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Offering lower-energy food swaps to customers of online supermarkets could help to decrease energy (kcal) purchased and consumed. However, acceptance rates of such food swaps tend to be low. This study aimed to see whether framing lower-energy food swaps in terms of cost savings or social norms could improve likelihood of acceptance relative to framing swaps in terms of health benefits. Participants (n = 900) were asked to shop from a 12-item shopping list in a simulation online supermarket. When a target high-energy food was identified in the shopping basket at check-out, one or two lower-energy foods would be suggested as an alternative (a "swap"). Participants were randomised to only see messages emphasising health benefits (fewer calories), cost benefits (lower price) or social norms (others preferred this product). Data were analysed for 713 participants after exclusions. Participants were offered a mean of 3.17 swaps (SD = 1.50), and 12.91% of swaps were accepted (health = 14.31%, cost = 11.49%, social norms = 13.18%). Swap acceptance was not influenced by the specific swap frame used (all p > .170). Age was significantly and positively associated with swap acceptance (b = 0.02, SE = 0.00, p < .001), but was also associated with smaller decreases in energy change (b = 0.46, SE = .19, p = .014). Overall, offering swaps reduced both energy (kcal) per product (b = -9.69, SE = 4.07, p = .017) and energy (kcal) per shopping basket (t712 = 11.09, p < .001) from pre- to post-intervention. Offering lower-energy food swaps could be a successful strategy for reducing energy purchased by customers of online supermarkets. Future research should explore alternative solutions for increasing acceptance rates of such swaps.

Social ostracism triggers an increase in affiliative behaviours. One such behaviour is the rapid copying of others' facial expressions, called facial mimicry. Insofar, it remains unknown how individual differences in intrinsic affiliation motivation regulate responses to social ostracism during early development. We examined children's facial mimicry following ostracism as modulated by individual differences in the affiliation motivation, expressed in their attachment tendencies. Resistant and avoidant tendencies are characterized by high and low affiliation motivation, and were hypothesized to lead to facial mimicry enhancement or suppression towards an ostracizing partner, respectively. Following an ostracism manipulation in which children played a virtual game (Cyberball) with an includer and an excluder peer, mimicry of the two peers' happy and sad facial expressions was recorded with electromyography (EMG). Attachment was assessed via parent-report questionnaire. We found that 5-year-olds smiled to sad facial expressions of the excluder peer, while they showed no facial reactions for the includer peer. Neither resistant nor avoidant tendencies predicted facial mimicry to the excluder peer. Yet, securely attached children smiled towards the excluder peer, when sad facial expressions were displayed. In conclusion, these findings suggest a modulation of facial reactions following ostracism by early attachment.

Previous work indicated that the incidence of travellers' diarrhoea (TD) is higher in soldiers of British origin, when compared to soldiers of Nepalese descent (Gurkhas). We hypothesise that the composition of the gut microbiota may be a contributing factor in the risk of developing TD in soldiers of British origin. This study aimed to characterise the gut microbial composition of Gurkha and non-Gurkha soldiers of the British Army. Recruitment of 38 soldiers (n = 22 Gurkhas, n = 16 non-Gurkhas) and subsequent stool collection, enabled shotgun metagenomic sequencing-based analysis of the gut microbiota. The microbiota of Gurkhas had significantly (P < 0.05) lower diversity, for both Shannon and Simpson diversity indices, using species level markers than the gut microbiota of non-Gurkha soldiers. Non-metric Multidimensional Scaling (NMDS) of the Bray-Curtis distance matrix revealed a significant difference in the composition of the gut microbiota between Gurkhas and non-Gurkha soldiers, at both the species level (P = 0.0178) and the genus level (P = 0.0483). We found three genera and eight species that were significantly enriched in the non-Gurkha group and one genus (Haemophilus) and one species (Haemophilus parainfluenzae) which were enriched in the Gurkha group. The difference in the microbiota composition between Gurkha soldiers and soldiers of British origin may contribute to higher colonization resistance against diarrhoeal pathogens in the former group. Our findings may enable further studies into interventions that modulate the gut microbiota of soldiers to prevent TD during deployment. [ABSTRACT FROM AUTHOR]

[This corrects the article DOI: 10.1371/journal.pone.0218676.].

From early in life, facial mimicry represents an important example of implicit non-verbal communication. Facial mimicry is conceived of as the automatic tendency to mimic another person's facial expressions and is thought to serve as a social glue among interaction partners. Although in adults mimicry has been shown to be moderated by the social context and one's needs to affiliate with others, evidence from behavioural mimicry studies suggest that 3-year-olds do not yet show sensitivity to social dynamics. Here, we examined whether attachment tendencies, as a proxy for interindividual differences in affiliation motivation, modulates facial mimicry in 3-year-olds. Resistant and avoidant insecure attachment tendencies are characterized by high and low affiliation motivation, respectively, and these were hypothesized to lead to either enhancement or suppression of mimicry. Additionally, we hypothesized that these effects will be moderated by inhibitory control skills. Facial mimicry of happy and sad expressions was recorded with electromyography (EMG), attachment tendencies were assessed with a parent-report questionnaire and inhibitory control with the gift delay task. The final sample consisted of 42 children, with overall scores suggesting secure attachment. Our findings revealed that 3-year-olds mimicked happy and sad facial expressions. Moreover, resistant tendencies predicted enhanced sad but not happy facial mimicry, whereas avoidant tendencies were not significantly related to mimicry. These effects were not moderated by inhibitory control skills. In conclusion, these findings provide the first evidence for the modulation of mimicry by attachment tendencies and their underlying motivation for affiliation in young children, specifically for negatively-valenced emotional expressions.

Childhood abuse is a major public health problem that has been linked to depression in adulthood. Although different types of childhood abuse often co-occur, few studies have examined their unique impact on negative mental health outcomes. Most studies have focused solely on the consequences of childhood physical or sexual abuse; however, it has been suggested that childhood emotional abuse is more strongly related to depression. It remains unclear which underlying psychological processes mediate the effect of childhood emotional abuse on depressive symptoms. In a cross-sectional study in 276 female college students, multiple linear regression analyses were used to determine whether childhood emotional abuse, physical abuse, and sexual abuse were independently associated with depressive symptoms, emotion dysregulation, and interpersonal problems. Subsequently, OLS regression analyses were used to determine whether emotion dysregulation and interpersonal problems mediate the relationship between childhood emotional abuse and depressive symptoms. Of all types of abuse, only emotional abuse was independently associated with depressive symptoms, emotion dysregulation, and interpersonal problems. The effect of childhood emotional abuse on depressive symptoms was mediated by emotion dysregulation and the following domains of interpersonal problems: cold/distant and domineering/controlling. The results of the current study indicate that detection and prevention of childhood emotional abuse deserves attention from Child Protective Services. Finally, interventions that target emotion regulation skills and interpersonal skills may be beneficial in prevention of depression.

