Genomic hotspots for adaptation: the population genetics of Müllerian mimicry in Heliconius erato

This is the final version of the article. Available from the publisher via the DOI in this record.Wing pattern evolution in Heliconius butterflies provides some of the most striking examples of adaptation by natural selection. The genes controlling pattern variation are classic examples of Mendelian loci of large effect, where allelic variation causes large and discrete phenotypic changes and is responsible for both convergent and highly divergent wing pattern evolution across the genus. We characterize nucleotide variation, genotype-by-phenotype associations, linkage disequilibrium (LD), and candidate gene expression patterns across two unlinked genomic intervals that control yellow and red wing pattern variation among mimetic forms of Heliconius erato. Despite very strong natural selection on color pattern, we see neither a strong reduction in genetic diversity nor evidence for extended LD across either patterning interval. This observation highlights the extent that recombination can erase the signature of selection in natural populations and is consistent with the hypothesis that either the adaptive radiation or the alleles controlling it are quite old. However, across both patterning intervals we identified SNPs clustered in several coding regions that were strongly associated with color pattern phenotype. Interestingly, coding regions with associated SNPs were widely separated, suggesting that color pattern alleles may be composed of multiple functional sites, conforming to previous descriptions of these loci as "supergenes." Examination of gene expression levels of genes flanking these regions in both H. erato and its co-mimic, H. melpomene, implicate a gene with high sequence similarity to a kinesin as playing a key role in modulating pattern and provides convincing evidence for parallel changes in gene regulation across co-mimetic lineages. The complex genetic architecture at these color pattern loci stands in marked contrast to the single casual mutations often identified in genetic studies of adaptation, but may be more indicative of the type of genetic changes responsible for much of the adaptive variation found in natural populations.Funding: Funding for this study was provided by National Science Foundation grants to WOM (DEB-0715096 and IBN-0344705) and BAC (DEB-0513424). Funding for work on H. melpomene came from a BBSRC grant to CDJ and RHf-C (011845). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Pathways to health: a framework for health-focused research and practice

Public health research and practice is faced with three problems: 1) a focus on disease instead of health, 2) consideration of risk factor/disease relationships one at a time, and 3) attention to individuals with limited regard for the communities in which they live. We propose a framework for health-focused research and practice. This framework encompasses individual and community pathways to health while incorporating the dynamics of context and overall population vulnerability and resilience. Individual pathways to health may differ, but commonalities will exist. By understanding these commonalities, communities can work to support health-promoting pathways in addition to removing barriers. The perspective afforded by viewing health as a dynamic process instead of as a collection of risk factors and diseases expands the number of approaches to improving health globally. Using this approach, multidisciplinary research teams working with active community participants have the potential to reshape health and intervention sciences

Identification and characterization of a novel non-structural protein of bluetongue virus

Bluetongue virus (BTV) is the causative agent of a major disease of livestock (bluetongue). For over two decades, it has been widely accepted that the 10 segments of the dsRNA genome of BTV encode for 7 structural and 3 non-structural proteins. The non-structural proteins (NS1, NS2, NS3/NS3a) play different key roles during the viral replication cycle. In this study we show that BTV expresses a fourth non-structural protein (that we designated NS4) encoded by an open reading frame in segment 9 overlapping the open reading frame encoding VP6. NS4 is 77–79 amino acid residues in length and highly conserved among several BTV serotypes/strains. NS4 was expressed early post-infection and localized in the nucleoli of BTV infected cells. By reverse genetics, we showed that NS4 is dispensable for BTV replication in vitro, both in mammalian and insect cells, and does not affect viral virulence in murine models of bluetongue infection. Interestingly, NS4 conferred a replication advantage to BTV-8, but not to BTV-1, in cells in an interferon (IFN)-induced antiviral state. However, the BTV-1 NS4 conferred a replication advantage both to a BTV-8 reassortant containing the entire segment 9 of BTV-1 and to a BTV-8 mutant with the NS4 identical to the homologous BTV-1 protein. Collectively, this study suggests that NS4 plays an important role in virus-host interaction and is one of the mechanisms played, at least by BTV-8, to counteract the antiviral response of the host. In addition, the distinct nucleolar localization of NS4, being expressed by a virus that replicates exclusively in the cytoplasm, offers new avenues to investigate the multiple roles played by the nucleolus in the biology of the cell

The effects of migrant remittances on population–environment dynamics in migrant origin areas: international migration, fertility, and consumption in highland Guatemala

International migration impacts origin regions in many ways. As examples, remittances from distant migrants may alter consumption patterns within sending communities, while exposure to different cultural norms may alter other behaviors. This paper combines these insights to offer a unique lens on migration’s environmental impact. From an environmental perspective, we ask the following question: is the likely rise in consumption brought about by remittances counterbalanced by a reduction in fertility in migrant households following exposure to lower fertility cultures? Based on ethnographic case studies in two western highland Guatemalan communities, we argue that the near-term rise in consumption due to remittances is not counterbalanced by rapid decline in migrant household fertility. However, over time, the environmental cost of consumption may be mitigated at the community level through diffusion of contraception and family planning norms yielding lower family size

