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

Methods for specifying the target difference in a randomised controlled trial : the Difference ELicitation in TriAls (DELTA) systematic review

Peer reviewedPublisher PD

MICB0106 gene polymorphism is associated with ulcerative colitis in central China

Background: The highly polymorphic nonclassical MHC class I chain-related genes A and B (MICA and MICB) encode stress-inducible glycoproteins expressed on various epithelial cells including intestinal epithelial cells. MICA and MICB gene polymorphisms and expressions are associated with autoimmune diseases but not known in ulcerative colitis (UC). Aims: To investigate the association of MICB exon 2-4 polymorphisms and soluble MICA (sMICA) expression with the susceptibility of UC in central China. Materials and methods: Genomic DNA was isolated from peripheral blood. The allele frequencies of MICB exon 2-4 were genotyped in 105 UC patients and 213 healthy controls by PCR single-stranded conformation polymorphism method. Thirty-two patients and 32 controls were selected for determining serum sMICA expression by ELISA. Results: Allele frequency of MICB0106 was significantly higher in UC patients than in healthy controls (19.0% vs. 8.9%, corrected P (Pc)=0.0006), especially in patients with extensive colitis (24.4% vs. 8.9%, Pc=0.0006), moderate and severe disease (24.1% vs. 8.9%, Pc=0.0006), extraintestinal manifestations (20.5% vs. 8.9%, Pc=0.012), male patients (22.1% vs. 8.0%, Pc=0.006), and patients over the age of 40 years (28.8% vs. 8.3%, Pc=0.0006). The sMICA level was significantly higher in UC than in healthy controls (604.41±480.43 pg/ml vs. 175.37±28.31 pg/ml, P=0.0001) but not associated with the MICB0106 genotypes. Conclusions: Overall, MICB0106 allele was positively associated with UC in the Han Chinese in central China. sMICA was highly expressed in UC but not associated with the MICB0106 genotype

Functional variants in the LRRK2 gene confer shared effects on risk for Crohn's disease and Parkinson's disease

Crohn’s disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the LRRK2 gene that conferred risk for CD (N2081D variant, P = 9.5 × 10−10) or protection from CD (N551K variant, tagging R1398H-associated haplotype, P = 3.3 × 10−8). These variants affected CD age of onset, disease location, LRRK2 activity, and autophagy. Bayesian network analysis of CD patient intestinal tissue further implicated LRRK2 in CD pathogenesis. Analysis of the extended LRRK2 locus in 24,570 CD cases, patients with Parkinson’s disease (PD), and healthy controls revealed extensive pleiotropy, with shared genetic effects between CD and PD in both Ashkenazi Jewish and non-Jewish cohorts. The LRRK2 N2081D CD risk allele is located in the same kinase domain as G2019S, a mutation that is the major genetic cause of familial and sporadic PD. Like the G2019S mutation, the N2081D variant was associated with increased kinase activity, whereas neither N551K nor R1398H variants on the protective haplotype altered kinase activity. We also confirmed that R1398H, but not N551K, increased guanosine triphosphate binding and hydrolyzing enzyme (GTPase) activity, thereby deactivating LRRK2. The presence of shared LRRK2 alleles in CD and PD provides refined insight into disease mechanisms and may have major implications for the treatment of these two seemingly unrelated diseases

Factors associated with disease evolution in Greek patients with inflammatory bowel disease

BACKGROUND: The majority of Crohn's disease patients with B1 phenotype at diagnosis (i.e. non-stricturing non-penetrating disease) will develop over time a stricturing or a penetrating pattern. Conflicting data exist on the rate of proximal disease extension in ulcerative colitis patients with proctitis or left-sided colitis at diagnosis. We aimed to study disease evolution in Crohn's disease B1 patients and ulcerative colitis patients with proctitis and left-sided colitis at diagnosis. METHODS: 116 Crohn's disease and 256 ulcerative colitis patients were followed-up for at least 5 years after diagnosis. Crohn's disease patients were classified according to the Vienna criteria. Data were analysed actuarially. RESULTS: B1 phenotype accounted for 68.9% of Crohn's disease patients at diagnosis. The cumulative probability of change in disease behaviour in B1 patients was 43.6% at 10 years after diagnosis. Active smoking (Hazard Ratio: 3.01) and non-colonic disease (non-L2) (Hazard Ratio: 3.01) were associated with behavioural change in B1 patients. Proctitis and left-sided colitis accounted for 24.2%, and 48.4% of ulcerative colitis patients at diagnosis. The 10 year cumulative probability of proximal disease extension in patients with proctitis and left-sided colitis was 36.8%, and 17.1%, respectively (p: 0.003). Among proctitis patients, proximal extension was more common in non-smokers (Hazard Ratio: 4.39). CONCLUSION: Classification of Crohn's disease patients in B1 phenotype should be considered as temporary. Smoking and non-colonic disease are risk factors for behavioural change in B1 Crohn's disease patients. Proximal extension is more common in ulcerative colitis patients with proctitis than in those with left-sided colitis. Among proctitis patients, proximal extension is more common in non-smokers