Lipopolysaccharide (LPS) expressed on the surface of Gram-negative bacteria activates pro-inflammatory pathways, dys-regulates the function of endometrial cells and is a key player in the mechanisms involved in endometritis. This study aimed to investigate the effects of LPS on bovine endometrial epithelial cells (bEEC) from whole transcriptome with a special focus on genes involved in embryo-maternal interactions. Following in vitro culture, bEEC from three cows were exposed to 0, 2, and 8 μg/mL LPS for 24h. RNA samples extracted at 0 and 24 hours were analyzed by RNA sequencing (RNA-seq). At 24h, 2035 differentially expressed genes (DEGs) were identified between controls and samples treated with 2 μg/mL LPS. Gene ontology analysis showed that over-expressed DEGs were associated to immune response, response to stress and external stimuli, catalytic activity, and cell cycle. Genes associated with cell membrane and cell adhesion pathways were under-expressed. LPS induced changes in expression of specific genes related to embryo-maternal interactions including under-expression of eight members of the cadherin superfamily, over-expression of six members of the mucin family, and differential expression of a large set of genes binding the above molecules and of more than 20 transcripts coding for cytokines and their receptors. Type I interferon-τ dependent genes were also over-expressed. From a sub-set of 19 genes, (biological replicates of bEEC from cows taken at time 6 (n = 3), 24 (n = 6) and 48 hours (n = 3), and 2 technical replicates per sample) differential gene expression was confirmed by RT2-qPCR (r2 between fold changes at 24 hours by RT2-qPCR and RNA-seq = 0.97). These results indicate that LPS affects the function of bEEC in many ways by differential transcription, glycolytic metabolism and oxidative stress. Many transcriptomic signatures related to implantation and embryo maternal interactions were strongly affected by LPS. These results pave the way for further studies to investigate the duration of these changes and their possible impact on endometrial function and fertility.

BackgroundAnxiety and depressive disorders are increasingly being viewed as chronic conditions with fluctuating symptom levels. Relapse prevention programmes are needed to increase self-management and prevent relapse. Fine-tuning relapse prevention programmes to the needs of patients may increase uptake and effectiveness.Materials and methodsA discrete choice experiment (DCE) was conducted amongst patients with a partially or fully remitted anxiety or depressive disorder. Patients were presented 20 choice tasks with two hypothetical treatment scenarios for relapse prevention, plus a "no treatment" option. Each treatment scenario was based on seven attributes of a hypothetical but realistic relapse prevention programme. Attributes considered professional contact frequency, treatment type, delivery mode, programme flexibility, a personal relapse prevention plan, time investment and effectiveness. Choice models were estimated to analyse the data.ResultsA total of 109 patients with a partially or fully remitted anxiety or depressive disorder completed the DCE. Attributes with the strongest impact on choice were high effectiveness, regular contact with a professional, low time investment and the inclusion of a personal prevention plan. A high heterogeneity in preferences was observed, related to both clinical and demographic characteristics: for example, a higher number of previous treatment episodes was related to a preference for a higher frequency of contact with a professional, while younger age was related to a stronger preference for high effectiveness.ConclusionsThis study using a DCE provides insights into preferences for a relapse prevention programme for anxiety and depressive disorders that can be used to guide the development of such a programme.

ObjectiveTo systematically review the literature on the metabolic costs of activities of daily living (ADL) in persons with a lower limb amputation (LLA).Data sourcesA literature search was undertaken in the Pubmed, Embase, CINAHL, CENTRAL, and PsycINFO databases using keywords and synonyms for LLA, metabolic costs, and ADL. The last search was performed on November 29th, 2017.Study selectionStudies were included if they met the following 2 criteria: participants were adults with a (unilateral or bilateral) LLA and metabolic costs were measured while participants performed a physical activity or ADL.Data extraction and synthesisData of 1,912 participants from 61 studies were included in the systematic review and meta-analysis. The studies used different terms to describe metabolic costs. Participants were recruited in different settings, relatively healthy, with few comorbidities. Limited data were available on metabolic costs of other activities than walking with a prosthesis. A linear mixed model analysis was performed based on the means reported, with study as unit of analysis and test results of different groups and measurement conditions as repeated measures within the unit of analysis. Predictors entered in the analysis were e.g. level and reason of amputation, age, weight, and height. During walking, oxygen consumption (ml O2/kg/min) and heart rate (beats/min) increased with a higher walking speed and a more proximal amputation. Additionally, oxygen consumption was determined by the interaction terms walking speed x amputation level and walking speed squared. Heart rate was determined by the interaction term walking speed squared.ConclusionDuring walking, oxygen consumption (ml O2/kg/min) and heart rate (beats/min) increased with a higher walking speed and a more proximal amputation. Data on metabolic costs of other activities were limited. The poor quality of the studies and the relatively healthy participants limited generalizability of the results of the meta-analysis.

BACKGROUND:Major depression is a prevalent mental disorder with a high risk of relapse or recurrence. Only few studies have focused on the cost-effectiveness of interventions aimed at the prevention of relapse or recurrence of depression in primary care. AIM:To evaluate the cost-effectiveness of a supported Self-help Preventive Cognitive Therapy (S-PCT) added to treatment-as-usual (TAU) compared with TAU alone for patients with a history of depression, currently in remission. METHODS:An economic evaluation alongside a multi-center randomised controlled trial was performed (n = 248) over a 12-month follow-up. Outcomes included relapse or recurrence of depression and quality-adjusted-life-years (QALYs) based on the EuroQol-5D. Analyses were performed from both a societal and healthcare perspective. Missing data were imputed using multiple imputations. Uncertainty was estimated using bootstrapping and presented using the cost-effectiveness plane and the Cost-Effectiveness Acceptability Curve (CEAC). Cost estimates were adjusted for baseline costs. RESULTS:S-PCT statistically significantly decreased relapse or recurrence by 15% (95%CI 3;28) compared to TAU. Mean total societal costs were €2,114 higher (95%CI -112;4261). From a societal perspective, the ICER for relapse or recurrence was 13,515. At a Willingness To Pay (WTP) of 22,000 €/recurrence prevented, the probability that S-PCT is cost-effective, in comparison with TAU, is 80%. The ICER for QALYs was 63,051. The CEA curve indicated that at a WTP of 30,000 €/QALY gained, the probability that S-PCT is cost-effective compared to TAU is 21%. CONCLUSIONS:Though ultimately depending on the WTP of decision makers, we expect that for both relapse or recurrence and QALYs, S-PCT cannot be considered cost-effective compared to TAU.

Despite emergent progress in many fields of bionics, a functional Bionic Voice prosthesis for laryngectomy patients (larynx amputees) has not yet been achieved, leading to a lifetime of vocal disability for these patients. This study introduces a novel framework of Pneumatic Bionic Voice Prostheses as an electronic adaptation of the Pneumatic Artificial Larynx (PAL) device. The PAL is a non-invasive mechanical voice source, driven exclusively by respiration with an exceptionally high voice quality, comparable to the existing gold standard of Tracheoesophageal (TE) voice prosthesis. Following PAL design closely as the reference, Pneumatic Bionic Voice Prostheses seem to have a strong potential to substitute the existing gold standard by generating a similar voice quality while remaining non-invasive and non-surgical. This paper designs the first Pneumatic Bionic Voice prosthesis and evaluates its onset and offset control against the PAL device through pre-clinical trials on one laryngectomy patient. The evaluation on a database of more than five hours of continuous/isolated speech recordings shows a close match between the onset/offset control of the Pneumatic Bionic Voice and the PAL with an accuracy of 98.45 ±0.54%. When implemented in real-time, the Pneumatic Bionic Voice prosthesis controller has an average onset/offset delay of 10 milliseconds compared to the PAL. Hence it addresses a major disadvantage of previous electronic voice prostheses, including myoelectric Bionic Voice, in meeting the short time-frames of controlling the onset/offset of the voice in continuous speech.

