The Immunomodulator 1-Methyltryptophan Drives Tryptophan Catabolism Toward the Kynurenic Acid Branch

Background: Animal model studies revealed that the application of 1-methyltryptophan (1-MT), a tryptophan (TRP) analog, surprisingly increased plasma levels of the TRP metabolite, kynurenic acid (KYNA). Under inflammatory conditions, KYNA has been shown to mediate various immunomodulatory effects. Therefore, the present study aims to confirm and clarify the effects of 1-MT on TRP metabolism in mice as well as in humans. Methods: Splenocytes from Balb/C or indoleamine 2,3-dioxygenase knockout (IDO1−/−) mice or whole human blood were stimulated with 1-MT for 6, 24, or 36 h. C57BL/6 mice received 1-MT in drinking water for 5 days. Cell-free supernatants and plasma were analyzed for TRP and its metabolites by tandem mass spectrometry (MS/MS). Results: 1-MT treatment induced an increase in TRP and its metabolite, KYNA in Balb/C, IDO−/− mice, and in human blood. Concurrently, the intermediate metabolite kynurenine (KYN), as well as the KYN/TRP ratio, were reduced after 1-MT treatment. The effects of 1-MT on TRP metabolites were similar after the in vivo application of 1-MT to C57BL/6 mice. Conclusions: The data indicate that 1-MT induced an increase of KYNA ex vivo and in vivo confirming previously described results. Furthermore, the results of IDO−/− mice indicate that this effect seems not to be mediated by IDO1. Due to the proven immunomodulatory properties of KYNA, a shift toward this branch of the kynurenine pathway (KP) may be one potential mode of action by 1-MT and should be considered for further applications

Overall Dynamic Body Acceleration in Straw-Colored Fruit Bats Increases in Headwinds but Not With Airspeed

Atmospheric conditions impact how animals use the aerosphere, and birds and bats should modify their flight to minimize energetic expenditure relative to changing wind conditions. To investigate how free-ranging straw-colored fruit bats (Eidolon helvum) fly with changing wind support, we use data collected from bats fit with GPS loggers and an integrated triaxial accelerometer and measure flight speeds, wingbeat frequency, and overall dynamic body acceleration (ODBA) as an estimate for energetic expenditure. We predicted that if ODBA reflects energetic expenditure, then we should find a curvilinear relationship between ODBA and airspeed consistent with aerodynamic theory. We expected that bats would lower their airspeed with tailwind support and that ODBA will decrease with increasing tailwinds and increase with wingbeat frequency. We found that wingbeat frequency has the strongest positive relationship with ODBA. There was a small, but negative, relationship between airspeed and ODBA, and bats decreased ODBA with increasing tailwind. Bats flew at ground speeds of 9.6 ± 2.4 ms−1 (Mean ± SD, range: 4.3–23.9 ms−1) and airspeeds of 10.2 ± 2.5 ms−1, and did not modify their wingbeat frequency with speed. Free-ranging straw-colored fruit bats therefore exerted more total ODBA in headwinds but not when they changed their airspeed. It is possible that the flexibility in wingbeat kinematics may make flight of free-ranging bats less costly than currently predicted or alternatively that the combination of ODBA and airspeed at our scales of measurement does not reflect this relationship in straw-colored fruit bats. Further work is needed to understand the full potential of free-ranging bat flight and how well bio-logging techniques reflect the costs of bat flight

Planning tiger recovery: Understanding intraspecific variation for effective conservation

Although significantly more money is spent on the conservation of tigers than on any other threatened species, today only 3200 to 3600 tigers roam the forests of Asia, occupying only 7% of their historical range. Despite the global significance of and interest in tiger conservation, global approaches to plan tiger recovery are partly impeded by the lack of a consensus on the number of tiger subspecies or management units, because a comprehensive analysis of tiger variation is lacking. We analyzed variation among all nine putative tiger subspecies, using extensive data sets of several traits [morphological (craniodental and pelage), ecological, molecular]. Our analyses revealed little variation and large overlaps in each trait among putative subspecies, and molecular data showed extremely low diversity because of a severe Late Pleistocene population decline. Our results support recognition of only two subspecies: the Sunda tiger, Panthera tigris sondaica, and the continental tiger, Panthera tigris tigris, which consists of two (northern and southern) management units. Conservation management programs, such as captive breeding, reintroduction initiatives, or trans-boundary projects, rely on a durable, consistent characterization of subspecies as taxonomic units, defined by robust multiple lines of scientific evidence rather than single traits or ad hoc descriptions of one or few specimens. Our multiple-trait data set supports a fundamental rethinking of the conventional tiger taxonomy paradigm, which will have profound implications for the management of in situ and ex situ tiger populations and boost conservation efforts by facilitating a pragmatic approach to tiger conservation management worldwid

