骨格筋におけるAktの役割の解明

学位の種別:課程博士University of Tokyo(東京大学

Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms

SummaryType 2 diabetes is characterized by insulin resistance and pancreatic β cell dysfunction, the latter possibly caused by a defect in insulin signaling in β cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in β cells and the pik3r2 gene systemically (βDKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. β cells of βDKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of βDKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in β cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes

Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma

Ameloblastin (AMBN), the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Previously, we found that AMBN promoted osteogenic differentiation via the interaction between CD63 and integrin β1, leading to the inactivation of Src; however, how AMBN affects the malignant behavior of osteosarcoma is still unclear. Osteosarcoma affects the bone and is associated with poor prognosis because of the high rate of pulmonary metastases and drug resistance. Here we demonstrated that stable overexpression of AMBN induced apoptosis and suppressed colony formation and cell migration via the inactivation of Src-Stat3 pathway in human osteosarcoma cells. Moreover, AMBN induced chemosensitivity to doxorubicin. Thus, AMBN induced a tumor suppressive phenotype and chemosensitivity to doxorubicin via the AMBN-Src-Stat3 axis in osteosarcoma. Indeed, immunohistochemical expression of AMBN was significantly correlated with better outcome of osteosarcoma patients. Our findings suggest that AMBN can be a new prognostic marker and therapeutic target for osteosarcoma combined with conventional doxorubicin treatment

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

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Nonalcoholic fatty liver disease with elevated alanine aminotransferase levels is negatively associated with bone mineral density: Cross-sectional study in U.S. adults

<div><p>Background</p><p>Nonalcoholic fatty liver disease (NAFLD) has been reported to have a negative effect on bone mineral density (BMD) in Asian populations. Whether such an association exists in Western populations is less clear.</p><p>Methods</p><p>This cross-sectional analysis of data from NHANES III, a United States national health survey conducted from 1988 to 1994, included 6089 participants aged 40–75 years, selected after excluding people with hepatitis virus serology, elevated alcohol consumption, decreased renal function, or steroid use, and pregnant females. The main outcome, BMD at the femoral neck, was measured using dual-energy X-ray absorptiometry. The primary exposure, NAFLD, was defined as moderate or severe hepatic steatosis diagnosed using abdominal ultrasonography.</p><p>Result</p><p>After controlling for gender and menopausal status, race/ethnicity, age and body mass index, NAFLD was not significantly associated with BMD (beta coefficient: −0.006, 95%CI: −0.016, 0.003). A secondary analysis categorized participants with NAFLD according to their serum alanine aminotransferase (ALT) levels into high and normal ALT NAFLD groups, and compared these with the non-NAFLD group. NAFLD with higher levels of ALT was associated with lower levels of BMD (beta coefficient: −0.023, 95% CI: −0.044, −0.002).</p><p>Conclusion</p><p>This study showed a relationship between NAFLD with high ALT and lower BMD in the general U.S. population.</p></div

HOMA-IR levels for the different NAFLD groups for different BMI ranges.

<p>The population was stratified by BMI into the ranges 15–20, 20–25, 25–30, 30–35, and 35–40 kg/m2. No one in the HA NAFLD group had a BMI in the range 15–20 kg/m2. Mean HOMA-IR values were obtained for each NAFLD group for the different BMI ranges. Abbreviations: HOMA-IR, homeostatic model assessment of insulin resistance; HA NAFLD, NAFLD with high alanine aminotransferase levels; NA NAFLD, NAFLD with normal alanine aminotransferase levels.</p

Participant selection.

<p>In the final step, 267 males and 266 females were excluded because of the lack of available ultrasonography results. 198 males and 276 females were excluded because bone mineral density results were not available.</p