Supergravity Microstates for BPS Black Holes and Black Rings

We demonstrate a solution generating technique, modulo some constraints, for a large class of smooth supergravity solutions with the same asymptotic charges as a five dimensional 3-charge BPS black hole or black ring, dual to a D1/D5/P system. These solutions are characterized by a harmonic function with both positive and negative poles, which induces a geometric transition whereby singular sources have disappeared and all of the net charge at infinity is sourced by fluxes through two-cycles joining the poles of the harmonic function.Comment: 25 pages, 1 figure. Fixed minor typos, references added, extra comment on gauge choic

An index for the Dirac operator on D3 branes with background fluxes

We study the problem of instanton generated superpotentials in Calabi-Yau orientifold compactifications directly in type IIB string theory. To this end, we derive the Dirac equation on a Euclidean D3 brane in the presence of background fluxes. We propose an index which governs whether the generation of a superpotential in the effective 4d theory by D3 brane instantons is possible. Applying the formalism to various classes of examples, including the K3 x T^2/Z_2 orientifold, in the absence and presence of fluxes, we show that our results are consistent with conclusions attainable via duality from an M-theory analysis.Comment: Fermion coupling to five-form restored, conclusions of the paper unchange

Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons

Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are likely dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension

Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia

SUMMARY Melanocortin 4 receptors (Mc4rs) are expressed by extra-hypothalamic neurons including cholinergic autonomic pre-ganglionic neurons. However, whether Mc4rs in these neurons are required to control energy and glucose homeostasis is unclear. Here we report that Mc4rs in sympathetic, but not parasympathetic, pre-ganglionic neurons are required to regulate energy expenditure and body weight including brown and white adipose tissue thermogenic responses to diet and cold exposure. In addition, deletion of Mc4rs in both sympathetic and parasympathetic cholinergic neurons impairs glucose homeostasis

The health-related quality of life in a Swedish sample of HIV-infected persons

The purposes of the present study are (1) to assess the health-related quality of life (HRQOL) and the subjective health status in a sample of human immunodeficiency virus (HIV)-infected persons (2) to relate the results to different population groups and (3) to investigate the relationship of medical and demographic variables with HRQOL. A total of 72 HIV-infected men were included. They answered the Swedish health-related quality of life questionnaire and the health index. Demographic and medical data were obtained from the medical records. The data collection took place before entering a therapeutic HIV vaccine trial. The results showed a more negative impact on the HRQOL and subjective health status in the HIV-positive subjects, compared with male population groups. The dimensions of emotional well-being were most affected. When comparisons were made according to the medical and demographic variables for different subgroups within the HIV sample, differences in the physical-dimension scales were most prominent. Symptomatic HIV infection or acquired immunodeficiency syndrome (AIDS), anti-retroviral treatment, sick leave or disability pension, low income and basic education were associated with worse HRQOL and health status. In conclusion, it is of utmost importance to take into account, aspects of the patients' emotional well-being in nursing, as well as in medical care and interventions. Moreover, individualized caring programs are needed because the disruptions in HRQOL fluctuated within the HIV sample

Continuous Flow Reactor for the Production of Stable Amyloid Protein Oligomers

The predominant working hypothesis of Alzheimer's disease is that the proximate pathologic agents are oligomers of the amyloid β-protein (Aβ). "Oligomer" is an ill-defined term. Many different types of oligomers have been reported, and they often exist in rapid equilibrium with monomers and higher-order assemblies. This has made formal structure-activity determinations difficult. Recently, Ono et al. [Ono, K., et al. (2009) Proc. Natl. Acad. Sci. U.S.A. 106, 14745-14750] used rapid, zero-length, in situ chemical cross-linking to stabilize the oligomer state, allowing the isolation and study of pure populations of oligomers of a specific order (number of Aβ monomers per assembly). This approach was successful but highly laborious and time-consuming, precluding general application of the method. To overcome these difficulties, we developed a "continuous flow reactor" with the ability to produce theoretically unlimited quantities of chemically stabilized Aβ oligomers. We show, in addition to its utility for Aβ, that this method can be applied to a wide range of other amyloid-forming proteins

A quality metric for homology modeling: the H-factor

<p>Abstract</p> <p>Background</p> <p>The analysis of protein structures provides fundamental insight into most biochemical functions and consequently into the cause and possible treatment of diseases. As the structures of most known proteins cannot be solved experimentally for technical or sometimes simply for time constraints, <it>in silico </it>protein structure prediction is expected to step in and generate a more complete picture of the protein structure universe. Molecular modeling of protein structures is a fast growing field and tremendous works have been done since the publication of the very first model. The growth of modeling techniques and more specifically of those that rely on the existing experimental knowledge of protein structures is intimately linked to the developments of high resolution, experimental techniques such as NMR, X-ray crystallography and electron microscopy. This strong connection between experimental and <it>in silico </it>methods is however not devoid of criticisms and concerns among modelers as well as among experimentalists.</p> <p>Results</p> <p>In this paper, we focus on homology-modeling and more specifically, we review how it is perceived by the structural biology community and what can be done to impress on the experimentalists that it can be a valuable resource to them. We review the common practices and provide a set of guidelines for building better models. For that purpose, we introduce the H-factor, a new indicator for assessing the quality of homology models, mimicking the R-factor in X-ray crystallography. The methods for computing the H-factor is fully described and validated on a series of test cases.</p> <p>Conclusions</p> <p>We have developed a web service for computing the H-factor for models of a protein structure. This service is freely accessible at <url>http://koehllab.genomecenter.ucdavis.edu/toolkit/h-factor</url>.</p

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value &lt; 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p &lt; 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe