the lead free bronze with sulfide dispersion were cast into the permanent mold for thesolidification cracking test. The applicability of the permanent mold casting process for bronzes was evaluated with comparison of the range of the solidificationtemperature. The lead free bronze with sulfide dispersion was more unbreakable than the other copper alloys. There were differences of the dendrite form near by the fracture and the distribution of the residual melt segregated at a part of theend of the solidification. The lead free bronze with sulfide dispersion may have a solidification form being unlikely to crack. It dispersion is possible to apply the permanent mold castings process rather than the other copper alloys, and the applicability is almost same as brass castings.70th World Foundry Congress 2012 (WFC 2012) held 25-27 April 2012, Monterrey, Mexico

Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation.

Interferon (IFN)-&gamma; is mainly secreted by CD4+ T helper 1 (Th1), natural killer (NK) and NKT cells after skin injury. Although IFN-&gamma; is well known regarding its inhibitory effects on collagen synthesis by fibroblasts in vitro, information is limited regarding its role in wound healing in vivo. In the present study, we analyzed how the defect of IFN-&gamma; affects wound healing. Full-thickness wounds were created on the backs of wild type (WT) C57BL/6 and IFN-&gamma;-deficient (KO) mice. We analyzed the percent wound closure, wound breaking strength, accumulation of leukocytes, and expression levels of COL1A1, COL3A1, and matrix metalloproteinases (MMPs). IFN-&gamma;KO mice exhibited significant attenuation in wound closure on Day 10 and wound breaking strength on Day 14 after wound creation, characteristics that are associated with prolonged neutrophil accumulation. Expression levels of COL1A1 and COL3A1 mRNA were lower in IFN-&gamma;KO than in WT mice, whereas expression levels of MMP-2 (gelatinase) mRNA were significantly greater in IFN-&gamma;KO than in WT mice. Moreover, under neutropenic conditions created with anti-Gr-1 monoclonal antibodies, wound closure in IFN-&gamma;KO mice was recovered through low MMP-2 expression levels. These results suggest that IFN-&gamma; may be involved in the proliferation and maturation stages of wound healing through the regulation of neutrophilic inflammatory responses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead