Genetic variants of SLC11A1 are associated with both autoimmune and infectious diseases: Systematic review and meta-analysis

© 2015 Macmillan Publishers Limited All rights reserved. A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT) n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR=1.47 (1.30-1.66), OR=0.76 (0.65-0.89), respectively) and infectious disease (OR=1.25 (1.10-1.42), OR=0.83 (0.74-0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR=0.94 (0.89-0.98)). On the basis of a stronger association of (GT) n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+14G/C polymorphism (rs3731865) and autoimmune disease (OR=1.30 (1.04-1.64)) and rheumatoid arthritis (OR=1.60 (1.20-2.13)) and between the -237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR=0.60 (0.43-0.84)). Further, significant associations were identified between the 469+14G/C, 1730G/A and 1729+55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility

The use of β-cell transcription factors in engineering artificial β cells from non-pancreatic tissue

Type 1 diabetes results from the autoimmune destruction of the insulin-producing pancreatic beta (β) cells. Patients with type 1 diabetes control their blood glucose levels using several daily injections of exogenous insulin; however, this does not eliminate the long-term complications of hyperglycaemia. Currently, the only clinically viable treatments for type 1 diabetes are whole pancreas and islet transplantation. As a result, there is an urgent need to develop alternative therapies. Recently, cell and gene therapy have shown promise as a potential cure for type 1 diabetes through the genetic engineering of 'artificial' β cells to regulate blood glucose levels without adverse side effects and the need for immunosuppression. This review compares putative target cells and the use of pancreatic transcription factors for gene modification, with the ultimate goal of engineering a glucose-responsive 'artificial' β cell that mimics the function of pancreatic β cells, while avoiding autoimmune destruction

Identification of flavin-containing monooxygenase 5 (FMO5) as a regulator of glucose homeostasis and a potential sensor of gut bacteria

We have previously identified flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic aging. The aim of the present study was to investigate the role of FMO5 in glucose homeostasis and the impact of diet and gut flora on the phenotype of mice in which the Fmo5 gene has been disrupted (Fmo5−/− mice). In comparison with wild-type (WT) counterparts, Fmo5−/− mice are resistant to age-related changes in glucose homeostasis and maintain the higher glucose tolerance and insulin sensitivity characteristic of young animals. When fed a high-fat diet, they are protected against weight gain and reduction of insulin sensitivity. The phenotype of Fmo5−/− mice is independent of diet and the gut microbiome and is determined solely by the host genotype. Fmo5−/− mice have metabolic characteristics similar to those of germ-free mice, indicating that FMO5 plays a role in sensing or responding to gut bacteria. In WT mice, FMO5 is present in the mucosal epithelium of the gastrointestinal tract where it is induced in response to a high-fat diet. In comparison with WT mice, Fmo5−/− mice have fewer colonic goblet cells, and they differ in the production of the colonic hormone resistin-like molecule β. Fmo5−/− mice have lower concentrations of tumor necrosis factor α in plasma and of complement component 3 in epididymal white adipose tissue, indicative of improved inflammatory tone. Our results implicate FMO5 as a regulator of body weight and of glucose disposal and insulin sensitivity and, thus, identify FMO5 as a potential novel therapeutic target for obesity and insulin resistance

Does spatial proximity drive norovirus transmission during outbreaks in hospitals?

OBJECTIVE: To assess the role of spatial proximity, defined as patients sharing bays, in the spread of norovirus during outbreaks in hospitals. DESIGN: Enhanced surveillance of norovirus outbreaks between November 2009 and November 2011. METHODS: Data were gathered during 149 outbreaks of norovirus in hospital wards from five hospitals in two major cities in England serving a population of two million. We used the time between the first two cases of each outbreak to estimate the serial interval for norovirus in this setting. This distribution and dates of illness onset were used to calculate epidemic trees for each outbreak. We then used a permutation test to assess whether proximity, for all outbreaks, was more extreme than would be expected by chance under the null hypothesis that proximity was not associated with transmission risk. RESULTS: 65 outbreaks contained complete data on both onset dates and ward position. We estimated the serial interval to be 1.86 days (95% CI 1.6 to 2.2 days), and with this value found strong evidence to reject the null hypothesis that proximity was not significant (p<0.001). Sensitivity analysis using different values of the serial interval showed that there was evidence to reject the null hypothesis provided the assumed serial interval was less than 2.5 days. CONCLUSIONS: Our results provide evidence that patients occupying the same bay as patients with symptomatic norovirus infection are at an increased risk of becoming infected by these patients compared with patients elsewhere in the same ward

Neonatal Rats Exhibit a Predominantly Anti-Inflammatory Response following Spinal Cord Injury.

