MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response.

The MEN1 gene, a tumor suppressor gene that encodes the protein menin, is mutated at high frequencies in neuroendocrine (NE) tumors; however, the biological importance of this gene in NE-type lung cancer in vivo remains unclear. Here, we established an ATII-specific KrasG12D/+/Men1-/- driven genetically engineered mouse model and show that deficiency of menin results in the accumulation of DNA damage and antagonizes oncogenic Kras-induced senescence and the epithelial-to-mesenchymal transition during lung tumorigenesis. The loss of menin expression in certain human primary lung cancers correlates with elevated NE profiles and reduced overall survival.

Abnormal expression of menin predicts the pathogenesis and poor prognosis of adult gliomas.

Several brain tumors is closely related to the disorder of chromatin histone modification, whereas the epigenetic mechanisms of the incidence of highly malignant adult glioma is not yet deeply studied. Deletion or mutation of the MEN1 gene, which encodes the epigenetic regulator menin, specifically induces poorly differentiated neuroendocrine tumors; however, the biological and clinical importance of MEN1 in the nervous system remains poorly understood. Menin expression was robustly activated in 44.4% of adult gliomas. Abnormally high expression of menin was closely related to a shorter median survival time of 20 months, a larger tumor volume and a higher percentage of Ki67 staining. Interestingly, menin expression was also activated in the cytoplasm of tumor cells (38.8%) and was also closely related to the poor prognosis of patients with glioma. Importantly, in a screening of 96 types of small-molecule targeted histone modification regulators, menin inhibitors were found to significantly block the proliferation of adult glioma cells. Our findings confirm that menin is a potential biomarker of poor prognosis in adult gliomas, independent of the WHO grade. Targeting menin may effectively inhibit certain gliomas, and this information provides novel insight into therapeutic strategies for glioma.

A study on effect of curcumin on anticerebral aneurysm in the male albino rats.

INTRODUCTION: This study investigated the curcumin effect on the cerebral aneurysm. Apoptosis is known to play a fundamental role in the pathogenesis of a cerebral aneurysm. Therefore, we investigated the effect of curcumin on apoptosis of smooth muscle cells of a cerebral aneurysm-induced male albino rats. METHODS: In this study, the cerebral aneurysm has been induced in the male albino rats by the CaCl2 administration. After cerebral aneurysm induction, smooth muscle cells were isolated. Cells were treated with curcumin (25 & 50 mg/kg bwt) for 48 hr. RESULTS: Curcumin reduced altered mitochondrial morphology significantly, evidenced through fluorescence and confocal study. Curcumin treatment reduced the expression of p53, caspase-3, and bax/bxl-2 ratio significantly. Curcumin treatment also reversed the cellular architecture of smooth muscle cell wall significantly. Fluorescence and the confocal study confirmed the reduction in apoptosis in a cerebral aneurysm-induced smooth muscle cells of male albino rats. CONCLUSION: Taking all these data together, it may suggest that the curcumin could significantly reduce the CaCl2-induced cerebral aneurysm through the inhibition of cell apoptosis in the cells.

Reprogramming of histone methylation controls the differentiation of monocytes into macrophages.

Subset heterogeneity of the mononuclear phagocyte system (MPS) is controlled by defined transcriptional networks and programs; however, the dynamic establishment of programs that control broad, orchestrated expression of transcription factors (TFs) during the progression of monocyte-into-phagocyte (MP) differentiation remains largely unexplored. By using chromatin immunoprecipitation assays, we show the extensive trimethylation of histone H3 lysine 4 (H3K4me3) as well as histone H3 lysine 27 (H3K27me3) occupancy with broad footprints at the promoters of MP differentiation-related TFs, such as HOXA and FOXO genes, KLF4, IRF8 and others. The rapid repression of HOXA genes was closely associated with the MP differentiation program. H3K4me3 participates in regulating HOXA genes at mild and terminal differentiation periods, while H3K27me3 maintains low-level expression of HOXA genes at phagocytic maintenance periods. Furthermore, the reprogramming of H3K27me3 plays a major role in the up-regulation of KLF4 and FOXO genes during MP differentiation. Importantly, the pharmacological inhibition of H3K4me3 and/or H3K27me3 strikingly promotes the differentiation programs of THP-1 and K562 cells. Together, these findings elucidate mechanisms crucial to the dynamic establishment of epigenetic memory, which is central to the maintenance of the MP differentiation blockade.

