Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

Heterosexual couples and prostate cancer support groups: a gender relations analysis.

Introduction: Men diagnosed with prostate cancer (PCa) can receive supportive care from an array of sources including female partners and prostate cancer support groups (PCSGs). However, little is known about how heterosexual gender relations and supportive care play out among couples who attend PCSGs. Distilling such gender relation patterns is a key to understanding and advancing supportive care for men who experience PCa and their families

Critical Trapped Surfaces Formation in the Collision of Ultrarelativistic Charges in (A)dS

We study the formation of marginally trapped surfaces in the head-on collision of two ultrarelativistic charges in $(A)dS$ space-time. The metric of ultrarelativistic charged particles in $(A)dS$ is obtained by boosting Reissner-Nordstr\"om $(A)dS$ space-time to the speed of light. We show that formation of trapped surfaces on the past light cone is only possible when charge is below certain critical - situation similar to the collision of two ultrarelativistic charges in Minkowski space-time. This critical value depends on the energy of colliding particles and the value of a cosmological constant. There is richer structure of critical domains in $dS$ case. In this case already for chargeless particles there is a critical value of the cosmological constant only below which trapped surfaces formation is possible. Appearance of arbitrary small nonzero charge significantly changes the physical picture. Critical effect which has been observed in the neutral case does not take place more. If the value of the charge is not very large solution to the equation on trapped surface exists for any values of cosmological radius and energy density of shock waves. Increasing of the charge leads to decrease of the trapped surface area, and at some critical point the formation of trapped surfaces of the type mentioned above becomes impossible.Comment: 30 pages, Latex, 7 figures, Refs. added and typos correcte

Gender differences in beliefs about health:A comparative qualitative study with Ghanaian and Indian migrants living in the United Kingdom

Background There is a well-established association between migration to high income countries and health status, with some groups reporting poorer health outcomes than the host population. However, processes that influence health behaviours and health outcomes across minority ethnic groups are complex and in addition, culture ascribes specific gender roles for men and women, which can further influence perspectives of health. The aim of this study was to undertake a comparative exploration of beliefs of health among male and female Ghanaian and Indian migrants and White British participants residing in an urban area within the UK. Methods Thirty-six participants (12 each Ghanaian, Indian and White British) were recruited through community settings and participated in a semi-structured interview focusing on participant’s daily life in the UK, perceptions of their own health and how they maintained their health. Interviews were analyzed using a Framework approach. Results Three super ordinate themes were identified and labelled (a) beliefs about health; (b) symptom interpretation and (c) self-management and help seeking. Gender differences in beliefs and health behaviour practices were apparent across participants. Conclusions This is the first study to undertake a comparative exploration of health beliefs among people who have migrated to the UK from Ghana and India and to compare with a local (White British) population. The results highlight a need to consider both cultural and gender-based diversity in guiding health behaviours, and such information will be useful in the development of interventions to support health outcomes among migrant populations

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2

IGF-I induced genes in stromal fibroblasts predict the clinical outcome of breast and lung cancer patients

<p>Abstract</p> <p>Background</p> <p>Insulin-like growth factor-1 (IGF-I) signalling is important for cancer initiation and progression. Given the emerging evidence for the role of the stroma in these processes, we aimed to characterize the effects of IGF-I on cancer cells and stromal cells separately.</p> <p>Methods</p> <p>We used an <it>ex vivo </it>culture model and measured gene expression changes after IGF-I stimulation with cDNA microarrays. <it>In vitro </it>data were correlated with <it>in vivo </it>findings by comparing the results with published expression datasets on human cancer biopsies.</p> <p>Results</p> <p>Upon stimulation with IGF-I, breast cancer cells and stromal fibroblasts show some common and other distinct response patterns. Among the up-regulated genes in the stromal fibroblasts we observed a significant enrichment in proliferation associated genes. The expression of the IGF-I induced genes was coherent and it provided a basis for the segregation of the patients into two groups. Patients with tumours with highly expressed IGF-I induced genes had a significantly lower survival rate than patients whose tumours showed lower levels of IGF-I induced gene expression (<it>P </it>= 0.029 - Norway/Stanford and <it>P </it>= 7.96e-09 - NKI dataset). Furthermore, based on an IGF-I induced gene expression signature derived from primary lung fibroblasts, a separation of prognostically different lung cancers was possible (<it>P </it>= 0.007 - Bhattacharjee and <it>P </it>= 0.008 - Garber dataset).</p> <p>Conclusion</p> <p>Expression patterns of genes induced by IGF-I in primary breast and lung fibroblasts accurately predict outcomes in breast and lung cancer patients. Furthermore, these IGF-I induced gene signatures derived from stromal fibroblasts might be promising predictors for the response to IGF-I targeted therapies.</p> <p>See the related commentary by Werner and Bruchim: <url>http://www.biomedcentral.com/1741-7015/8/2</url></p

RUNX3 Mediates Suppression of Tumor Growth and Metastasis of Human CCRCC by Regulating Cyclin Related Proteins and TIMP-1

Here we presented that the expression of RUNX3 was significantly decreased in 75 cases of clear cell renal cell carcinoma (CCRCC) tissues (p<0.05). Enforced RUNX3 expression mediated 786-O cells to exhibit inhibition of growth, G1 cell-cycle arrest and metastasis in vitro, and to lost tumorigenicity in nude mouse model in vivo. RUNX3-induced growth suppression was found partially to regulate various proteins, including inhibition of cyclinD1, cyclinE, cdk2, cdk4 and p-Rb, but increase of p27Kip1, Rb and TIMP-1. Therefore, RUNX3 had the function of inhibiting the proliferative and metastatic abilities of CCRCC cells by regulating cyclins and TIMP1