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GMCSF

BACKGROUND & AIMS: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects. METHODS: We performed exome-sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls). To validate our findings, we performed genotype analyses of an additional 1515 CD cases and 7052 controls for frameshift mutations in the colony stimulating factor 2 receptor beta common subunit gene (CSF2RB). Intestinal tissues and blood samples were collected from patients with CD; lamina propria leukocytes were isolated and expression of CSF2RB and GMCSF-responsive cells were defined by mass cytometry (CyTOF analysis). Variants of CSF2RB were transfected into HEK293 cells and expression and functions of gene products were compared. RESULTS: In the discovery cohort, we associated CD with a frameshift mutation in CSF2RB (P=8.52x10-4); the finding was validated in the replication cohort (combined P=3.42x10-6). Incubation of intestinal lamina propria leukocytes with GMCSF resulted in high levels of phosphorylation of STAT5 and lesser increases in phosphorylation of ERK and AKT. Cells co-transfected with full-length and mutant forms of CSF2RB had reduced pSTAT5 following stimulation with GMCSF, compared to cells transfected with control CSF2RB, indicating a dominant negative effect of the mutant gene. Monocytes from patients with CD who were heterozygous for the frameshift mutation (6% of CD cases analyzed) had reduced responses to GMCSF and markedly decreased activity of aldehyde dehydrogenase; activity of this enzyme has been associated with immune tolerance. CONCLUSIONS: In a genetic analysis of Ashkenazi Jewish individuals, we associated CD with a frameshift mutation in CSF2RB. Intestinal monocytes from carriers of this mutation had reduced responses to GMCSF, providing an additional mechanism for alterations to the innate immune response in individuals with CD

The impact of training and working conditions on junior doctors' intention to leave clinical practice

Background: The shortage of physicians is an evolving problem throughout the world. In this study we aimed to identify to what extent junior doctors' training and working conditions determine their intention to leave clinical practice after residency training. Methods: A prospective cohort study was conducted in 557 junior doctors undergoing residency training in German hospitals. Self-reported specialty training conditions, working conditions and intention to leave clinical practice were measured over three time points. Scales covering training conditions were assessed by structured residency training, professional support, and dealing with lack of knowledge; working conditions were evaluated by work overload, job autonomy and social support, based on the Demand-Control-Support model. Multivariate ordinal logistic regression analyses with random intercept for longitudinal data were applied to determine the odds ratio of having a higher level of intention to leave clinical practice. Results: In the models that considered training and working conditions separately to predict intention to leave clinical practice we found significant baseline effects and change effects. After modelling training and working conditions simultaneously, we found evidence that the change effect of job autonomy (OR 0.77, p = .005) was associated with intention to leave clinical practice, whereas for the training conditions, only the baseline effects of structured residency training (OR 0.74, p = .017) and dealing with lack of knowledge (OR 0.74, p = .026) predicted intention to leave clinical practice. Conclusions: Junior doctors undergoing specialty training experience high workload in hospital practice and intense requirements in terms of specialty training. Our study indicates that simultaneously improving working conditions over time and establishing a high standard of specialty training conditions may prevent junior doctors from considering leaving clinical practice after residency training

The quest for genetic risk factors for Crohn's disease in the post-GWAS era

Multiple genome-wide association studies (GWASs) and two large scale meta-analyses have been performed for Crohn's disease and have identified 71 susceptibility loci. These findings have contributed greatly to our current understanding of the disease pathogenesis. Yet, these loci only explain approximately 23% of the disease heritability. One of the future challenges in this post-GWAS era is to identify potential sources of the remaining heritability. Such sources may include common variants with limited effect size, rare variants with higher effect sizes, structural variations, or even more complicated mechanisms such as epistatic, gene-environment and epigenetic interactions. Here, we outline potential sources of this hidden heritability, focusing on Crohn's disease and the currently available data. We also discuss future strategies to determine more about the heritability; these strategies include expanding current GWAS, fine-mapping, whole genome sequencing or exome sequencing, and using family-based approaches. Despite the current limitations, such strategies may help to transfer research achievements into clinical practice and guide the improvement of preventive and therapeutic measures