A STRIPAK component Strip regulates neuronal morphogenesis by affecting microtubule stability

During neural development, regulation of microtubule stability is essential for proper morphogenesis of neurons. Recently, the striatin-interacting phosphatase and kinase (STRIPAK) complex was revealed to be involved in diverse cellular processes. However, there is little evidence that STRIPAK components regulate microtubule dynamics, especially in vivo. Here, we show that one of the core STRIPAK components, Strip, is required for microtubule organization during neuronal morphogenesis. Knockdown of Strip causes a decrease in the level of acetylated α-tubulin in Drosophila S2 cells, suggesting that Strip influences the stability of microtubules. We also found that Strip physically and genetically interacts with tubulin folding cofactor D (TBCD), an essential regulator of α- and β-tubulin heterodimers. Furthermore, we demonstrate the genetic interaction between strip and Down syndrome cell adhesion molecule (Dscam), a cell surface molecule that is known to work with TBCD. Thus, we propose that Strip regulates neuronal morphogenesis by affecting microtubule stability.This work was supported by grants from the Japanese Ministry of Education, Science, Sports, Culture and Technology (MEXT), the Japan Society for the Promotion of Science and the Japan Science and Technology Agency (to C.S., M.O., M.M. and T.C.)

Status of 48Ca double beta decay search in CANDLES

We study a strategy to reduce veto-time in the search for neutrino-less double-beta decay (0υββ) with CANDLES-III system. We develop a new likelihood analysis and apply it to our new Run010 data. We show that we can increase the un-vetoed live-time by 11.8%. Thanks to this improvements, We expect to increase a limit on the life-time of 0υββ by a factor of three by analyzing both Run009 and Run010 data

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed

The Strip-Hippo Pathway Regulates Synaptic Terminal Formation by Modulating Actin Organization at the Drosophila Neuromuscular Synapses

SummarySynapse formation requires the precise coordination of axon elongation, cytoskeletal stability, and diverse modes of cell signaling. The underlying mechanisms of this interplay, however, remain unclear. Here, we demonstrate that Strip, a component of the striatin-interacting phosphatase and kinase (STRIPAK) complex that regulates these processes, is required to ensure the proper development of synaptic boutons at the Drosophila neuromuscular junction. In doing so, Strip negatively regulates the activity of the Hippo (Hpo) pathway, an evolutionarily conserved regulator of organ size whose role in synapse formation is currently unappreciated. Strip functions genetically with Enabled, an actin assembly/elongation factor and the presumptive downstream target of Hpo signaling, to modulate local actin organization at synaptic termini. This regulation occurs independently of the transcriptional co-activator Yorkie, the canonical downstream target of the Hpo pathway. Our study identifies a previously unanticipated role of the Strip-Hippo pathway in synaptic development, linking cell signaling to actin organization

Association of serum levels of fibrosis-related biomarkers with disease activity in patients with IgG4-related disease

Background: The aim of this study was to identify fibrosis-related serological surrogate outcome measures in patients with immunoglobulin G4-related disease (IgG4-RD). Methods: This was a clinical observational study of 72 patients with untreated IgG4-RD from four institutions in Japan.The serum concentrations of growth differentiation factor 15 (GDF-15), CCL2, hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assays. The enhanced liver fibrosis (ELF) score was calculated from the TIMP-1, PIIINP, and HA values. We evaluated associations between the values of these biomarkers and laboratory data, the IgG4-RD responder index (IgG4-RD RI) score, and organ involvements. Results: Compared with the 44 healthy controls, the patients with IgG4-RD showed significantly elevated serum concentrations of GDF-15, MCP-1, HA, PIIINP, and TIMP-1 and ELF scores. The patients\u27 serum concentrations of GDF-15, CCL2, HA, and TIMP-1 (but not PIIINP) were positively correlated with each other. Among them, serum GDF-15 most efficiently distinguished patients with IgG4-RD from healthy controls. Serum GDF-15 was not associated with the IgG4-RD RI score or the number of organ involvements but was independently associated with the presence of retroperitoneal fibrosis and with parotid gland involvement. Conclusions: We observed increased serological surrogate outcome measures of fibrosis in IgG4-RD. GDF-15 may precisely reflect the fibrotic degree in patients with IgG4-RD

Gene expression in PBMCs from 20 patients with IgG4-RD, before and after steroid treatment.

<p>(A) CLC; Charcot—Leyden crystal protein. (B) IL8RA; interleukin 8 receptor alpha. (C) IL8RB; interleukin 8 receptor beta. (D) MS4A3; membrane-spanning 4-domain subfamily A member 3. (E) DEFA3; defensin alpha 3. (F) DEFA4; defensin alpha 4. Levels of CLC, IL8RA and IL8RB mRNA were not altered in IgG4-RD patients by steroid therapy (A-C), whereas those of MS4A3, DEFA3 and DEFA4 were significantly increased following steroid therapy (D-F, p<0.01).</p

Decreased Expression of Innate Immunity-Related Genes in Peripheral Blood Mononuclear Cells from Patients with IgG4-Related Disease

<div><p>Background</p><p>IgG4-related disease (IgG4-RD) is a new clinical entity of unknown etiology characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. Although aberrancies in acquired immune system functions, including increases in Th2 and Treg cytokines observed in patients with IgG4-RD, its true etiology remains unclear. To investigate the pathogenesis of IgG4-RD, this study compared the expression of genes related to innate immunity in patients with IgG4-RD and healthy controls.</p><p>Materials and Methods</p><p>Peripheral blood mononuclear cells (PBMCs) were obtained from patients with IgG4-RD before and after steroid therapy and from healthy controls. Total RNA was extracted and DNA microarray analysis was performed in two IgG4-RD patients to screen for genes showing changes in expression. Candidate genes were validated by real-time RT-PCR in 27 patients with IgG4-RD and 13 healthy controls.</p><p>Results</p><p>DNA microarray analysis identified 21 genes that showed a greater than 3-fold difference in expression between IgG4-RD patients and healthy controls and 30 genes that showed a greater than 3-fold change in IgG4-RD patients following steroid therapy. Candidate genes related to innate immunity, including those encoding Charcot–Leyden crystal protein (CLC), membrane-spanning 4-domain subfamily A member 3 (MS4A3), defensin alpha (DEFA) 3 and 4, and interleukin-8 receptors (IL8R), were validated by real-time RT-PCR. Expression of all genes was significantly lower in IgG4-RD patients than in healthy controls. Steroid therapy significantly increased the expression of DEFA3, DEFA4 and MS4A3, but had no effect on the expression of CLC, IL8RA and IL8RB.</p><p>Conclusions</p><p>The expression of genes related to allergy or innate immunity, including CLC, MS4A3, DEFA3, DEFA4, IL8RA and IL8RB, was lower in PBMCs from patients with IgG4-RD than from healthy controls. Although there is the limitation in the number of patients applied in DNA microarray, impaired expression of genes related to innate immunity may be involved in the pathogenesis of IgG4-RD as well as in abnormalities of acquired immunity.</p></div

Comparison of gene expression between patients with IgG4-RD and healthy controls.

<p>Relative expression of genes in PBMCs from 27 patients with IgG4-RD and 20 healthy controls. (A) CLC; Charcot—Leyden crystal protein. (B) IL8RA; interleukin 8 receptor alpha. (C) IL8RB; interleukin 8 receptor beta. (D) MS4A3; membrane-spanning 4-domain subfamily A member 3. (E) DEFA3; defensin alpha 3. (F) DEFA4; defensin alpha 4. Expression of all genes was significantly lower in PBMCs from untreated IgG4-RD patients than from healthy controls (p< 0.01).</p