The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of scleroderma, is caused by mutations in the sole Arg-Gly-Asp (RGD) sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the pro-fibrotic cytokine transforming growth factor β (TGFβ). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFβ concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis (SSc), a more common acquired form of scleroderma, suggests broad pathogenic relevance.

Background:Little is known about the role of JNK mitochondrial signaling in cardiomyocyte cell death. Results: Global and mitochondrial inhibition of JNK protects against I/R injury thus reducing infarct volume. Conclusion: Blocking JNK mitochondrial translocation or JNK inhibition may be an effective treatment for I/R-induced cardiomyocyte death. Significance: These findings suggest a new molecular target for JNK inhibition.

The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure–activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.

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SummaryThe fibrillins and latent transforming growth factor-β binding proteins (LTBPs) form a superfamily of structurally-related proteins consisting of calcium-binding epidermal growth factor-like (cbEGF) domains interspersed with 8-cysteine-containing transforming growth factor β-binding protein-like (TB) and hybrid (hyb) domains. Fibrillins are the major components of the extracellular 10–12 nm diameter microfibrils, which mediate a variety of cell-matrix interactions. Here we present the crystal structure of a fibrillin-1 cbEGF9-hyb2-cbEGF10 fragment, solved to 1.8 Å resolution. The hybrid domain fold is similar, but not identical, to the TB domain fold seen in previous fibrillin-1 and LTBP-1 fragments. Pairwise interactions with neighboring cbEGF domains demonstrate extensive interfaces, with the hyb2-cbEGF10 interface dependent on Ca2+ binding. These observations provide accurate constraints for models of fibrillin organization within the 10–12 nm microfibrils and provide further molecular insights into how Ca2+ binding influences the intermolecular interactions and biomechanical properties of fibrillin-1.

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For the attainment of individual’s cognitive and social benefits the employee turnover is becoming popular trend in all organization. This research paper reports on examination of variables that may be predictive to leave a job. More precisely this current paper shows the direct and indirect impact of job stress, job satisfaction on turnover. Organizational commitment is the antecedent of turnover intention. It highlights the impact of leadership support on job satisfaction. In order to collect the data for understanding the situation about the employee turnover intention, a sample of 200 respondents was ask to participate in a self-administered questionnaire.50 questionnaires are not giving right answers so only 150 samples are selected for research. The current research paper uses a non-probability technique of sampling. We choose this sample of people from different institutions of Bahawalpur. Four major clusters was target to collect the sample data like the Islamia University of Bahawalpur, Allama Iqbal college of Bahawalpur, Army public school and college system and Sadiq Public School. Finding shows that employee turnover intention has a significant relationship with all the variables i.e. organizational commitment, job satisfaction, job stress and leadership support.

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