During adult interactions, behavioral mimicry, the implicit copying of an interaction partner's postures and mannerisms, communicates liking and affiliation. While this social behavior likely develops during early childhood, it is unclear which factors contribute to its emergence. Here, the roles of inhibitory control and social understanding on 5-year-olds' behavioral mimicry were investigated. Following a social manipulation in which one experimenter shared a sticker with the child and the other experimenter kept two stickers for herself, children watched a video in which these experimenters each told a story. During this story session, children in the experimental group (n = 28) observed the experimenters perform face and hand rubbing behaviors whereas the control group (n = 23) did not see these behaviors. Children's inhibitory control was assessed using the day-night task and their social understanding was measured through a parental questionnaire. Surprisingly, group-level analyses revealed that the experimental group performed the behaviors significantly less than the control group (i.e. a negative mimicry effect) for both the sticker-sharer and sticker-keeper. Yet, the hypothesized effects of inhibitory control and social understanding were found. Inhibitory control predicted children's selective mimicry of the sticker-keeper versus sticker-sharer and children's overall mimicry was correlated with social understanding. These results provide the first indications to suggest that factors of social and cognitive development dynamically influence the emergence and specificity of behavioral mimicry during early childhood.

Study of disease in the past can help illuminate patterns of human health, disease, and aging in the present. As average human life expectancy and incidence of chronic disease have increased in the last century, efforts to understand this epidemiologic shift have led to more investigation of healthy aging. Using osteological and radiological methods of analysis, this study examined 212 mostly nineteenth century adult skeletons from the crypt of St. Bride's in London, in order to investigate the relationship between age-at-death, sex, and number of lesions observed in bone. Lesions were classified into macro-level categories according to the Rapid Method for Recording Human Skeletal Data, and the correlation between age group and number of lesions in each category, as well as the total number of lesions, were analyzed. Correlations between age-at-death and the number and type of lesions were compared across both methods of analysis. A greater total number of lesions and a greater number of types of lesions was observed for the osteologically analyzed data, compared to the radiologically analyzed data. Correlations between age-at-death and specific pathology groups were in general weak, though stronger for the osteologically analyzed data. For each method of analysis, there were statistically significant differences between the total number of lesions and age group, with total number of lesions increasing with age, regardless of method of analysis. Joint and metabolic lesions were the most significant predictors of age-at-death. The correlations between total lesions observed and age-at-death were similar for radiologically and osteologically analyzed data, for the same set of bones. This suggests that, for the bones analyzed, while the number of lesions recorded differed according to method of analysis, the relationship between overall observed lesion burden and age-at-death was similar for both osteological and radiological analysis.

[This corrects the article DOI: 10.1371/journal.pone.0162866.].

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named 'bovine neonatal pancytopenia' (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0-280.1). This was also the case for the practices of feeding calves colostrum from the calf's own dam (OR 2.0; 95% CI: 1.1-3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9-8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves.

In order to predict the features of non-raiding human warfare in small-scale, socially stratified societies, we study a coalitionary model of war that assumes that individuals participate voluntarily because their decisions serve to maximize fitness. Individual males join the coalition if war results in a net economic and thus fitness benefit. Within the model, viable offensive war ensues if the attacking coalition of males can overpower the defending coalition. We assume that the two groups will eventually fuse after a victory, with ranks arranged according to the fighting abilities of all males and that the new group will adopt the winning group's skew in fitness payoffs. We ask whether asymmetries in skew, group size and the amount of resources controlled by a group affect the likelihood of successful war. The model shows, other things being equal, that (i) egalitarian groups are more likely to defeat their more despotic enemies, even when these are stronger, (ii) defection to enemy groups will be rare, unless the attacked group is far more despotic than the attacking one, and (iii) genocidal war is likely under a variety of conditions, in particular when the group under attack is more egalitarian. This simple optimality model accords with several empirically observed correlations in human warfare. Its success underlines the important role of egalitarianism in warfare.

Pharmacogenomics aims to correlate inter-individual differences of drug efficacy and/or toxicity with the underlying genetic composition, particularly in genes encoding for protein factors and enzymes involved in drug metabolism and transport. In several European populations, particularly in countries with lower income, information related to the prevalence of pharmacogenomic biomarkers is incomplete or lacking. Here, we have implemented the microattribution approach to assess the pharmacogenomic biomarkers allelic spectrum in 18 European populations, mostly from developing European countries, by analyzing 1,931 pharmacogenomics biomarkers in 231 genes. Our data show significant inter-population pharmacogenomic biomarker allele frequency differences, particularly in 7 clinically actionable pharmacogenomic biomarkers in 7 European populations, affecting drug efficacy and/or toxicity of 51 medication treatment modalities. These data also reflect on the differences observed in the prevalence of high-risk genotypes in these populations, as far as common markers in the CYP2C9, CYP2C19, CYP3A5, VKORC1, SLCO1B1 and TPMT pharmacogenes are concerned. Also, our data demonstrate notable differences in predicted genotype-based warfarin dosing among these populations. Our findings can be exploited not only to develop guidelines for medical prioritization, but most importantly to facilitate integration of pharmacogenomics and to support pre-emptive pharmacogenomic testing. This may subsequently contribute towards significant cost-savings in the overall healthcare expenditure in the participating countries, where pharmacogenomics implementation proves to be cost-effective.

Non-human primates face major environmental changes due to increased human impacts all over the world. Although some species are able to survive in certain landscapes with anthropogenic impact, their long-term viability and fitness may be decreased due to chronic stress. Here we assessed long-term stress levels through cortisol analysis in chimpanzee hair obtained from sleeping nests in northwestern Uganda, in order to estimate welfare in the context of ecotourism, forest fragmentation with human-wildlife conflicts, and illegal logging with hunting activity (albeit not of primates), compared with a control without human contact or conflict. Concerning methodological issues, season [F(2,129) = 37.4, p < 0.0001, r2 = 0.18] and the age of nests [F(2,178) = 20.3, p < 0.0001, r2 = 0.11] significantly predicted hair cortisol concentrations (HCC). With regard to effects of anthropogenic impacts, our results neither showed elevation of HCC due to ecotourism, nor due to illegal logging compared to their control groups. We did, however, find significantly increased HCC in the fragment group compared to chimpanzees living in a nearby intact forest [F(1,88) = 5.0, p = 0.03, r2 = 0.20]. In conclusion, our results suggest that hair cortisol analysis is a powerful tool that can help understanding the impact of anthropogenic disturbances on chimpanzee well-being and could be applied to other great ape species.