Dynamics of bridge helix bending in RNA polymerase II.

One of critical issues for RNA polymerase is how the enzyme translocates along the DNA substrate during transcription elongation cycle. Comparisons of the structure of RNA polymerase II (Pol II) with that of bacterial enzyme have suggested that the transition of the bridge helix (BH) from straight to flipped-out conformations facilitates the translocation of upstream DNA-RNA hybrid. However, the flipped-out conformation of BH in Pol II has not been observed up to now and the detailed mechanism of how the BH facilitating upstream hybrid translocation still remains obscure. Here we use all-atom molecular dynamics simulations to study the transition dynamics of BH in Pol II. Two different flipped-out conformations (termed as F1 and F2) are derived from our simulation trajectories, both of which could contribute to upstream hybrid translocation. In particular, the structure of BH in F2 conformation shows nearly identical to that observed in free bacterial enzyme, showing the existence of the flipped-out conformation in Pol II. Analysis of hydrogen bonds and salt bridge formed intra BH in different conformations indicates that the flipped-out conformations are more unstable than the straight conformation. Moreover, a detailed understanding of how the transition of BH conformations facilitating upstream hybrid translocation is given. Proteins 2017; 85:614-629. © 2016 Wiley Periodicals, Inc.

[Research of TCM synthetic rehabilitation on the recovery of wrist joint after distal radius fractures].

OBJECTIVE: To evaluate efficacy and advantages of the Traditional Chinese Medicine (TCM) synthetic rehabilitation therapy in the treatment of wrist dysfunction after distal radius fractures. METHODS: From May 2014 to October 2015, 72 patients with distal radius fracture meeting standards were treated using central randomization system for clinical research. All the patients were divided into two groups: 36 patients in test group and 36 in control group. Sixty-nine cases were finished treatment and followed up in the end. The test group fell off 1 case, and the control group fell off 2 cases. The test group was given TCM synthetic rehabilitation (manipulative therapy, joint mobilization, soaking-washing with Chinese medicinal herbs, functional exercise), and the control group was given functional exercise as well as soaking-washing with Chinese medicinal herbs, 3 weeks for both. Five evaluation standards were used in this research, which were grip strength, patient-rated wrist evaluation (PRWE), Gartland and Werley wrist score, self-rating anxiety scale(SAS) and the overall curative effect evaluation. Before treatment(baseline), after 3 weeks of treatment and 3 months after fracture were the three points in time when collected the data. RESULTS: After 3 weeks of treatment and 3 months after fracture, the test group had a significantly better results than those of control group in the PRWE, G-W wrist score and the overall curative effect evaluation(P<0.05). In terms of grip strength recovery, after 3 weeks of treatment, the intergroup difference between the test group and the control group were statistically significant relative to the baseline regarding grip strength of ipsilateral wrist by group t-test(P<0.05). However, the test group and the control group had no statistically significant relative to the baseline at 3 months after fracture in grip strength(P<0.05). For the anxiety of patients, compared with the test group and control group at before and after rehabilitation treatment, the anxiety of both test group and control group cases was eased(P<0.05). However, The degree of anxiety relief in test group and control group cases had no difference(P>0.05). CONCLUSIONS: The TCM synthetic rehabilitation therapy has better curative effects on the treatment of functional disability of wrist joints after distal radius fractures than the general therapy of soaking-washing with Chinese medicinal herbs and functional exercise.

Optimal numbers of residues in linkers of DNA polymerase I, T7 primase and DNA polymerase IV.

DNA polymerase I (PolI), T7 primase and DNA polymerase IV (Dpo4) have a common feature in their structures that the two main domains are connected by an unstructured polypeptide linker. To perform their specific enzymatic activities, the enzymes are required to rearrange the position and orientation of one domain relative to the other into an active mode. Here, we show that the three enzymes share the same mechanism of the transition from the inert to active modes and use the minimum numbers of residues in their linkers to achieve the most efficient transitions. The transition time to the finally active mode is sensitively dependent on the stretched length of the linker in the finally active mode while is insensitive to the position and orientation in the initially inert state. Moreover, we find that for any enzyme whose two domains are connected by an unstructured flexible linker, the stretched length (L) of the linker in the finally active mode and the optimal number (Nopt) of the residues in the linker satisfy relation L ≈ αNopt, with α = 0.24-0.27 nm being a constant insensitive to the system.