Dynamics of Arachidonic Acid Metabolism in Macrophages From Delayed‐Type Hypersensitivity (Schistosoma mansoni egg) and Foreign‐Body‐Type Granulomas

The present study examines the kinetics of arachidonic acid (AA) metabolism by murine macrophages isolated from sites of experimentally induced pulmonary granulomatous inflammation. Macrophages of T‐cell‐mediated hypersensitivity lesions induced by Schistosoma mansoni eggs (SE‐GM) and non‐T‐cell‐mediated foreign‐body‐type lesions (FB‐GM) induced by Sephadex beads were examined. Overall, macrophages from both types of lesions produced mainly lipoxygenase pathway metabolites, leukotrienes, and monohydroxyeicosatetraenoic acids (mono‐HETEs). Early after induction (4 days [4D]), SE‐GM showed an augmented zymosan‐stimulated AA release and metabolism compared to resident peritoneal macrophages. Macrophages from mature lesions (8–32D) showed constitutive synthesis of metabolites and were refractory to zymosan stimulation. Both SE‐GM and FB‐GM showed augmented AA uptake incorporating a large proportion into neutral lipids. A direct comparison of SE‐GM and FB‐GM revealed that the T‐cell‐mediated lesion produced lesser amounts of prostaglandins and leukotrienes and showed reduced incorporation of AA into phosphatidylcholine. These data suggest that AA metabolism by granuloma macrophages is sequentially modified during recruitment and activation at sites of chronic inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141165/1/jlb0671.pd

A Genome-Wide Association Study Using a Custom Genotyping Array Identifies Variants in GPR158 Associated with Reduced Energy Expenditure in American Indians

Pima Indians living in Arizona have a high prevalence of obesity, and we have previously shown that a relatively lower energy expenditure (EE) predicts weight and fat mass gain in this population. EE is a familial trait (heritability = 0.52); therefore, in the current study, we aimed to identify genetic variants that affect EE and thereby influence BMI and body fatness in Pima Indians. Genotypic data from 491,265 variants were analyzed for association with resting metabolic rate (RMR) and 24-h EE assessed in a whole-room calorimeter in 507 and 419 Pima Indians, respectively. Variants associated with both measures of EE were analyzed for association with maximum BMI and percent body fat (PFAT) in 5,870 and 912 Pima Indians, respectively. rs11014566 nominally associated with both measures of EE and both measures of adiposity in Pima Indians, where the G allele (frequency: Pima Indians = 0.60, Europeans <0.01) associated with lower 24-h EE ( = -33 kcal/day per copy), lower RMR ( = -31 kcal/day), higher BMI ( = +0.6 kg/m(2)), and higher PFAT ( = +0.9%). However, the association of rs11014566 with BMI did not directionally replicate when assessed in other ethnic groups. rs11014566 tags rs144895904, which affected promoter function in an in vitro luciferase assay. These variants map to GPR158, which is highly expressed in the brain and interacts with two other genes (RGS7 and CACNA1B) known to affect obesity in knockout mice. Our results suggest that common ethnic-specific variation in GPR158 may influence EE; however, its role in weight gain remains controversial, as it either had no association with BMI or associated with BMI but in the opposite direction in other ethnic groups

Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Warped Wilson Line DBI Inflation

We propose a novel inflationary scenario in string theory in which the inflaton field is a 'Wilson line' degree of freedom in the worldvolume of a probe Dp-brane, in a warped flux compactification. Kinetic terms for Wilson line fields on the world volume of a D-brane take a nonstandard Dirac-Born-Infeld (DBI) form. Thus, we work in the framework of DBI inflation. This extends the original slow roll Wilson line inflationary scenario, where only the quadratic piece was considered. Warped DBI Wilson line inflation offers an attractive alternative to ordinary (position field) DBI inflation, inasmuch as observational and theoretical constraints get considerably relaxed. Besides the standard large non-Gaussianities in DBI scenarios, it is also possible to achieve an observable amount of gravitational waves.Comment: v3: Typos corrected, Published in JCAP; 21 page

Etiopathogenesis of type 1 diabetes mellitus: prognostic factors for the evolution of residual β cell function

Type 1A diabetes mellitus (T1ADM) is a progressive autoimmune disease mediated by T lymphocytes with destruction of beta cells. Up to now, we do not have precise methods to assess the beta cell mass, "in vivo" or "ex-vivo". The studies about its genetic susceptibility show strong association with class II antigens of the HLA system (particularly DQ). Others genetics associations are weaker and depend on the population studied. A combination of precipitating events may occur at the beginning of the disease. There is a silent loss of immune-mediated beta cells mass which velocity has an inverse relation with the age, but it is influenced by genetic and metabolic factors. We can predict the development of the disease primarily through the determination of four biochemically islet auto antibodies against antigens like insulin, GAD65, IA2 and Znt8. Beta cell destruction is chronically progressive but at clinical diagnosis of the disease a reserve of these cells still functioning. The goal of secondary disease prevention is halt the autoimmune attack on beta cells by redirecting or dampening the immune system. It is remains one of the foremost therapeutic goals in the T1ADM. Glycemic intensive control and immunotherapeutic agents may preserve beta-cell function in newly diagnosed patients with T1ADM. It may be assessed through C-peptide values, which are important for glycemic stability and for the prevention of chronic complications of this disease. This article will summarize the etiopathogenesis mechanisms of this disease and the factors can influence on residual C-peptide and the strategies to it preservation

A systematic review of patient reported factors associated with uptake and completion of cardiovascular lifestyle behaviour change

Background: Healthy lifestyles are an important facet of cardiovascular risk management. Unfortunately many individuals fail to engage with lifestyle change programmes. There are many factors that patients report as influencing their decisions about initiating lifestyle change. This is challenging for health care professionals who may lack the skills and time to address a broad range of barriers to lifestyle behaviour. Guidance on which factors to focus on during lifestyle consultations may assist healthcare professionals to hone their skills and knowledge leading to more productive patient interactions with ultimately better uptake of lifestyle behaviour change support. The aim of our study was to clarify which influences reported by patients predict uptake and completion of formal lifestyle change programmes. Methods: A systematic narrative review of quantitative observational studies reporting factors (influences) associated with uptake and completion of lifestyle behaviour change programmes. Quantitative observational studies involving patients at high risk of cardiovascular events were identified through electronic searching and screened against pre-defined selection criteria. Factors were extracted and organised into an existing qualitative framework. Results: 374 factors were extracted from 32 studies. Factors most consistently associated with uptake of lifestyle change related to support from family and friends, transport and other costs, and beliefs about the causes of illness and lifestyle change. Depression and anxiety also appear to influence uptake as well as completion. Many factors show inconsistent patterns with respect to uptake and completion of lifestyle change programmes. Conclusion: There are a small number of factors that consistently appear to influence uptake and completion of cardiovascular lifestyle behaviour change. These factors could be considered during patient consultations to promote a tailored approach to decision making about the most suitable type and level lifestyle behaviour change support

Theory and Phenomenology of Type I strings and M-theory

The physical motivations and the basic construction rules for Type I strings and M-theory compactifications are reviewed in light of the recent developments. The first part contains the basic theoretical ingredients needed for building four-dimensional supersymmetric models, models with broken supersymmetry and for computing low-energy actions and quantum corrections to them. The second part contains some phenomenological applications to brane world scenarios with low values of the string scale and large extra dimensions.Comment: 129 pages, 7 eps figures, LaTeX, version to appear in Class. Quantum Gra