Edited by Noboru MizushimaKeywords: Syntabulin Microtubule cAMP Epac2 Insulin secretion INS-1E cell a b s t r a c t Syntabulin is a microtubule-associated protein that mediates anterograde transport of vesicles to neuronal processes. Here, we found that syntabulin was expressed in mouse pancreas and insulin-secreting b-cells, and that it partially co-localized with microtubule and insulin-containing granules. The association of syntabulin with these organelles increased upon glucose stimulation. Knock-down of syntabulin by shRNA reduced both basal and glucose-stimulated insulin secretion, and diminished cAMP-Epac2 and cAMP-PKA potentiated insulin secretion. Additionally, syntabulin was preferentially phosphorylated by the Epac2 agonist 8-pCPT-2 0 -O-Me-cAMP, suggesting that syntabulin could be a novel effector of Epac2 and play a critical role in cAMP-enhanced insulin secretion.

The use of enzymes in nonaqueous solvent has been one of the most exciting facets of enzymology in recent times; however, the mechanism of how organic solvent and essential water influence on structure and function of enzyme has been not satisfactorily explained in experiments, which limit its further application. Herein, we used molecular dynamics (MD) simulation to study γ-chymotrypsin in two types of media (viz., acetonitrile media with inclusion of 151 crystal water molecules and aqueous solution). On the basis of the MD result, the truncated active site modes containing two specific solvent molecules are furthered studied at the B3LYP/6-31+G(d,p) level of theory within the framework of PCM model. The results show that the acetontrile solvent gives rise to an extent deviation of enzyme structure from the native one, a drop in the flexibility and the total SASA of enzyme. The QM study further reveals that the structure variation of the active pocket caused by acetonitrile would lead to a weakened strength in the catalytic H-bond network, a drop in the pK(a) value of His57, and an increase in the proton transfer barriers from the Ser195 to the His57 residue, which may contribute to the drop in the enzymatic activity in acetontrile media. In addition, the crystal waters play an importance role in retaining the catalytic H-bond network and weakening the acetonitrile-induced variations above, which may be associated with the fact that the enzyme could retain catalytic activity in microhydration acetonitrile media.

Background The aim of this study was to investigate the effect of Iguratimod (T-614) on rat knee osteoarthritis (KOA) and further to explore its underlying mechanism. Methods In this study, papain-induced KOA model was constructed. Hematoxylin and eosin (H&E) staining was conducted to observe the pathological changes of cartilage tissue and Mankin scoring principle was used for quantitative scoring. Transmission electron microscopy (TEM) was applied to observe the ultrastructure of cartilage tissue. ELISA was used to measure the levels of matrix metalloproteinase 13 (MMP-13) and inflammatory factors (interleukin (IL)-6 and tumor necrosis factor a (TNF-a)) in serum. RT-qPCR and immunohistochemistry were conducted to detect mRNA expression and protein expression of key genes in Wnt/β-catenin pathway. Results H&E, Mankin scoring, and TEM data confirmed that compared with model group, T-614 significantly improved the degeneration of articular cartilage. Besides, we observed that low, middle, and high doses of T-614 could decrease the levels of MMP13, TNF-α, and IL-6 in serum to different degrees. Mechanically, T-614 downregulated the mRNA and protein expression of β-catenin and MMP13 in cartilage tissue via a dose-dependent manner, and on the contrary upregulated the mRNA and protein expression of glucogen synthase kinase-3 beta (GSK-3β). Conclusion Our results suggested that T-614 can reduce the level of its downstream target gene MMP-13 and downregulate the expression of inflammatory cytokines TNF-α and IL-6 by regulating the Wnt/β-catenin signaling pathway, thereby inhibiting joint inflammation and controlling KOA degeneration of articular cartilage.

Many in-service teachers take a passive position regarding multicultural issues such as race, class, ethnicity, socio-economic, religion, gender, and sexual orientation. This passive position impacts classroom dynamics and has social justice consequences. The present qualitative study focuses on 12 in-service teachers' perspectives on multicultural issues. It describes the transformation of their perspectives and practices as they take a semester-long course on diversity. Data sources include the participating teachers' written reflections on assigned readings, classroom discussions and activities, paper presentations, instructor's field notes, and the teachers' final implementation papers. The findings of the study suggest that classroom activities and discussions provided teachers with opportunities to critically reflect on who they are and make changes in their perspectives and practices. Also, the study discusses the vital role of classroom social norms established by the instructor and the participating teachers as a form of praxis. This step is crucial for creating caring communities relative to cross-cultural interaction and individual transformation, which in turn has social justice implications in terms of rethinking teaching and learning as well as school reform.

Based on the current processing technology of large-scale spherical roller bearing rings, the dimensional expansion and contraction and the geometric variation of large-scale spherical roller bearing rings before and after heat treatment have been studied through several groups of processing experiment and data analysis. Optimization design of grinding allowance of large-scale spherical roller bearing rings have been implemented by using calculation formula of grinding allowance in bearing industry, which improved the production efficiency of the large spherical roller bearing rings and saved the manufacturing cost.