It has been reported that children may respond better than adults to a spinal cord injury (SCI) of similar severity. There are known biomechanical differences in the developing spinal cord that may contribute to this "infant lesion effect," but the underlying mechanisms are unknown. Using immunohistochemistry, we have previously demonstrated a different injury progression and immune cell response after a mild thoracic contusion SCI in infant rats, as compared to adult rats. Here, we investigated the acute inflammatory responses using flow cytometry and ELISA at 1 h, 24 h, and 1 week after SCI in neonatal (P7) and adult (9 weeks) rats, and locomotor recovery was examined for 6 weeks after injury. Adult rats exhibited a pronounced pro-inflammatory response characterized by neutrophils and M1-like macrophage infiltration and Th1 cytokine secretion. Neonatal rats exhibited a decreased pro-inflammatory response characterized by a higher proportion of M2-like macrophages and reduced Th1 cytokine responses, as compared to adults. These results suggest that the initial inflammatory response to SCI is predominantly anti-inflammatory in very young animals

Deuteron and antideuteron production in Au+Au collisions at sqrt(s_NN)=200 GeV

The production of deuterons and antideuterons in the transverse momentum range 1.1 < p_T < 4.3 GeV/c at mid-rapidity in Au + Au collisions at sqrt(s_NN)=200 GeV has been studied by the PHENIX experiment at RHIC. A coalescence analysis comparing the deuteron and antideuteron spectra with those of protons and antiprotons, has been performed. The coalescence probability is equal for both deuterons and antideuterons and increases as a function of p_T, which is consistent with an expanding collision zone. Comparing (anti)proton yields p_bar/p = 0.73 +/- 0.01, with (anti)deuteron yields: d_bar/d = 0.47 +/- 0.03, we estimate that n_bar/n = 0.64 +/- 0.04.Comment: 326 authors, 6 pages text, 5 figures, 1 Table. Submitted to PRL. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Single Electrons from Heavy Flavor Decays in p+p Collisions at sqrt(s) = 200 GeV

The invariant differential cross section for inclusive electron production in p+p collisions at sqrt(s) = 200 GeV has been measured by the PHENIX experiment at the Relativistic Heavy Ion Collider over the transverse momentum range $0.4 <= p_T <= 5.0 GeV/c at midrapidity (eta <= 0.35). The contribution to the inclusive electron spectrum from semileptonic decays of hadrons carrying heavy flavor, i.e. charm quarks or, at high p_T, bottom quarks, is determined via three independent methods. The resulting electron spectrum from heavy flavor decays is compared to recent leading and next-to-leading order perturbative QCD calculations. The total cross section of charm quark-antiquark pair production is determined as sigma_(c c^bar) = 0.92 +/- 0.15 (stat.) +- 0.54 (sys.) mb.Comment: 329 authors, 6 pages text, 3 figures. Submitted to Phys. Rev. Lett. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Mutations specific to the Rac-GEF domain of <i>TRIO</i> cause intellectual disability and microcephaly

Background: Neurodevelopmental disorders have challenged clinical genetics for decades, with over 700 genes implicated and many whose function remains unknown. The application of whole-exome sequencing is proving pivotal in closing the genotype/phenotype gap through the discovery of new genes and variants that help to unravel the pathogenic mechanisms driving neuropathogenesis. One such discovery includes TRIO, a gene recently implicated in neurodevelopmental delay. Trio is a Dbl family guanine nucleotide exchange factor (GEF) and a major regulator of neuronal development, controlling actin cytoskeleton dynamics by activating the GTPase Rac1.Methods: Whole-exome sequencing was undertaken on a family presenting with global developmental delay, microcephaly and mild dysmorphism. Father/daughter exome analysis was performed, followed by confirmatory Sanger sequencing and segregation analysis on four individuals. Three further patients were recruited through the deciphering developmental disorders (DDD) study. Functional studies were undertaken using patient-specific Trio protein mutations.Results: We identified a frameshift deletion in TRIO that segregated autosomal dominantly. By scrutinising data from DDD, we further identified three unrelated children with a similar phenotype who harboured de novo missense mutations in TRIO. Biochemical studies demonstrated that in three out of four families, the Trio mutations led to a markedly reduced Rac1 activation.Conclusions: We describe an inherited global developmental delay phenotype associated with a frameshift deletion in TRIO. Additionally, we identify pathogenic de novo missense mutations in TRIO associated with the same consistent phenotype, intellectual disability, microcephaly and dysmorphism with striking digital features. We further functionally validate the importance of the GEF domain in Trio protein function. Our study demonstrates how genomic technologies are yet again proving prolific in diagnosing and advancing the understanding of neurodevelopmental disorders.<br/

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal