Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Recognition and Alleviation of Pain in Animals

The pain and distress which animals experience as a consequence of their use by man figures prominently in discussions of animal welfare. Some improvements have been made in animal housing and husbandry practices and it is likely that further progress will be made in this field. In comparison, relatively little attention has been given to the problem of minimizing the pain and distress caused to animals by the various procedures to which they are subjected. The most publicized of these are the wide range of experimental techniques which are undertaken using laboratory animals, but also includes procedures such as castration of farm animals and neutering operations carried out on pet animals. The prevention or alleviation of the pain associated with such procedures is a complex problem with no single, simple solution. Consideration must be given to the use of analgesic drugs, the provision of high standards of general care, and the use of special nursing techniques. When dealing with post-operative care, the pre-operative management ofthe animal, the operative procedures and the anesthetic regime must all be evaluated and, when necessary, modified to minimize pain or discomfort

Risk behaviors of 15–21 year olds in Mexico lead to a high prevalence of sexually transmitted infections: results of a survey in disadvantaged urban areas

BACKGROUND: Due to the fact that adolescents are more likely to participate in high-risk behaviors, this sector of the population is particularly vulnerable to contracting sexually transmitted infections (STIs) and resultant health problems. METHODS: A survey was carried out among adolescents from poor homes in 204 small-urban areas of Mexico. Information was collected in relation to risk behaviors and socio-economic environment. A sub-group of the participants also provided blood and urine samples which were analyzed to detect sexually transmitted infections. RESULTS: The presence of Chlamydia was detected in nearly 8% of participants who had stated that they were sexually active (18%) and approximately 12% were positive for herpes type 2-specific antibodies. For both, a greater proportion of girls resulted positive compared to boys. The presence of these biological outcomes of sexual risk behavior was associated with other risk behaviors (smoking), but not with self-reported indicators of protected sex (reported use of condom during most recent sexual activity). CONCLUSION: The results presented in this study show a startlingly high prevalence of HSV-2 among sexually active Mexican adolescents in poor urban areas, suggesting that this group has participated to a great extent in risky sexual practices. The relationships between socioeconomic environment and adolescent risk behavior need to be better understood if we are to design preventive interventions that modify the determinants of risk behaviors

Ataxin-1 Fusion Partners Alter PolyQ Lethality and Aggregation

Intranuclear inclusion bodies (IBs) are the histopathologic markers of multiple protein folding diseases. IB formation has been extensively studied using fluorescent fusion products of pathogenic polyglutamine (polyQ) expressing proteins. These studies have been informative in determining the cellular targets of expanded polyQ protein as well as the methods by which cells rid themselves of IBs. The experimental thrust has been to intervene in the process of polyQ aggregation in an attempt to alleviate cytotoxicity. However new data argues against the notion that polyQ aggregation and cytotoxicity are inextricably linked processes. We reasoned that changing the protein context of a disease causing polyQ protein could accelerate its precipitation as an IB, potentially reducing its cytotoxicity. Our experimental strategy simply exploited the fact that conjoined proteins influence each others folding and aggregation properties. We fused a full-length pathogenic ataxin-1 construct to fluorescent tags (GFP and DsRed1-E5) that exist at different oligomeric states. The spectral properties of the DsRed1-E5-ataxin-1 transfectants had the additional advantage of allowing us to correlate fluorochrome maturation with cytotoxicity. Each fusion protein expressed a distinct cytotoxicity and IB morphology. Flow cytometric analyses of transfectants expressing the greatest fluorescent signals revealed that the DsRed1-E5-ataxin-1 fusion was more toxic than GFP fused ataxin-1 (31.8±4.5% cell death versus 12.85±3%), although co-transfection with the GFP fusion inhibited maturation of the DsRed1-E5 fluorochrome and diminished the toxicity of the DsRed1-E5-ataxin-1 fusion. These data show that polyQ driven aggregation can be influenced by fusion partners to generate species with different toxic properties and provide new opportunities to study IB aggregation, maturation and lethality

Individual working memory capacity is uniquely correlated with feature-based attention when combined with spatial attention

A growing literature suggests that working memory and attention are closely related constructs. Both involve the selection of task-relevant information, and both are characterized by capacity limits. Furthermore, studies using a variety of methodological approaches have demonstrated convergent working memory and attention-related processing at the individual, neural and behavioral level. Given the varieties of both constructs, the specific kinds of attention and WM must be considered. We find that individuals’ working memory capacity (WMC) uniquely interacts with feature-based attention when combined with spatial attention in a cuing paradigm (Posner, 1980). Our findings suggest a positive correlation between WM and feature-based attention only within the spotlight of spatial attention. This finding lends support to the controlled attention view of working memory by demonstrating that integrated feature-based expectancies are uniquely correlated with individual performance on a working memory task

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration