MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. We recently demonstrated that levels of miR-106b were significantly decreased in the vitreous and plasma of patients with neovascular age-related macular degeneration (AMD). Here we show that expression of the miR-106b-25 cluster is negatively regulated by the unfolded protein response pathway of protein kinase RNA-like ER kinase (PERK) in a mouse model of neovascular AMD. A reduction in levels of miR-106b triggers vascular growth both in vivo and in vitro by inducing production of pro-angiogenic factors. We demonstrate that therapeutic delivery of miR-106b to the retina with lentiviral vectors protects against aberrant retinal angiogenesis in two distinct mouse models of pathological retinal neovascularization. Results from this study suggest that miRNAs such as miR-106b have the potential to be used as multitarget therapeutics for conditions characterized by pathological retinal angiogenesis.DNA repair mechanisms play a crucial role in maintaining genome integrity. However, the increased frequency of DNA double-strand breaks (DSBs) and genome rearrangements in aged individuals suggests an age-associated DNA repair deficiency. Previous work from our group revealed a delayed firing of the DNA damage response in human mammary epithelial cells (HMECs) from aged donors. We now report a decreased activity of the main DSB repair pathways, the canonical non-homologous end-joining (c-NHEJ) and the homologous recombination (HR) in these HMECs from older individuals. We describe here a deficient recruitment of 53BP1 to DSB sites in G1 cells, probably influenced by an altered epigenetic regulation. 53BP1 absence at some DSBs is responsible for the age-associated DNA repair defect, as it permits the ectopic formation of BRCA1 foci while still in the G1 phase. CtIP and RPA foci are also formed in G1 cells from aged donors, but RAD51 is not recruited, thus indicating that extensive DNA-end resection occurs in these breaks although HR is not triggered. These results suggest an age-associated switch of DSB repair from canonical to highly mutagenic alternative mechanisms that promote the formation of genome rearrangements, a source of genome instability that might contribute to the aging process.Duchenne Muscular Dystrophy (DMD) patients often suffer from both muscle wasting and osteoporosis. Our previous studies have revealed reduced regeneration potential in skeletal muscle and bone, concomitant with ectopic calcification of soft tissues in double knockout (dKO, dystrophin-/-; utrophin-/-) mice, a severe murine model for DMD. We found significant involvement of RhoA/ROCK (Rho-Associated Protein Kinase) signaling in mediating ectopic calcification of muscles in dKO mice. However, the cellular identity of these RhoA+ cells, and the role that RhoA plays in the chronic inflammation-associated pathologies has not been elucidated. Here, we report that CD68+ macrophages are highly prevalent at the sites of ectopic calcification of dKO mice, and that these macrophages highly express RhoA. Macrophages from dKO mice feature a shift towards a more pro-inflammatory M1 polarization and an increased expression of various senescence-associated secretory phenotype (SASP) factors that was reduced with the RhoA/ROCK inhibitor Y-27632. Further, systemic inhibition of RhoA activity in dKO mice led to reduced number of RhoA+/CD68+ cells, as well as a reduction in fibrosis and ectopic calcification. Together, these data revealed that RhoA signaling may be a key regulator of imbalanced mineralization in the dystrophic musculoskeletal system and consequently a therapeutic target for the treatment of DMD or other related muscle dystrophies.
  This exploratory qualitative study conducted among Thai medical students aimed to investigate factors related to the development of medical students' depression and how these factors interact in contributing to depressive disorders.
 
  Forty-three undergraduate medical students of the six-year Doctor of Medicine program were identified as having moderate to severe depression on an annual depression screening. From these, eighteen students agreed to participate in individual in-depth interviews. Transcriptions of the interviews were analyzed by independent reviewers using a thematic analysis approach.
 
  Among 43 participants screened as having moderate-to-severe depression, major depressive disorder and adjustment disorder were 9.3% and 14.0%, respectively. Reported factors related to medical students' disorders were personal vulnerabilities, medical educational administration, academic achievement, learning environment, intrinsic motivation, self-care and self-management, relationship, and community. In partchievement, and relationship problems can precipitate the onset of depressive disorders, if not being properly addressed. The 4P framework of predisposing, precipitating, perpetuating, and protective factors are suggested to understand the onset and development of students' depressive disorders and to identify targets for institutional and educational intervention.Lenticulostriate artery (LSA) aneurysm is relatively rare, and the need for surgical intervention is controversial. Here, we report a case of ruptured LSA aneurysm which was accompanied by familial Mediterranean fever (FMF). A 45-year-old woman with a history of FMF presented with sudden onset of headache and vertigo. Computed tomography revealed hemorrhage in the right caudate nucleus and lateral ventricles. Digital subtraction angiography revealed a fusiform aneurysm (3mm) at the distal site of medial LSA. Observation was selected, and the aneurysm gradually decreased and eventually disappeared on the 105th day from the onset. This was the first report describing an LSA aneurysm associated with FMF. It suggests that such aneurysms could be treated conservatively with close radiological follow-up.Although context can be presumed to exert effects on both language and visual information processing, the relevant brain regions have not been elucidated.  https://www.selleckchem.com/products/ipi-549.html  In the present study, we used silent manga to focus on mental states induced by visual stimuli alone. When participants read manga on a double-page spread with preserved context, significant activation was observed in the bilateral visual cortex and cerebellum. Moreover, the activated region corresponded to lesions associated with hemispatial neglect, when this condition was directly compared with a single-page presentation that impaired context. These results indicate that higher-order visual information processing is enhanced by context.