It is well known that signals encoded by mechanoreceptors facilitate precise object manipulation in humans. It is therefore of interest to study signals encoded by the mechanoreceptors because this will contribute further towards the understanding of fundamental sensory mechanisms that are responsible for coordinating force components during object manipulation. From a practical point of view, this may suggest strategies for designing sensory-controlled biomedical devices and robotic manipulators. We use a two-stage nonlinear decoding paradigm to reconstruct the force stimulus given signals from slowly adapting type one (SA-I) tactile afferents. First, we describe a nonhomogeneous Poisson encoding model which is a function of the force stimulus and the force's rate of change. In the decoding phase, we use a recursive nonlinear Bayesian filter to reconstruct the force profile, given the SA-I spike patterns and parameters described by the encoding model. Under the current encoding model, the mode ratio of force to its derivative is: 1.26 to 1.02. This indicates that the force derivative contributes significantly to the rate of change to the SA-I afferent spike modulation. Furthermore, using recursive Bayesian decoding algorithms is advantageous because it can incorporate past and current information in order to make predictions--consistent with neural systems--with little computational resources. This makes it suitable for interfacing with prostheses.

Calcium-imaging is a sensitive method for monitoring calcium dynamics during neuronal activity. As intracellular calcium concentration is correlated to physiological and pathophysiological activity of neurons, calcium imaging with fluorescent indicators is one of the most commonly used techniques in neuroscience today. Current methodologies for loading calcium dyes into the tissue require prolonged incubation time (45-150 min), in addition to dissection and recovery time after the slicing procedure. This prolonged incubation curtails experimental time, as tissue is typically maintained for 6-8 hours after slicing. Using a recently introduced recovery chamber that extends the viability of acute brain slices to more than 24 hours, we tested the effectiveness of calcium AM staining following long incubation periods post cell loading and its impact on the functional properties of calcium signals in acute brain slices and wholemount retinae. We show that calcium dyes remain within cells and are fully functional >24 hours after loading. Moreover, the calcium dynamics recorded >24 hrs were similar to the calcium signals recorded in fresh tissue that was incubated for 24hrs after dissection. These methods will not only extend experimental time for those using acute neuronal tissue, but also may reduce the number of animals required to complete experimental goals.

Realistic appraisal of paleoclimatic information obtained from a particular location requires accurate knowledge of its paleolatitude defined relative to the Earth's spin-axis. This is crucial to, among others, correctly assess the amount of solar energy received at a location at the moment of sediment deposition. The paleolatitude of an arbitrary location can in principle be reconstructed from tectonic plate reconstructions that (1) restore the relative motions between plates based on (marine) magnetic anomalies, and (2) reconstruct all plates relative to the spin axis using a paleomagnetic reference frame based on a global apparent polar wander path. Whereas many studies do employ high-quality relative plate reconstructions, the necessity of using a paleomagnetic reference frame for climate studies rather than a mantle reference frame appears under-appreciated. In this paper, we briefly summarize the theory of plate tectonic reconstructions and their reference frames tailored towards applications of paleoclimate reconstruction, and show that using a mantle reference frame, which defines plate positions relative to the mantle, instead of a paleomagnetic reference frame may introduce errors in paleolatitude of more than 15° (>1500 km). This is because mantle reference frames cannot constrain, or are specifically corrected for the effects of true polar wander. We used the latest, state-of-the-art plate reconstructions to build a global plate circuit, and developed an online, user-friendly paleolatitude calculator for the last 200 million years by placing this plate circuit in three widely used global apparent polar wander paths. As a novelty, this calculator adds error bars to paleolatitude estimates that can be incorporated in climate modeling. The calculator is available at www.paleolatitude.org. We illustrate the use of the paleolatitude calculator by showing how an apparent wide spread in Eocene sea surface temperatures of southern high latitudes may be in part explained by a much wider paleolatitudinal distribution of sites than previously assumed.

Coxiella burnetii is a Gram-negative, obligate intracellular bacterium and the causative agent of Q fever. Infections are usually acquired after inhalation of contaminated particles, where C. burnetii infects its cellular target cells, alveolar macrophages. Respiratory pathogens encounter the C-type lectin surfactant protein D (SP-D) during the course of natural infection. SP-D is a component of the innate immune response in the lungs and other mucosal surfaces. Many Gram-negative pulmonary pathogens interact with SP-D, which can cause aggregation, bactericidal effects and aid in bacterial clearance. Here we show that SP-D binds to C. burnetii in a calcium-dependent manner with no detectable bacterial aggregation or bactericidal effects. Since SP-D interactions with bacteria often alter macrophage interactions, it was determined that SP-D treatment resulted in a significant decrease in C. burnetii interactions to a mouse alveolar macrophage model cell line MH-S indicating SP-D causes a significant decrease in phagocytosis. The ability of SP-D to modulate macrophage activation by C. burnetii was tested and it was determined that SP-D does not alter the correlates measured for macrophage activation. Taken together these studies support those demonstrating limited activation of alveolar macrophages with C. burnetii and demonstrate interactions with SP-D participate in reduction of phagocyte attachment and phagocytosis.

Sex differences in immatures predict behavioural differences in adulthood in many mammal species. Because most studies have focused on sex differences in social interactions, little is known about possible sex differences in 'preparation' for adult life with regards to tool use skills. We investigated sex and age differences in object manipulation in immature apes. Chimpanzees use a variety of tools across numerous contexts, whereas bonobos use few tools and none in foraging. In both species, a female bias in adult tool use has been reported. We studied object manipulation in immature chimpanzees at Kalinzu (Uganda) and bonobos at Wamba (Democratic Republic of Congo). We tested predictions of the 'preparation for tool use' hypothesis. We confirmed that chimpanzees showed higher rates and more diverse types of object manipulation than bonobos. Against expectation, male chimpanzees showed higher object manipulation rates than females, whereas in bonobos no sex difference was found. However, object manipulation by male chimpanzees was play-dominated, whereas manipulation types of female chimpanzees were more diverse (e.g., bite, break, carry). Manipulation by young immatures of both species was similarly dominated by play, but only in chimpanzees did it become more diverse with age. Moreover, in chimpanzees, object types became more tool-like (i.e., sticks) with age, further suggesting preparation for tool use in adulthood. The male bias in object manipulation in immature chimpanzees, along with the late onset of tool-like object manipulation, indicates that not all (early) object manipulation (i.e., object play) in immatures prepares for subsistence tool use. Instead, given the similarity with gender differences in human children, object play may also function in motor skill practice for male-specific behaviours (e.g., dominance displays). In conclusion, even though immature behaviours almost certainly reflect preparation for adult roles, more detailed future work is needed to disentangle possible functions of object manipulation during development.

