Nuclear SUN1 stabilizes endothelial cell junctions via microtubules to regulate blood vessel formation

Endothelial cells line all blood vessels, where they coordinate blood vessel formation and the blood-tissue barrier via regulation of cell-cell junctions. The nucleus also regulates endothelial cell behaviors, but it is unclear how the nucleus contributes to endothelial cell activities at the cell periphery. Here, we show that the nuclear-localized linker of the nucleoskeleton and cyto-skeleton (LINC) complex protein SUN1 regulates vascular sprouting and endothelial cell-cell junction morphology and function. Loss of murine endothelial Sun1 impaired blood vessel formation and destabilized junctions, angiogenic sprouts formed but retracted in SUN1-depleted sprouts, and zebrafish vessels lacking Sun1b had aberrant junctions and defective cell-cell connections. At the cellular level, SUN1 stabilized endothelial cell-cell junctions, promoted junction function, and regulated contractility. Mechanistically, SUN1 depletion altered cell behaviors via the cytoskeleton without changing transcriptional profiles. Reduced peripheral microtubule density, fewer junction contacts, and increased catastrophes accompanied SUN1 loss, and microtubule depolymerization phenocopied effects on junctions. Depletion of GEF-H1, a microtubule-regulated Rho activator, or the LINC complex protein nesprin-1 rescued defective junctions of SUN1-depleted endothelial cells. Thus, endothelial SUN1 regulates peripheral cell-cell junctions from the nucleus via LINC complex-based microtubule interactions that affect peripheral microtubule dynamics and Rho-regulated contractility, and this long-range regulation is important for proper blood vessel sprouting and junction integrity

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Psychology and aggression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68264/2/10.1177_002200275900300301.pd

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

Plasticity Changes in Central Auditory Systems of School-Age Children Following a Brief Training With a Remote Microphone System.

The objective of this study was to investigate whether a brief speech-in-noise training with a remote microphone (RM) system (favorable listening condition) would contribute to enhanced post-training plasticity changes in the auditory system of school-age children. Before training, event-related potentials (ERPs) were recorded from 49 typically developing children, who actively identified two syllables in quiet and in noise (+5 dB signal-to-noise ratio [SNR]). During training, children completed the same syllable identification task as in the pre-training noise condition, but received feedback on their performance. Following random assignment, half of the sample used an RM system during training (experimental group), while the other half did not (control group). That is, during training' children in the experimental group listened to a more favorable speech signal (+15 dB SNR) than children from the control group (+5 dB SNR). ERPs were collected after training at +5 dB SNR to evaluate the effects of training with and without the RM system. Electrical neuroimaging analyses quantified the effects of training in each group on ERP global field power (GFP) and topography, indexing response strength and network changes, respectively. Behavioral speech-perception-in-noise skills of children were also evaluated and compared before and after training. We hypothesized that training with the RM system (experimental group) would lead to greater enhancement of GFP and greater topographical changes post-training than training without the RM system (control group). We also expected greater behavioral improvement on the speech-perception-in-noise task when training with than without the RM system. GFP was enhanced after training only in the experimental group. These effects were observed on early time-windows corresponding to traditional P1-N1 (100 to 200 msec) and P2-N2 (200 to 400 msec) ERP components. No training effects were observed on response topography. Finally, both groups increased their speech-perception-in-noise skills post-training. Enhanced GFP after training with the RM system indicates plasticity changes in the neural representation of sound resulting from listening to an enriched auditory signal. Further investigation of longer training or auditory experiences with favorable listening conditions is needed to determine if that results in long-term speech-perception-in-noise benefits

Endoscopia gastroduodenal após administração de nimesulida, monofenilbutazona e meloxicam em cães Gastroduodenal endoscopy after nimesulide, monophenylbutazone and meloxicam administration in dogs

Avaliaram-se os aspectos da mucosa gastroduodenal em cães tratados experimentalmente com nimesulida, monofenilbutazona e meloxicam. Foram formados quatro grupos com oito cães. Os grupos 1, 2 e 3 receberam, respectivamente, tratamento com nimesulida, monofenilbutazona e meloxicam durante 21 dias, e o grupo 4 foi utilizado como controle. Todos os animais foram avaliados por exames endoscópicos do estômago e duodeno antes do experimento e aos 10 e 21 dias de tratamento. Os cães não manifestaram qualquer alteração clínica ou laboratorial durante o período de estudo. A avaliação endoscópica da mucosa gastroduodenal apresentou apenas lesões consideradas de baixo grau. Esses antiinflamatórios mostraram-se seguros para o trato gastrintestinal de cães clinicamente saudáveis.<br>The gastroduodenal mucosa in dogs experimentally treated with nimesulide, monophenylbutazone and meloxicam was evaluated. There were four groups with eight dogs in each. Groups one, two and three were given nimesulide, monophenylbutazone and meloxicam, respectively, during 21 days and group four was used as control. All animals were evaluated by gastroduodenoscopy before the study and on the 10th and 21st days. The dogs did not show any clinical or laboratorial changes during the study. The endoscopic evaluation of gastroduodenal mucosa showed only low degree lesions. These anti-inflammatory drugs showed to be safe for the gastrointestinal tract in healthy dogs