Ribosomal S6K1 in POMC and AgRP Neurons Regulates Glucose Homeostasis but Not Feeding Behavior in Mice.

SummaryHypothalamic ribosomal S6K1 has been suggested as a point of convergence for hormonal and nutrient signals in the regulation of feeding behavior, bodyweight, and glucose metabolism. However, the long-term effects of manipulating hypothalamic S6K1 signaling on energy homeostasis and the cellular mechanisms underlying these roles are unclear. We therefore inactivated S6K1 in pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, but in contrast to the current view, we found no evidence that S6K1 regulates food intake and bodyweight. In contrast, S6K1 signaling in POMC neurons regulated hepatic glucose production and peripheral lipid metabolism and modulated neuronal excitability. S6K1 signaling in AgRP neurons regulated skeletal muscle insulin sensitivity and was required for glucose sensing by these neurons. Our findings suggest that S6K1 signaling is not a general integrator of energy homeostasis in the mediobasal hypothalamus but has distinct roles in the regulation of glucose homeostasis by POMC and AgRP neurons

Ethnic differences in Glycaemic control in people with type 2 diabetes mellitus living in Scotland

Background and Aims: Previous studies have investigated the association between ethnicity and processes of care and intermediate outcomes of diabetes, but there are limited population-based studies available. The aim of this study was to use population-based data to investigate the relationships between ethnicity and glycaemic control in men and women with diabetes mellitus living in Scotland.<p></p> Methods: We used a 2008 extract from the population-based national electronic diabetes database of Scotland. The association between ethnicity with mean glycaemic control in type 2 diabetes mellitus was examined in a retrospective cohort study, including adjustment for a number of variables including age, sex, socioeconomic status, body mass index (BMI), prescribed treatment and duration of diabetes.<p></p> Results: Complete data for analyses were available for 56,333 White Scottish adults, 2,535 Pakistanis, 857 Indians, 427 Chinese and 223 African-Caribbeans. All other ethnic groups had significantly (p<0.05) greater proportions of people with suboptimal glycaemic control (HbA1c >58 mmol/mol, 7.5%) compared to the White Scottish group, despite generally younger mean age and lower BMI. Fully adjusted odds ratios for suboptimal glycaemic control were significantly higher among Pakistanis and Indians (1.85, 95% CI: 1.68–2.04, and 1.62,95% CI: 1.38–1.89) respectively.<p></p> Conclusions: Pakistanis and Indians with type 2 diabetes mellitus were more likely to have suboptimal glycaemic control than the white Scottish population. Further research on health services and self-management are needed to understand the association between ethnicity and glycaemic control to address ethnic disparities in glycaemic control.<p></p&gt

Early star-forming galaxies and the reionization of the Universe

Star forming galaxies represent a valuable tracer of cosmic history. Recent observational progress with Hubble Space Telescope has led to the discovery and study of the earliest-known galaxies corresponding to a period when the Universe was only ~800 million years old. Intense ultraviolet radiation from these early galaxies probably induced a major event in cosmic history: the reionization of intergalactic hydrogen. New techniques are being developed to understand the properties of these most distant galaxies and determine their influence on the evolution of the universe.Comment: Review article appearing in Nature. This posting reflects a submitted version of the review formatted by the authors, in accordance with Nature publication policies. For the official, published version of the review, please see http://www.nature.com/nature/archive/index.htm

Primary and malignant cholangiocytes undergo CD40 mediated Fas dependent Apoptosis, but are insensitive to direct activation with exogenous fas ligand