Recent advances in training deep (multi-layer) architectures have inspired a renaissance in neural network use. For example, deep convolutional networks are becoming the default option for difficult tasks on large datasets, such as image and speech recognition. However, here we show that error rates below 1% on the MNIST handwritten digit benchmark can be replicated with shallow non-convolutional neural networks. This is achieved by training such networks using the 'Extreme Learning Machine' (ELM) approach, which also enables a very rapid training time (∼ 10 minutes). Adding distortions, as is common practise for MNIST, reduces error rates even further. Our methods are also shown to be capable of achieving less than 5.5% error rates on the NORB image database. To achieve these results, we introduce several enhancements to the standard ELM algorithm, which individually and in combination can significantly improve performance. The main innovation is to ensure each hidden-unit operates only on a randomly sized and positioned patch of each image. This form of random 'receptive field' sampling of the input ensures the input weight matrix is sparse, with about 90% of weights equal to zero. Furthermore, combining our methods with a small number of iterations of a single-batch backpropagation method can significantly reduce the number of hidden-units required to achieve a particular performance. Our close to state-of-the-art results for MNIST and NORB suggest that the ease of use and accuracy of the ELM algorithm for designing a single-hidden-layer neural network classifier should cause it to be given greater consideration either as a standalone method for simpler problems, or as the final classification stage in deep neural networks applied to more difficult problems.

During autumn in the temperate zone of both the new and old world, bats of many species assemble at underground sites in a behaviour known as swarming. Autumn swarming behaviour is thought to primarily serve as a promiscuous mating system, but may also be related to the localization and assessment of hibernacula. Bats subsequently make use of the same underground sites during winter hibernation, however it is currently unknown if the assemblages that make use of a site are comparable across swarming and hibernation seasons. Our purpose was to characterize the bat assemblages found at five underground sites during both the swarming and the hibernation season and compare the assemblages found during the two seasons both across sites and within species. We found that the relative abundance of individual species per site, as well as the relative proportion of a species that makes use of each site, were both significantly correlated between the swarming and hibernation seasons. These results suggest that swarming may indeed play a role in the localization of suitable hibernation sites. Additionally, these findings have important conservation implications, as this correlation can be used to improve monitoring of underground sites and predict the importance of certain sites for rare and cryptic bat species.

Every person carries a vast repertoire of CD4+ T-helper cells and CD8+ cytotoxic T cells for a healthy immune system. Somatic VDJ recombination at genomic loci that encode the T-cell receptor (TCR) is a key step during T-cell development, but how a single T cell commits to become either CD4+ or CD8+ is poorly understood. To evaluate the influence of TCR sequence variation on CD4+/CD8+ lineage commitment, we sequenced rearranged TCRs for both α and β chains in naïve T cells isolated from healthy donors and investigated gene segment usage and recombination patterns in CD4+ and CD8+ T-cell subsets. Our data demonstrate that most V and J gene segments are strongly biased in the naïve CD4+ and CD8+ subsets with some segments increasing the odds of being CD4+ (or CD8+) up to five-fold. These V and J gene associations are highly reproducible across individuals and independent of classical HLA genotype, explaining ~11% of the observed variance in the CD4+ vs. CD8+ propensity. In addition, we identified a strong independent association of the electrostatic charge of the complementarity determining region 3 (CDR3) in both α and β chains, where a positively charged CDR3 is associated with CD4+ lineage and a negatively charged CDR3 with CD8+ lineage. Our findings suggest that somatic variation in different parts of the TCR influences T-cell lineage commitment in a predominantly additive fashion. This notion can help delineate how certain structural features of the TCR-peptide-HLA complex influence thymic selection.

The aim of this study was to estimate the quantity of antibiotics and classes of antibiotics used in the small ruminant industry in the Netherlands in 2011 and 2012. Twelve large veterinary practices, located throughout the Netherlands were selected for this study. All small ruminant farms associated with these practices that had complete records on the quantity of antibiotics prescribed were included. The veterinary practices provided data on all antibiotics prescribed, and the estimated animal used daily dose of antibiotics per year (AUDD/Y) was calculated for each farm. The median AUDD/Y in small ruminant farms was zero in both years (mean 0.60 in 2011, and 0.62 in 2012). The largest quantity of antibiotic use was observed in the professional goat industry (herds of ≥32 goats) with a median AUDD/Y of 1.22 in 2011 and 0.73 in 2012. In the professional sheep industry (flocks of ≥32 sheep), the median AUDD/Y was 0 in 2011 and 0.10 in 2012. In the small scale industry (flocks or herds of

In Northwestern Europe, an epizootic outbreak of congenital malformations in newborn lambs due to infection with Schmallenberg virus (SBV) started at the end of 2011. The objectives of this study were to describe clinical symptoms of SBV infection, the effect of infection on mortality rates, and reproductive performance in sheep, as well as to identify and quantify flock level risk factors for SBV infections resulting in malformations in newborn lambs. A case-control study design was used, with 93 case flocks that had notified malformed lambs and 84 control flocks with no such lambs. Overall animal seroprevalence in case flocks was estimated at 82.0% (95% CI: 74.3-87.8), and was not significantly different from the prevalence in control flocks being 76.4% (95% CI: 67.2-83.6). The percentages of stillborn lambs or lambs that died before weaning, repeat breeders, and lambs with abnormal suckling behaviour were significantly higher in case flocks compared to control flocks. However, effect of SBV infection on mortality rates and reproductive performance seemed to be limited. Multivariable analysis showed that sheep flocks with an early start of the mating season, i.e. before August 2011 (OR = 33.1; 95% CI: 10.0-109.8) and in August 2011 (OR = 8.2; 95% CI: 2.7-24.6) had increased odds of malformations in newborn lambs caused by SBV compared to sheep flocks with a start of the mating season in October 2011. Other flock-level risk factors for malformations in newborn lambs were purchase of silage (OR 5.0; 95% CI: 1.7-15.0) and flocks with one or more dogs (OR = 3.3; 95% CI: 1.3-8.3). Delaying mating until October could be a potential preventive measure for naïve animals to reduce SBV induced losses. As duration of immunity after infection with SBV is expected to last for several years, future SBV induced congenital malformations are mainly expected in offspring of early mated seronegative animals.

An early diagnosis of Intensive Care Unit-acquired weakness (ICU-AW) using muscle strength assessment is not possible in most critically ill patients. We hypothesized that development of ICU-AW can be predicted reliably two days after ICU admission, using patient characteristics, early available clinical parameters, laboratory results and use of medication as parameters.Newly admitted ICU patients mechanically ventilated ≥2 days were included in this prospective observational cohort study. Manual muscle strength was measured according to the Medical Research Council (MRC) scale, when patients were awake and attentive. ICU-AW was defined as an average MRC score

Mobile HIV screening may facilitate early HIV diagnosis. Our objective was to examine the cost-effectiveness of adding a mobile screening unit to current medical facility-based HIV testing in Cape Town, South Africa.We used the Cost Effectiveness of Preventing AIDS Complications International (CEPAC-I) computer simulation model to evaluate two HIV screening strategies in Cape Town: 1) medical facility-based testing (the current standard of care) and 2) addition of a mobile HIV-testing unit intervention in the same community. Baseline input parameters were derived from a Cape Town-based mobile unit that tested 18,870 individuals over 2 years: prevalence of previously undiagnosed HIV (6.6%), mean CD4 count at diagnosis (males 423/µL, females 516/µL), CD4 count-dependent linkage to care rates (males 31%-58%, females 49%-58%), mobile unit intervention cost (includes acquisition, operation and HIV test costs, $29.30 per negative result and $31.30 per positive result). We conducted extensive sensitivity analyses to evaluate input uncertainty. Model outcomes included site of HIV diagnosis, life expectancy, medical costs, and the incremental cost-effectiveness ratio (ICER) of the intervention compared to medical facility-based testing. We considered the intervention to be "very cost-effective" when the ICER was less than South Africa's annual per capita Gross Domestic Product (GDP) ($8,200 in 2012). We projected that, with medical facility-based testing, the discounted (undiscounted) HIV-infected population life expectancy was 132.2 (197.7) months; this increased to 140.7 (211.7) months with the addition of the mobile unit. The ICER for the mobile unit was $2,400/year of life saved (YLS). Results were most sensitive to the previously undiagnosed HIV prevalence, linkage to care rates, and frequency of HIV testing at medical facilities.The addition of mobile HIV screening to current testing programs can improve survival and be very cost-effective in South Africa and other resource-limited settings, and should be a priority.

Two vector borne diseases, caused by the Bluetongue and Schmallenberg viruses respectively, have emerged in the European ruminant populations since 2006. Several diseases are transmitted by the same vectors and could emerge in the future. Syndromic surveillance, which consists in the routine monitoring of indicators for the detection of adverse health events, may allow an early detection. Milk yield is routinely measured in a large proportion of dairy herds and could be incorporated as an indicator in a surveillance system. However, few studies have evaluated continuous indicators for syndromic surveillance. The aim of this study was to develop a framework for the quantification of both disease characteristics and model predictive abilities that are important for a continuous indicator to be sensitive, timely and specific for the detection of a vector-borne disease emergence. Emergences with a range of spread characteristics and effects on milk production were simulated. Milk yields collected monthly in 48 713 French dairy herds were used to simulate 576 disease emergence scenarios. First, the effect of disease characteristics on the sensitivity and timeliness of detection were assessed: Spatio-temporal clusters of low milk production were detected with a scan statistic using the difference between observed and simulated milk yields as input. In a second step, the system specificity was evaluated by running the scan statistic on the difference between observed and predicted milk yields, in the absence of simulated emergence. The timeliness of detection depended mostly on how easily the disease spread between and within herds. The time and location of the emergence or adding random noise to the simulated effects had a limited impact on the timeliness of detection. The main limitation of the system was the low specificity i.e. the high number of clusters detected from the difference between observed and predicted productions, in the absence of disease.

The process of eukaryotic transcription initiation involves the assembly of basal transcription factor complexes on the gene promoter. The recruitment of TFIID is an early and important step in this process. Gene promoters contain distinct DNA sequence elements and are marked by the presence of post-translationally modified nucleosomes. The contributions of these individual features for TFIID recruitment remain to be elucidated. Here, we use immobilized reconstituted promoter nucleosomes, conventional biochemistry and quantitative mass spectrometry to investigate the influence of distinct histone modifications and functional DNA-elements on the binding of TFIID. Our data reveal synergistic effects of H3K4me3, H3K14ac and a TATA box sequence on TFIID binding in vitro. Stoichiometry analyses of affinity purified human TFIID identified the presence of a stable dimeric core. Several peripheral TAFs, including those interacting with distinct promoter features, are substoichiometric yet present in substantial amounts. Finally, we find that the TAF3 subunit of TFIID binds to poised promoters in an H3K4me3-dependent manner. Moreover, the PHD-finger of TAF3 is important for rapid induction of target genes. Thus, fine-tuning of TFIID engagement on promoters is driven by synergistic contacts with both DNA-elements and histone modifications, eventually resulting in a high affinity interaction and activation of transcription.

BackgroundHIV counseling and testing may serve as an entry point for non-communicable disease screening.ObjectivesTo determine the yield of newly-diagnosed HIV, tuberculosis (TB) symptoms, diabetes and hypertension, and to assess CD4 count testing, linkage to care as well as correlates of linkage and barriers to care from a mobile testing unit.MethodsA mobile unit provided screening for HIV, TB symptoms, diabetes and hypertension in Cape Town, South Africa between March 2010 and September 2011. The yield of newly-diagnosed cases of these conditions was measured and clients were followed-up between January and November 2011 to assess linkage. Linkage to care was defined as accessing care within one, three or six months post-HIV diagnosis (dependent on CD4 count) and one month post-diagnosis for other conditions. Clinical and socio-demographic correlates of linkage to care were evaluated using Poisson regression and barriers to care were determined.ResultsOf 9,806 clients screened, the yield of new diagnoses was: HIV (5.5%), TB suspects (10.1%), diabetes (0.8%) and hypertension (58.1%). Linkage to care for HIV-infected clients, TB suspects, diabetics and hypertensives was: 51.3%, 56.7%, 74.1% and 50.0%. Only disclosure of HIV-positive status to family members or partners (RR=2.6, 95% CI: 1.04-6.3, p=0.04) was independently associated with linkage to HIV care. The main barrier to care reported by all groups was lack of time to access a clinic.ConclusionScreening for HIV, TB symptoms and hypertension at mobile units in South Africa has a high yield but inadequate linkage. After-hours and weekend clinics may overcome a major barrier to accessing care.

Enterococcus faecium is a gut commensal of humans and animals. In the intestinal tract, E. faecium will have access to a wide variety of carbohydrates, including maltodextrins and maltose, which are the sugars that result from the enzymatic digestion of starch by host-derived and microbial amylases. In this study, we identified the genetic determinants for maltodextrin utilization of E. faecium E1162. We generated a deletion mutant of the mdxABCD-pulA gene cluster that is homologous to maltodextrin uptake genes in other Gram-positive bacteria, and a deletion mutant of the mdxR gene, which is predicted to encode a LacI family regulator of mdxABCD-pulA. Both mutations impaired growth on maltodextrins but had no effect on the growth on maltose and glucose. Comparative transcriptome analysis showed that eight genes (including mdxABCD-pulA) were expressed at significantly lower levels in the isogenic ΔmdxR mutant strain compared to the parental strain when grown on maltose. Quantitative real-time RT-PCR confirmed the results of transcriptome analysis and showed that the transcription of a putative maltose utilization gene cluster is induced in a semi-defined medium supplemented with maltose but is not regulated by MdxR. Understanding the maltodextrin metabolism of E. faecium could yield novel insights into the underlying mechanisms that contribute to the gut commensal lifestyle of E. faecium.

The ability to plan for the future beyond immediate needs would be adaptive to many animal species, but is widely thought to be uniquely human. Although studies in captivity have shown that great apes are capable of planning for future needs, it is unknown whether and how they use this ability in the wild. Flanged male Sumatran orangutans (Pongo abelii) emit long calls, which females use to maintain earshot associations with them. We tested whether long calls serve to communicate a male's ever-changing predominant travel direction to facilitate maintaining these associations. We found that the direction in which a flanged male emits his long calls predicts his subsequent travel direction for many hours, and that a new call indicates a change in his main travel direction. Long calls given at or near the night nest indicate travel direction better than random until late afternoon on the next day. These results show that male orangutans make their travel plans well in advance and announce them to conspecifics. We suggest that such a planning ability is likely to be adaptive for great apes, as well as in other taxa.

Nowadays, Enterococcus faecium is one of the leading nosocomial pathogens worldwide. Strains causing clinical infections or hospital outbreaks are enriched in the enterococcal surface protein (Esp) encoding ICEEfm1 mobile genetic element. Previous studies showed that Esp is involved in biofilm formation, endocarditis and urinary tract infections. In this study, we characterized the role of the putative AraC type of regulator (locus tag EfmE1162_2351), which we renamed ebrB and which is, based on the currently available whole genome sequences, always located upstream of the esp gene, and studied its role in Esp surface exposure during growth. A markerless deletion mutant of ebrB resulted in reduced esp expression and complete abolishment of Esp surface exposure, while Esp cell-surface exposure was restored when this mutant was complemented with an intact copy of ebrB. This demonstrates a role for EbrB in esp expression. However, during growth, ebrB expression levels did not change over time, while an increase in esp expression at both RNA and protein level was observed during mid-log and late-log phase. These results indicate the existence of a secondary regulation system for esp, which might be an unknown quorum sensing system as the enhanced esp expression seems to be cell density dependent. Furthermore, we determined that esp is part of an operon of at least 3 genes putatively involved in biofilm formation. A semi-static biofilm model revealed reduced biofilm formation for the EbrB deficient mutant, while dynamics of biofilm formation using a flow cell system revealed delayed biofilm formation in the ebrB mutant. In a mouse intestinal colonization model the ebrB mutant was less able to colonize the gut compared to wild-type strain, especially in the small intestine. These data indicate that EbrB positively regulates the esp operon and is implicated in biofilm formation and intestinal colonization.

Bovine neonatal pancytopenia (BNP), a high fatality condition causing haemorrhages in calves aged less than 4 weeks, was first reported in 2007 in Germany and subsequently observed at low incidence in other European countries and New Zealand. A multi-country matched case-control study was conducted in 2011 to identify calf-level risk factors for BNP. 405 BNP cases were recruited from 330 farms in Belgium, France, Germany and the Netherlands by laboratory confirmation of farmer-reported cases. Up to four calves of similar age from the same farm were selected as controls (1154 calves). Risk factor data were collected by questionnaire. Multivariable modelling using conditional logistic regression indicated that PregSure®BVD (PregSure, Pfizer Animal Health) vaccination of the dam was strongly associated with BNP cases (adjusted matched Odds Ratio - amOR 17.8 first lactation dams; 95% confidence interval - ci 2.4, 134.4; p = 0.005), and second or more lactation PregSure-vaccinated dams were more likely to have a case than first lactation vaccinated dams (amOR 2.2 second lactation; ci 1.1, 4.3; p = 0.024; amOR 5.3 third or more lactation; ci 2.9, 9.8; p =

Desktop virtual environments (VEs) are increasingly deployed to study the effects of environmental qualities and interventions on human behavior and safety related concerns in built environments. For these applications it is essential that users appraise the affective qualities of the VE similar to those of its real world counterpart. Previous studies have shown that factors like simulated lighting, sound and dynamic elements all contribute to the affective appraisal of a desktop VE. Since ambient odor is known to affect the affective appraisal of real environments, and has been shown to increase the sense of presence in immersive VEs, it may also be an effective tool to tune the affective appraisal of desktop VEs. This study investigated if exposure to ambient odor can modulate the affective appraisal of a desktop VE with signs of public disorder.Participants explored a desktop VE representing a suburban neighborhood with signs of public disorder (neglect, vandalism and crime), while being exposed to either room air or subliminal levels of unpleasant (tar) or pleasant (cut grass) ambient odor. Whenever they encountered signs of disorder they reported their safety related concerns and associated affective feelings.Signs of crime in the desktop VE were associated with negative affective feelings and concerns for personal safety and personal property. However, there was no significant difference between reported safety related concerns and affective connotations in the control (no-odor) and in each of the two ambient odor conditions.Ambient odor did not affect safety related concerns and affective connotations associated with signs of disorder in the desktop VE. Thus, semantic congruency between ambient odor and a desktop VE may not be sufficient to influence its affective appraisal, and a more realistic simulation in which simulated objects appear to emit scents may be required to achieve this goal.

Because conflicts among social group members are inevitable, their management is crucial for group stability. The rarest and most interesting form of conflict management is policing, i.e., impartial interventions by bystanders, which is of considerable interest due to its potentially moral nature. Here, we provide descriptive and quantitative data on policing in captive chimpanzees. First, we report on a high rate of policing in one captive group characterized by recently introduced females and a rank reversal between two males. We explored the influence of various factors on the occurrence of policing. The results show that only the alpha and beta males acted as arbitrators using manifold tactics to control conflicts, and that their interventions strongly depended on conflict complexity. Secondly, we compared the policing patterns in three other captive chimpanzee groups. We found that although rare, policing was more prevalent at times of increased social instability, both high-ranking males and females performed policing, and conflicts of all sex-dyad combinations were policed. These results suggest that the primary function of policing is to increase group stability. It may thus reflect prosocial behaviour based upon "community concern." However, policing remains a rare behaviour and more data are needed to test the generality of this hypothesis.

BackgroundSeveral studies suggested great ape cultures, arguing that human cumulative culture presumably evolved from such a foundation. These focused on conspicuous behaviours, and showed rich geographic variation, which could not be attributed to known ecological or genetic differences. Although geographic variation within call types (accents) has previously been reported for orang-utans and other primate species, we examine geographic variation in the presence/absence of discrete call types (dialects). Because orang-utans have been shown to have geographic variation that is not completely explicable by genetic or ecological factors we hypothesized that this will be similar in the call domain and predict that discrete call type variation between populations will be found.Methodology/principal findingsWe examined long-term behavioural data from five orang-utan populations and collected fecal samples for genetic analyses. We show that there is geographic variation in the presence of discrete types of calls. In exactly the same behavioural context (nest building and infant retrieval), individuals in different wild populations customarily emit either qualitatively different calls or calls in some but not in others. By comparing patterns in call-type and genetic similarity, we suggest that the observed variation is not likely to be explained by genetic or ecological differences.Conclusion/significanceThese results are consistent with the potential presence of 'call cultures' and suggest that wild orang-utans possess the ability to invent arbitrary calls, which spread through social learning. These findings differ substantially from those that have been reported for primates before. First, the results reported here are on dialect and not on accent. Second, this study presents cases of production learning whereas most primate studies on vocal learning were cases of contextual learning. We conclude with speculating on how these findings might assist in bridging the gap between vocal communication in non-human primates and human speech.

BACKGROUND: Ampicillin-resistant Enterococcus faecium (ARE) has emerged as a nosocomial pathogen. Here, we quantified ARE carriage in different community sources and determined genetic relatedness with hospital ARE. METHODS AND RESULTS: ARE was recovered from rectal swabs of 24 of 79 (30%) dogs, 11 of 85 (13%) cats and 0 of 42 horses and from 3 of 40 (8%) faecal samples of non-hospitalized humans receiving amoxicillin. Multi-locus Sequence Typing revealed 21 sequence types (STs), including 5 STs frequently associated with hospital-acquired infections. Genes previously found to be enriched in hospital ARE, such as IS16, orf903, orf905, orf907, were highly prevalent in community ARE (≥79%), while genes with a proposed role in pathogenesis, such as esp, hyl and ecbA, were found rarely (≤5%) in community isolates. Comparative genome analysis of 2 representative dog isolates revealed that the dog strain of ST192 was evolutionarily closely linked to two previously sequenced hospital ARE, but had, based on gene content, more genes in common with the other, evolutionarily more distantly related, dog strain (ST266). CONCLUSION: ARE were detected in dogs, cats and sporadically in healthy humans, with evolutionary linkage to hospital ARE. Yet, their accessory genome has diversified, probably as a result of niche adaptation.

Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.

Bornean orang-utans experienced a major demographic decline and local extirpations during the Pleistocene and Holocene due to climate change, the arrival of modern humans, of farmers and recent commercially-driven habitat loss and fragmentation. The recent loss of habitat and its dramatic fragmentation has affected the patterns of genetic variability and differentiation among the remaining populations and increased the extinction risk of the most isolated ones. However, the contribution of recent demographic events to such genetic patterns is still not fully clear. Indeed, it can be difficult to separate the effects of recent anthropogenic fragmentation from the genetic signature of prehistoric demographic events. Here, we investigated the genetic structure and population size dynamics of orang-utans from different sites. Altogether 126 individuals were analyzed and a full-likelihood Bayesian approach was applied. All sites exhibited clear signals of population decline. Population structure is known to generate spurious bottleneck signals and we found that it does indeed contribute to the signals observed. However, population structure alone does not easily explain the observed patterns. The dating of the population decline varied across sites but was always within the 200-2000 years period. This suggests that in some sites at least, orang-utan populations were affected by demographic events that started before the recent anthropogenic effects that occurred in Borneo. These results do not mean that the recent forest exploitation did not leave its genetic mark on orang-utans but suggests that the genetic pool of orang-utans is also impacted by more ancient events. While we cannot identify the main cause for this decline, our results suggests that the decline may be related to the arrival of the first farmers or climatic events, and that more theoretical work is needed to understand how multiple demographic events impact the genome of species and how we can assess their relative contributions.

The geographic distribution of Bornean orang-utans and its overlap with existing land-use categories (protected areas, logging and plantation concessions) is a necessary foundation to prioritize conservation planning. Based on an extensive orang-utan survey dataset and a number of environmental variables, we modelled an orang-utan distribution map. The modelled orang-utan distribution map covers 155,106 km(2) (21% of Borneo's landmass) and reveals four distinct distribution areas. The most important environmental predictors are annual rainfall and land cover. The overlap of the orang-utan distribution with land-use categories reveals that only 22% of the distribution lies in protected areas, but that 29% lies in natural forest concessions. A further 19% and 6% occurs in largely undeveloped oil palm and tree plantation concessions, respectively. The remaining 24% of the orang-utan distribution range occurs outside of protected areas and outside of concessions. An estimated 49% of the orang-utan distribution will be lost if all forest outside of protected areas and logging concessions is lost. To avoid this potential decline plantation development in orang-utan habitats must be halted because it infringes on national laws of species protection. Further growth of the plantation sector should be achieved through increasing yields in existing plantations and expansion of new plantations into areas that have already been deforested. To reach this goal a large scale island-wide land-use masterplan is needed that clarifies which possible land uses and managements are allowed in the landscape and provides new standardized strategic conservation policies. Such a process should make much better use of non-market values of ecosystem services of forests such as water provision, flood control, carbon sequestration, and sources of livelihood for rural communities. Presently land use planning is more driven by vested interests and direct and immediate economic gains, rather than by approaches that take into consideration social equity and environmental sustainability.

BACKGROUND: The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC. METHODS: Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined. RESULTS: At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups. CONCLUSIONS: Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients. TRIAL REGISTRATION: TrialRegister.nl NTR2009.

In 5-40% of respiratory infections in children, the diagnostics remain negative, suggesting that the patients might be infected with a yet unknown pathogen. Virus discovery cDNA-AFLP (VIDISCA) is a virus discovery method based on recognition of restriction enzyme cleavage sites, ligation of adaptors and subsequent amplification by PCR. However, direct discovery of unknown pathogens in nasopharyngeal swabs is difficult due to the high concentration of ribosomal RNA (rRNA) that acts as competitor. In the current study we optimized VIDISCA by adjusting the reverse transcription enzymes and decreasing rRNA amplification in the reverse transcription, using hexamer oligonucleotides that do not anneal to rRNA. Residual cDNA synthesis on rRNA templates was further reduced with oligonucleotides that anneal to rRNA but can not be extended due to 3'-dideoxy-C6-modification. With these modifications >90% reduction of rRNA amplification was established. Further improvement of the VIDISCA sensitivity was obtained by high throughput sequencing (VIDISCA-454). Eighteen nasopharyngeal swabs were analysed, all containing known respiratory viruses. We could identify the proper virus in the majority of samples tested (11/18). The median load in the VIDISCA-454 positive samples was 7.2 E5 viral genome copies/ml (ranging from 1.4 E3-7.7 E6). Our results show that optimization of VIDISCA and subsequent high-throughput-sequencing enhances sensitivity drastically and provides the opportunity to perform virus discovery directly in patient material.

To measure HIV prevalence and uptake of HIV counseling and testing (HCT) in a peri-urban South African community. To assess predictors for previous HIV testing and the association between the yield of previously undiagnosed HIV and time of last negative HIV testA random sample of 10% of the adult population (≥15 years) were invited to attend a mobile HCT service. Study procedures included a questionnaire, HIV testing and CD4 counts. Predictors for previous testing were determined using a binominal model.1,144 (88.0%) of 1,300 randomly selected individuals participated in the study. 71.0% (68.3-73.6) had previously had an HIV test and 37.5% (34.6-40.5) had tested in the past 12 months. Men, migrants and older (>35 years) and younger (

Various studies have shown that the population densities of a number of forest vertebrates, such as orangutans, are higher on Sumatra than Borneo, and that several species exhibit smaller body sizes on Borneo than Sumatra and mainland Southeast Asia. It has been suggested that differences in forest fruit productivity between the islands can explain these patterns. Here we present a large-scale comparison of forest fruit production between the islands to test this hypothesis.Data on fruit production were collated from Sumatran and Bornean sites. At six sites we assessed fruit production in three forest types: riverine, peat swamp and dryland forests. We compared fruit production using time-series models during different periods of overall fruit production and in different tree size classes. We examined overall island differences and differences specifically for fruiting period and tree size class. The results of these analyses indicate that overall the Sumatran forests are more productive than those on Borneo. This difference remains when each of the three forest types (dryland, riverine, and peat) are examined separately. The difference also holds over most tree sizes and fruiting periods.Our results provide strong support for the hypothesis that forest fruit productivity is higher on Sumatra than Borneo. This difference is most likely the result of the overall younger and more volcanic soils on Sumatra than Borneo. These results contribute to our understanding of the determinants of faunal density and the evolution of body size on both islands.