Patterns and correlates of claims for brown bear damage on a continental scale

Wildlife damage to human property threatens human-wildlife coexistence. Conflicts arising from wildlife damage in intensively managed landscapes often undermine conservation efforts, making damage mitigation and compensation of special concern for wildlife conservation. However, the mechanisms underlying the occurrence of damage and claims at large scales are still poorly understood. Here, we investigated the patterns of damage caused by brown bears Ursus arctos and its ecological and socio-economic correlates at a continental scale. We compiled information about compensation schemes across 26 countries in Europe in 2005-2012 and analysed the variation in the number of compensated claims in relation to (i) bear abundance, (ii) forest availability, (iii) human land use, (iv) management practices and (v) indicators of economic wealth. Most European countries have a posteriori compensation schemes based on damage verification, which, in many cases, have operated for more than 30 years. On average, over 3200 claims of bear damage were compensated annually in Europe. The majority of claims were for damage to livestock (59%), distributed throughout the bear range, followed by damage to apiaries (21%) and agriculture (17%), mainly in Mediterranean and eastern European countries. The mean number of compensated claims per bear and year ranged from 0·1 in Estonia to 8·5 in Norway. This variation was not only due to the differences in compensation schemes; damage claims were less numerous in areas with supplementary feeding and with a high proportion of agricultural land. However, observed variation in compensated damage was not related to bear abundance. Synthesis and applications. Compensation schemes, management practices and human land use influence the number of claims for brown bear damage, while bear abundance does not. Policies that ignore this complexity and focus on a single factor, such as bear population size, may not be effective in reducing claims. To be effective, policies should be based on integrative schemes that prioritize damage prevention and make it a condition of payment of compensation that preventive measures are applied. Such integrative schemes should focus mitigation efforts in areas or populations where damage claims are more likely to occur. Similar studies using different species and continents might further improve our understanding of conflicts arising from wildlife damage

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents

Utilization of acute and long-term care in the last year of life: comparison with survivors in a population-based study

Background. It is well-known that the use of care services is most intensive in the last phase of life. However, so far only a few determinants of end-of-life care utilization are known. The aims of this study were to describe the utilization of acute and long-term care among older adults in their last year of life as compared to those not in their last year of life, and to examine which of a broad range of determinants can account for observed differences in care utilization. Methods. Data were used from the Longitudinal Aging Study Amsterdam (LASA). In a random, age and sex stratified population-based cohort of 3107 persons aged 55 ? 85 years at baseline and representative of the Netherlands, follow-up cycles took place at 3, 6 and 9 years. Those who died within one year directly after a cycle were defined as the "end-of-life group" (n = 262), and those who survived at least three years after a cycle were defined as the "survivors". Utilization of acute and long-term care services, including professional and informal care, were recorded at each cycle, as well as a broad range of health-related and psychosocial variables. Results. The end-of-life group used more care than the survivors. In the younger-old this difference was most pronounced for acute care, and in the older-old, for long-term care. Use of both acute and long-term home care in the last year of life was fully accounted for by health problems. Use of institutional care at the end of life was partly accounted for by health problems, but was not fully explained by the determinants included. Conclusion. This study shows that severity of health problems are decisive in the explanation of the increase in use of care services towards the end-of-life. This information is essential for an appropriate allocation of professional health care to the benefit of older persons themselves and their informal caregivers. © 2009 Pot et al; licensee BioMed Central Ltd

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

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Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes.Peer reviewe

Up-scaling local-habitat models for large-scale conservation : Assessing suitable areas for the brown bear comeback in Europe

Aim:Large carnivore populations in Europe are expanding into new areas. This generates opportunities to improve their conservation status, but also creates a need to address new conflicts with humans. Species management units are constrained by administrative boundaries, but effective conservation and conflict management require a continental‐scale perspective on the opportunities and limitations for expanding populations. We assessed the conservation applicability and the uncertainties of transferring and up‐scaling local habitat suitability models from multiple populations in support of large‐scale, transboundary species conservation. Location Europe.Methods:We evaluated the accuracy of local population models to predict European brown bear (Ursus arctos) distribution patterns in other populations and at the continental scale. We also assessed the benefits of combining predictions from multiple local population models, and we evaluated the limitations of transferring models among populations and environmental settings. Last, we estimated the availability of unoccupied suitable habitats in Europe for colonization by expanding populations.Results:We found that integrating habitat predictions from multiple populations outperformed predictions from most individual populations. Results showed that about 37% of potentially suitable brown bear habitat in Europe remains unoccupied. As a synthesis of our results, we provide a set of predictive maps for the expansion of brown bears at the continental scale, including predictions from individual habitat models and a multimodel predictive map.Main conclusions:We show that integrating habitat models from multiple populations provides richer and more reliable information on the distribution of suitable habitats in data deficient areas. This integration yields more reliable predictions compared to those based on individual populations and has important implications to manage species expansions and the associated conflicts. We also identified major limitations in transferring predictions among habitats; therefore, it is critical to enhance the reproducibility of habitat suitability models to apply local‐scale habitat studies to broader‐scale conservation practice.publishe