Introduction Cholangiocarcinoma is a rare malignancy of the biliary tract, the incidence of which is rising, but the pathogenesis of which remains uncertain. No common genetic defects have been described but it is accepted that chronic inflammation is an important contributing factor. We have shown that primary human cholangiocyte and hepatocyte survival is tightly regulated via co-operative interactions between two tumour necrosis family (TNF) receptor family members; CD40 and Fas (CD95). Functional deficiency of CD154, the ligand for CD40, leads to a failure of clearance of biliary tract infections and a predisposition to cholangiocarcinoma implying a direct link between TNF receptor-mediated apoptosis and the development of cholangiocarcinoma. Aims To determine whether malignant cholangiocytes display defects in CD40 mediated apoptosis. By comparing CD40 and Fas-mediated apoptosis and intracellular signalling in primary human cholangiocytes and three cholangiocyte cell lines. Results Primary cholangiocytes and cholangiocyte cell lines were relatively insensitive to direct Fas-mediated killing with exogenous FasL when compared with Jurkat cells, which readily underwent Fas-mediated apoptosis, but were extremely sensitive to CD154 stimulation. The sensitivity of cells to CD40 activation was similar in magnitude in both primary and malignant cells and was STAT-3 and AP-1 dependent in both. Conclusions 1) Both primary and malignant cholangiocytes are relatively resistant to Fas–mediated killing but show exquisite sensitivity to CD154, suggesting that the CD40 pathway is intact and fully functional in both primary and malignant cholangiocytes 2) The relative insensitivity of cholangiocytes to Fas activation demonstrates the importance of CD40 augmentation of Fas dependent death in these cells. Agonistic therapies which target CD40 and associated intracellular signalling pathways may be effective in promoting apoptosis of malignant cholangiocytes

Gene expression and splicing alterations analyzed by high throughput RNA sequencing of chronic lymphocytic leukemia specimens.

BackgroundTo determine differentially expressed and spliced RNA transcripts in chronic lymphocytic leukemia specimens a high throughput RNA-sequencing (HTS RNA-seq) analysis was performed.MethodsTen CLL specimens and five normal peripheral blood CD19+ B cells were analyzed by HTS RNA-seq. The library preparation was performed with Illumina TrueSeq RNA kit and analyzed by Illumina HiSeq 2000 sequencing system.ResultsAn average of 48.5 million reads for B cells, and 50.6 million reads for CLL specimens were obtained with 10396 and 10448 assembled transcripts for normal B cells and primary CLL specimens respectively. With the Cuffdiff analysis, 2091 differentially expressed genes (DEG) between B cells and CLL specimens based on FPKM (fragments per kilobase of transcript per million reads and false discovery rate, FDR q < 0.05, fold change >2) were identified. Expression of selected DEGs (n = 32) with up regulated and down regulated expression in CLL from RNA-seq data were also analyzed by qRT-PCR in a test cohort of CLL specimens. Even though there was a variation in fold expression of DEG genes between RNA-seq and qRT-PCR; more than 90 % of analyzed genes were validated by qRT-PCR analysis. Analysis of RNA-seq data for splicing alterations in CLL and B cells was performed by Multivariate Analysis of Transcript Splicing (MATS analysis). Skipped exon was the most frequent splicing alteration in CLL specimens with 128 significant events (P-value <0.05, minimum inclusion level difference >0.1).ConclusionThe RNA-seq analysis of CLL specimens identifies novel DEG and alternatively spliced genes that are potential prognostic markers and therapeutic targets. High level of validation by qRT-PCR for a number of DEG genes supports the accuracy of this analysis. Global comparison of transcriptomes of B cells, IGVH non-mutated CLL (U-CLL) and mutated CLL specimens (M-CLL) with multidimensional scaling analysis was able to segregate CLL and B cell transcriptomes but the M-CLL and U-CLL transcriptomes were indistinguishable. The analysis of HTS RNA-seq data to identify alternative splicing events and other genetic abnormalities specific to CLL is an added advantage of RNA-seq that is not feasible with other genome wide analysis

Testing the theory of immune selection in cancers that break the rules of transplantation

Modification of cancer cells likely to reduce their immunogenicity, including loss or down-regulation of MHC molecules, is now well documented and has become the main support for the concept of immune surveillance. The evidence that these modifications, in fact, result from selection by the immune system is less clear, since the possibility that they may result from reorganized metabolism associated with proliferation or from cell de-differentiation remains. Here, we (a) survey old and new transplantation experiments that test the possibility of selection and (b) survey how transmissible tumours of dogs and Tasmanian devils provide naturally evolved tests of immune surveillance

Improving prevention, monitoring and management of diabetes among ethnic minorities: contextualizing the six G’s approach

Objective: People from Black, Asian and Minority Ethnic (BAME) groups are known to have an increased risk of devel-oping diabetes and face greater barriers to accessing healthcare resources compared to their ‘white British’ counter-parts. The extent of these barriers varies by demographics and different socioeconomic circumstances that people find themselves in. The purpose of this paper is to present and discuss a new framework to understand, disentangle and tackle these barriers so that improvements in the effectiveness of diabetes interventions for BAME communities can be achieved. Results: The main mediators of lifestyle behavioural change are gender, generation, geography, genes, God/religion, and gaps in knowledge and economic resources. Dietary and cultural practices of these individuals significantly vary according to gender, generation, geographical origin and religion. Recognition of these factors is essential in increas-ing knowledge of healthy eating, engagement in physical activity and utilisation of healthcare services. Use of the six G’s framework alongside a community centred approach is crucial in developing and implementing culturally sensi-tive interventions for diabetes prevention and management in BAME communities. This could improve their health outcomes and overall wellbeing

Ion-beam Sculpting at Nanometre Length Scales

Manipulating matter at the nanometre scale is important for many electronic, chemical and biological advances, but present solid-state fabrication methods do not reproducibly achieve dimensional control at the nanometre scale. Here we report a means of fashioning matter at these dimensions that uses low-energy ion beams and reveals surprising atomic transport phenomena that occur in a variety of materials and geometries. The method is implemented in a feedback-controlled sputtering system that provides fine control over ion beam exposure and sample temperature. We call the method "ion-beam sculpting", and apply it to the problem of fabricating a molecular-scale hole, or nanopore, in a thin insulating solid-state membrane. Such pores can serve to localize molecular-scale electrical junctions and switches, and function as masks to create other small-scale structures. Nanopores also function as membrane channels in all living systems, where they serve as extremely sensitive electro-mechanical devices that regulate electric potential, ionic flow, and molecular transport across cellular membranes. We show that ion-beam sculpting can be used to fashion an analogous solid-state device: a robust electronic detector consisting of a single nanopore in a Si3N4 membrane, capable of registering single DNA molecules in aqueous solution.PhysicsEngineering and Applied SciencesMolecular and Cellular Biolog

Intervention, recruitment and evaluation challenges in the Bangladeshi community: Experience from a peer lead educational course

<p>Abstract</p> <p>Background</p> <p>The incidence of Type 2 diabetes is increasing worldwide and diabetes is four times more common among ethnic minority groups than among the general Caucasian population. This study reflects on the specific issues of engaging people and evaluating interventions through written questionnaires within older ethnic minority groups.</p> <p>Methods</p> <p>The original protocol set out to evaluate an adapted version of the X-PERT^®patient program <url>http://www.xpert-diabetes.org.uk/</url> using questionnaires and interviews.</p> <p>Results</p> <p>Questionnaires, even verbally completed, were unsuccessful and difficult to administer as participants found the questionnaire structure and design difficult to follow and did not perceive any benefit to completing the questionnaires. The benefits of attending the course were also poorly understood by participants and in many cases people participated in coming to the course as a favour to the researcher. Engaging participants required word of mouth and the involvement of active members of the community.</p> <p>Conclusion</p> <p>Peer led courses and their evaluation in older ethnic minority communities needs a very different approach for that in younger Caucasian patients. A structured approached to evaluation (favoured by western educational system) is inappropriate. Engaging participants is difficult and the employment of local well known people is essential.</p

Enhancement of Naringenin Bioavailability by Complexation with Hydroxypropoyl-β-Cyclodextrin

The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-β-cyclodextrin (HPβCD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HPβCD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and Cmax increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42% and increased the rate of glucose clearance by 64% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1α in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HPβCD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (K01DK080241)Harvard Clinical Nutrition Research Center (P30-DK040561)European Research Council (Starting Grant (TMIHCV 242699))Massachusetts General Hospital (BioMEMS Resource Center (P41 EB-002503))Alexander Silberman Institute of Life Science