General practitioners apply the usual care for shoulder complaints better than expected – analysis of videotaped consultations

BACKGROUND: The education and activation program (EAP) is a newly developed intervention to prevent the development of chronic shoulder complaints (SCs). Trained general practitioners (GPs) administer the EAP. The EAP addresses inadequate cognitions and maladaptive behavior related to the SCs. The effect of the EAP is evaluated in a randomized clinical trial. The aim of the present study is to use videotaped consultations to study (1) the performance of trained GPs administering the EAP and (2) the presence of key features of the EAP already embedded in usual care (UC). METHODS: Five trained GPs were videotaped while treating a standardized patient with EAP. Additionally, five GPs administering UC were videotaped. Two blinded observers evaluated the videotapes in relation to key features of the EAP which were scored on the EAP checklist. RESULTS: The mean total score on the EAP checklist was 4.7 (SD = 2.9) for the UC group and 7.1 (SD = 2.1) for the EAP group. Neither group reached a score higher than 8, which was considered to reflect an acceptable number of key EAP features. CONCLUSION: Our comparison of the presence of key features of EAP shows that the UC and EAP groups differed less than was expected. GPs in the UC group performed above expectation, with a mean total score of 4.7. Moreover, the low number of key features present in the EAP group may very well have led to a reduced effectiveness of the EAP. The results of this study can be used to optimize the training of GPs using the EAP

Latent Epstein-Barr Virus Can Inhibit Apoptosis in B Cells by Blocking the Induction of NOXA Expression

Latent Epstein-Barr virus (EBV) has been shown to protect Burkitt's lymphoma-derived B cells from apoptosis induced by agents that cause damage to DNA, in the context of mutant p53. This protection requires expression of the latency-associated nuclear proteins EBNA3A and EBNA3C and correlates with their ability to cooperate in the repression of the gene encoding the pro-apoptotic, BH3-only protein BIM. Here we confirm that latent EBV in B cells also inhibits apoptosis induced by two other agents – ionomycin and staurosporine – and show that these act by a distinct pathway that involves a p53-independent increase in expression of another pro-apoptotic, BH3-only protein, NOXA. Analyses employing a variety of B cells infected with naturally occurring EBV or B95.8 EBV-BAC recombinant mutants indicated that the block to NOXA induction does not depend on the well-characterized viral latency-associated genes (EBNAs 1, 2, 3A, 3B, 3C, the LMPs or the EBERs) or expression of BIM. Regulation of NOXA was shown to be at least partly at the level of mRNA and the requirement for NOXA to induce cell death in this context was demonstrated by NOXA-specific shRNA-mediated depletion experiments. Although recombinant EBV with a deletion removing the BHRF1 locus – that encodes the BCL2-homologue BHRF1 and three microRNAs – partially abrogates protection against ionomycin and staurosporine, the deletion has no effect on the EBV-mediated block to NOXA accumulation

A prospective multi-center cohort study of acute non-displaced fractures of the scaphoid: operative versus non-operative treatment [NCT00205985]

BACKGROUND: Acute scaphoid fractures are common in active adults and do lead to reasonable time lost to work. One important goal of treatment is early return to work or sport. On this background, the adequate treatment of non-displaced acute scaphoid fractures is still under discussion. The aim of this study is to compare time to return to previous activity level comparing surgical versus non-surgical treatment of non-displaced acute scaphoid fractures. METHODS/DESIGN: The study is designed as a non-randomized multiple center cohort study including 12 sites in Germany and Austria. The inclusion period is planned to be 12 months with a follow up of 6 months. Allocation to operative or non-operative treatment is choosen by the patient together with his treating surgeon. The primary outcome is time to return to previous activity level adapted for loading of the wrist in daily life as measured by a newly developed questionnaire (PLDL-wrist). Factors identified a priori to be associated with the outcome, e.g., poverty status, age, education, smoking status, gender, and occupation, are measured to ensure adequate control for their potential confounding effects. DISCUSSION: The rationale and the design of a multiple center cohort study are presented. As it is not considered feasible to randomize patients in this study, potential confounding effects need to be controlled adequately

