DNA-dependent conversion of Oct-1 and Oct-2 into transcriptional repressors by Groucho/TLE

POU domain proteins contain a bipartite DNA-binding element that can confer allosteric control of coactivator recruitment. Dimerization of Oct-1 and Oct-2 on palindromic response elements results in the conformational dependent inclusion or exclusion of the transcriptional coactivator OBF-1. In this paper, we demonstrate that Oct-1 and Oct-2 can function as transcriptional repressors by recruiting and physically interacting with members of the Grg/TLE family of corepressors. In accordance with a model of DNA induced cofactor assembly, and analogous to the recruitment of the OBF-1 coactivator, the different Grg/TLE members can discriminate between both Oct-1 and Oct-2, and the monomeric or dimeric nature of the POU/DNA complex

Cesarean delivery, preterm birth and risk of food allergy : nationwide Swedish cohort study of over 1 million children

Background & Objectives: Little is known about early life risk factors for food allergy in children. We examined the association between perinatal characteristics and future risk of food allergy in offspring. Methods: This nationwide Swedish cohort study of 1,086,378 children born in Sweden in 2001-2012 used prospectively recorded data from health care registers. Using Cox regression, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between perinatal characteristics (e.g. caesarean delivery, preterm birth) and food allergy as defined by diagnoses in the National Patient Register, adjusting for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index and asthma/pulmonary disease). Results: During the 13-year follow-up, 26,732 children (2.5%) were diagnosed with food allergy. Food allergy was positively associated with caesarean delivery (HR=1.21; 95%CI=1.18-1.25), large for gestational age (HR=1.15; 95%CI=1.10-1.19) and low 5-minute Apgar score (HR=1.22, 95CI=1.10-1.36) but negatively associated with very preterm birth (<32 weeks of gestation: HR=0.74; 95%CI=0.56-0.98). No association was found between food allergy and moderately preterm birth, low birth weight or small for gestational age. Risk estimates were similar when the outcome was restricted to two records of diagnosed food allergy. In 1,000 children undergoing caesarean delivery, an extra 5 developed food allergy compared with the reference group, suggesting that 17% of food allergy in children born with caesarean delivery can be explained by this exposure (attributable fraction). Conclusions: Caesarean delivery was associated with increased risk of food allergy, whereas very preterm birth with decreased risk.NoneAccepte

Gene-Environment Interaction in the Onset of Eczema in Infancy: Filaggrin Loss-of-Function Mutations Enhanced by Neonatal Cat Exposure

Background Loss-of-function variants in the gene encoding filaggrin (FLG) are major determinants of eczema. We hypothesized that weakening of the physical barrier in FLG-deficient individuals may potentiate the effect of environmental exposures. Therefore, we investigated whether there is an interaction between FLG loss-of-function mutations with environmental exposures (pets and dust mites) in relation to the development of eczema. Methods and Findings We used data obtained in early life in a high-risk birth cohort in Denmark and replicated the findings in an unselected birth cohort in the United Kingdom. Primary outcome was age of onset of eczema; environmental exposures included pet ownership and mite and pet allergen levels. In Copenhagen(n = 379), FLG mutation increased the risk of eczema during the first year of life (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.27–4.00, p = 0.005), with a further increase in risk related to cat exposure at birth amongst children with FLG mutation (HR 11.11, 95% CI 3.79–32.60, p < 0.0001); dog exposure was moderately protective (HR 0.49, 95% CI 0.24–1.01, p = 0.05), but not related to FLG genotype. In Manchester (n = 503) an independent and significant association of the development of eczema by age 12 mo with FLG genotype was confirmed (HR 1.95, 95% CI 1.13–3.36, p = 0.02). In addition, the risk increased because of the interaction of cat ownership at birth and FLG genotype (HR 3.82, 95% CI 1.35–10.81, p = 0.01), with no significant effect of the interaction with dog ownership (HR 0.59, 95% CI 0.16–2.20, p = 0.43). Mite-allergen had no effects in either cohort. The observed effects were independent of sensitisation. Conclusions We have demonstrated a significant interaction between FLG loss-of-function main mutations (501x and 2282del4) and cat ownership at birth on the development of early-life eczema in two independent birth cohorts. Our data suggest that cat but not dog ownership substantially increases the risk of eczema within the first year of life in children with FLG loss-of-function variants, but not amongst those without. FLG-deficient individuals may need to avoid cats but not dogs in early life

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P-Bonferroni <1.06 x 10(-7)). In additional analyses in 7,278 participants,Peer reviewe

Long-term risks and benefits associated with cesarean delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis

BACKGROUND:Cesarean birth rates continue to rise worldwide with recent (2016) reported rates of 24.5% in Western Europe, 32% in North America, and 41% in South America. The objective of this systematic review is to describe the long-term risks and benefits of cesarean delivery for mother, baby, and subsequent pregnancies. The primary maternal outcome was pelvic floor dysfunction, the primary baby outcome was asthma, and the primary subsequent pregnancy outcome was perinatal death. METHODS AND FINDINGS:Medline, Embase, Cochrane, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases were systematically searched for published studies in human subjects (last search 25 May 2017), supplemented by manual searches. Included studies were randomized controlled trials (RCTs) and large (more than 1,000 participants) prospective cohort studies with greater than or equal to one-year follow-up comparing outcomes of women delivering by cesarean delivery and by vaginal delivery. Two assessors screened 30,327 abstracts. Studies were graded for risk of bias by two assessors using the Scottish Intercollegiate Guideline Network (SIGN) Methodology Checklist and the Risk of Bias Assessment tool for Non-Randomized Studies. Results were pooled in fixed effects meta-analyses or in random effects models when significant heterogeneity was present (I2 ≥ 40%). One RCT and 79 cohort studies (all from high income countries) were included, involving 29,928,274 participants. Compared to vaginal delivery, cesarean delivery was associated with decreased risk of urinary incontinence, odds ratio (OR) 0.56 (95% CI 0.47 to 0.66; n = 58,900; 8 studies) and pelvic organ prolapse (OR 0.29, 0.17 to 0.51; n = 39,208; 2 studies). Children delivered by cesarean delivery had increased risk of asthma up to the age of 12 years (OR 1.21, 1.11 to 1.32; n = 887,960; 13 studies) and obesity up to the age of 5 years (OR 1.59, 1.33 to 1.90; n = 64,113; 6 studies). Pregnancy after cesarean delivery was associated with increased risk of miscarriage (OR 1.17, 1.03 to 1.32; n = 151,412; 4 studies) and stillbirth (OR 1.27, 1.15 to 1.40; n = 703,562; 8 studies), but not perinatal mortality (OR 1.11, 0.89 to 1.39; n = 91,429; 2 studies). Pregnancy following cesarean delivery was associated with increased risk of placenta previa (OR 1.74, 1.62 to 1.87; n = 7,101,692; 10 studies), placenta accreta (OR 2.95, 1.32 to 6.60; n = 705,108; 3 studies), and placental abruption (OR 1.38, 1.27 to 1.49; n = 5,667,160; 6 studies). This is a comprehensive review adhering to a registered protocol, and guidelines for the Meta-analysis of Observational Studies in Epidemiology were followed, but it is based on predominantly observational data, and in some meta-analyses, between-study heterogeneity is high; therefore, causation cannot be inferred and the results should be interpreted with caution. CONCLUSIONS:When compared with vaginal delivery, cesarean delivery is associated with a reduced rate of urinary incontinence and pelvic organ prolapse, but this should be weighed against the association with increased risks for fertility, future pregnancy, and long-term childhood outcomes. This information could be valuable in counselling women on mode of delivery

Associations between Attention-Deficit/Hyperactivity Disorder and various eating disorders: A Swedish nationwide population study using multiple genetically informative approaches

Background Although attention-deficit hyperactivity/impulsivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs (OED, including bulimia nervosa [BN]). Methods We applied different genetically informative designs to register-based information of a Swedish nationwide population (N=3,550,118). We first examined the familial co-aggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores (PRS) and ED symptoms, and between AN PRS and ADHD symptoms, in a genotyped population-based sample (N=13,472). Results Increased risk of all types of EDs was found in individuals with ADHD (any ED: OR [95% CI]=3.97 [3.81-4.14], AN: 2.68 [2.15-2.86], OED: 4.66 [4.47-4.87], BN: 5.01 [4.63-5.41]) and their relatives compared to individuals without ADHD and their relatives. The magnitude of the associations reduced as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with OED (0.37 [0.31-0.42]) than with AN (0.14 [0.05-0.22]). ADHD PRS correlated positively with ED symptom measures overall and sub-scales “drive for thinness” and “body dissatisfaction”, despite small effect sizes. Conclusions We observed stronger genetic association with ADHD for non-AN EDs than AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders

Epstein-barr virus nuclear antigen 1, oct & groucho/TLE in control of promoter regulation

The human herpes virus Epstein-Barr virus (EBV) is carried by approximately 95% of the adult population. It can form a lifelong latent infection in the B-cells by avoiding our immune system. A latent EBV infection is usually asymptomatic but a few EBV associated cancer forms has been described (e.g. Burkitt's lymphoma (BL)). EBV can avoid the immune system by restricting expression of its latent genes. Based on variation in viral gene expression several different latency forms have been described, e.g. latency 111 where all latency genes are expressed and latency 1 (e.g. BL) where only the nuclear protein EBNA l is expressed. EBNA l has three important functions, replication and maintenance of the viral genome and to regulate transcription. In latency 111 cells EBNA l is transcribed from the C promoter (Cp) together with six other proteins (EBNA l -6). The more restricted gene expression pattern in latency 1 cells is associated with a down regulation of the Cp and activity from the Q promoter (Qp) which leads to selective EBNA1 gene transcription. A switch between Cp and Qp usage might be instrumental in driving the host cell between latency forms. This thesis concerns the upstream control of Cp regulation with an emphasis on the interplay between cellular transcription factors and viral proteins. An EBNA1 responsive element called Family of Repeats (FR) is situated upstream of the Cp. EBNA1 can bind to each of the 20 repeats found in FR, thereby activating transcription. We have used various methods to show that the two cellular transcription factors Oct-1 and Oct-2 can bind to the FR sequence in vivo and in vitro and that the binding varies between the different repeats. We also show that binding has an impact on promoter activity in which Oct-2 alone and Oct-1 together with Bob.1 can substitute for the effect of EBNA1 on FR or further enhance the effect of EBNA1. We also describe the finding of a corepressor for Oct-proteins, namely the cellular protein Grg/TLE. The repression was shown to be highly dependent on the sequence to which Oct binds. This finding also applied to FR in EBV. All full-length Grg/TLE proteins as well as the truncated version Grg-5 can repress FR dependent Oct-2 activity. Binding of Grg/TLE to FR was also demonstrated both in vivo and in vitro. Repression by Grg/TLE could be cancelled by EBNA l, as well as the EBNA l induced activity could be repressed by Oct-2 + Grg/TLE

Vad sa du? : En studie av kommunikation med länkar till oro under en fusion.

This thesis aims to explore the area of communication and its links to anxiety. The methods used are interviews in conjunction with a grounded theory approach. We found that there are several different types of misunderstandings that can occur between management and employees, which also cause the level of anxiety felt among the employees to rise. Important aspects to consider for management seem to be to use several communication channels and choose the appropriate channel depending on the content of the message. It is also necessary for management to convey information on the same knowledge level as the employees and to take the interests of the employees into account when deciding what information to give them. To create a positive attitude and to avoid ambiguous messages will also improve communication and lessen the anxiety felt.Denna uppsats avser att undersöka ämnet kommunikation och dess länkar till oro. Den använda metoden är intervjuer i samband med en grounded theory ansats. Vi fann att det är en antal olika typer av missförstånd som kan uppkomma mellan ledningen och de anställda, vilka även leder till att den upplevda oron hos de anställda stiger. Viktiga aspekter för ledningen att tänka på är att använda flera kommunikations kanaler och att välja kanal beroende av meddelandets innehåll. Det är också nödvändigt för ledningen att förmedla information på de anställdas kunskapsnivå och att tänka på vad de anställda kan förväntas vara intresserade av. Att skapa en positiv attityd och att undvika tvetydiga meddelanden kan också förbättra kommunikationen och minska den upplevda oron

Vad sa du? : En studie av kommunikation med länkar till oro under en fusion.

This thesis aims to explore the area of communication and its links to anxiety. The methods used are interviews in conjunction with a grounded theory approach. We found that there are several different types of misunderstandings that can occur between management and employees, which also cause the level of anxiety felt among the employees to rise. Important aspects to consider for management seem to be to use several communication channels and choose the appropriate channel depending on the content of the message. It is also necessary for management to convey information on the same knowledge level as the employees and to take the interests of the employees into account when deciding what information to give them. To create a positive attitude and to avoid ambiguous messages will also improve communication and lessen the anxiety felt.Denna uppsats avser att undersöka ämnet kommunikation och dess länkar till oro. Den använda metoden är intervjuer i samband med en grounded theory ansats. Vi fann att det är en antal olika typer av missförstånd som kan uppkomma mellan ledningen och de anställda, vilka även leder till att den upplevda oron hos de anställda stiger. Viktiga aspekter för ledningen att tänka på är att använda flera kommunikations kanaler och att välja kanal beroende av meddelandets innehåll. Det är också nödvändigt för ledningen att förmedla information på de anställdas kunskapsnivå och att tänka på vad de anställda kan förväntas vara intresserade av. Att skapa en positiv attityd och att undvika tvetydiga meddelanden kan också förbättra kommunikationen och minska den upplevda oron