Bacterial Effector Binding to Ribosomal Protein S3 Subverts NF-κB Function

Enteric bacterial pathogens cause food borne disease, which constitutes an enormous economic and health burden. Enterohemorrhagic Escherichia coli (EHEC) causes a severe bloody diarrhea following transmission to humans through various means, including contaminated beef and vegetable products, water, or through contact with animals. EHEC also causes a potentially fatal kidney disease (hemolytic uremic syndrome) for which there is no effective treatment or prophylaxis. EHEC and other enteric pathogens (e.g., enteropathogenic E. coli (EPEC), Salmonella, Shigella, Yersinia) utilize a type III secretion system (T3SS) to inject virulence proteins (effectors) into host cells. While it is known that T3SS effectors subvert host cell function to promote diarrheal disease and bacterial transmission, in many cases, the mechanisms by which these effectors bind to host proteins and disrupt the normal function of intestinal epithelial cells have not been completely characterized. In this study, we present evidence that the E. coli O157:H7 nleH1 and nleH2 genes encode T3SS effectors that bind to the human ribosomal protein S3 (RPS3), a subunit of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) transcriptional complexes. NleH1 and NleH2 co-localized with RPS3 in the cytoplasm, but not in cell nuclei. The N-terminal region of both NleH1 and NleH2 was required for binding to the N-terminus of RPS3. NleH1 and NleH2 are autophosphorylated Ser/Thr protein kinases, but their binding to RPS3 is independent of kinase activity. NleH1, but not NleH2, reduced the nuclear abundance of RPS3 without altering the p50 or p65 NF-κB subunits or affecting the phosphorylation state or abundance of the inhibitory NF-κB chaperone IκBα NleH1 repressed the transcription of a RPS3/NF-κB-dependent reporter plasmid, but did not inhibit the transcription of RPS3-independent reporters. In contrast, NleH2 stimulated RPS3-dependent transcription, as well as an AP-1-dependent reporter. We identified a region of NleH1 (N40-K45) that is at least partially responsible for the inhibitory activity of NleH1 toward RPS3. Deleting nleH1 from E. coli O157:H7 produced a hypervirulent phenotype in a gnotobiotic piglet model of Shiga toxin-producing E. coli infection. We suggest that NleH may disrupt host innate immune responses by binding to a cofactor of host transcriptional complexes

Short and long term effects of a lifestyle intervention for construction workers at risk for cardiovascular disease: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The prevalence of overweight and elevated cardiovascular disease (CVD) risk among workers in the construction industry is relatively high. Improving lifestyle lowers CVD risk and may have work-related benefits. The purpose of the study was to evaluate the effects on physical activity (PA), diet, and smoking of a lifestyle intervention consisting of individual counseling among male workers in the construction industry with an elevated risk of cardiovascular disease (CVD).</p> <p>Methods</p> <p>In a randomized controlled trial including 816 male blue- and white-collar workers in the construction industry with an elevated risk of CVD, usual care was compared to a 6-month lifestyle intervention. The intervention consisted of individual counseling using motivational interviewing techniques, and was delivered by an occupational physician or occupational nurse. In three face to face and four telephone contacts, the participant's risk profile, personal determinants, and barriers for behavior change were discussed, and personal goals were set. Participants chose to aim at either diet and PA, or smoking. Data were collected at baseline and after six and 12 months, by means of a questionnaire. To analyse the data, linear and logistic regression analyses were performed.</p> <p>Results</p> <p>The intervention had a statistically significant beneficial effect on snack intake (β-1.9, 95%CI -3.7; -0.02) and fruit intake (β 1.7, 95%CI 0.6; 2.9) at 6 months. The effect on snack intake was sustained until 12 months; 6 months after the intervention had ended (β -1.9, 95%CI -3.6; -0.2). The intervention effects on leisure time PA and metabolic equivalent-minutes were not statistically significant. The beneficial effect on smoking was statistically significant at 6 (OR smoking 0.3, 95%CI 0.1;0.7), but not at 12 months (OR 0.8, 95%CI 0.4; 1.6).</p> <p>Conclusions</p> <p>Beneficial effects on smoking, fruit, and snack intake can be achieved by an individual-based lifestyle intervention among male construction workers with an elevated risk of CVD. Future research should be done on strategies to improve leisure time PA and on determinants of maintenance of changed behavior. Considering the rising prevalence of unhealthy lifestyle and CVD, especially in the aging population, implementation of this intervention in the occupational health care setting is recommended.</p> <p>Trial registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN60545588">ISRCTN60545588</a></p

Nuclear Factor Kappa B Activation Occurs in the Amnion Prior to Labour Onset and Modulates the Expression of Numerous Labour Associated Genes

Background: Prior to the onset of human labour there is an increase in the synthesis of prostaglandins, cytokines and chemokines in the fetal membranes, particular the amnion. This is associated with activation of the transcription factor nuclear factor kappa B (NFkB). In this study we characterised the level of NFkB activity in amnion epithelial cells as a measure of amnion activation in samples collected from women undergoing caesarean section at 39 weeks gestation prior to the onset of labour. Methodology/Principal Findings: We found that a proportion of women exhibit low or moderate NFkB activity while other women exhibit high levels of NFkB activity (n = 12). This activation process does not appear to involve classical pathways of NFkB activation but rather is correlated with an increase in nuclear p65-Rel-B dimers. To identify the full range of genes upregulated in association with amnion activation, microarray analysis was performed on carefully characterised nonactivated amnion (n = 3) samples and compared to activated samples (n = 3). A total of 919 genes were upregulated in response to amnion activation including numerous inflammatory genes such cyclooxygenase-2 (COX-2, 44-fold), interleukin 8 (IL-8, 6-fold), IL-1 receptor accessory protein (IL-1RAP, 4.5-fold), thrombospondin 1 (TSP-1, 3-fold) and, unexpectedly, oxytocin receptor (OTR, 24-fold). Ingenuity Pathway Analysis of the microarray data reveal the two main gene networks activated concurrently with amnion activation are i) cell death, cancer and morphology and ii) cell cycle, embryoni