Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

6Questionnaire-based approach to assess schoolchildren's physical fitness and its potential role in exploring the putative impact of helminth and Plasmodium spp. infections in Côte d'Ivoire

BACKGROUND: Disability weights (DWs) are important for estimating burden of disease in terms of disability-adjusted life years. The previous practice of eliciting DWs by expert opinion has been challenged. More recent approaches employed quality of life (QoL) questionnaires to establish patient-based DWs, but results are ambiguous. METHODS: In early 2010, we administered a questionnaire pertaining to physical fitness to 200 schoolchildren in Cote d'Ivoire. Helminth and Plasmodium spp. infections were determined and schoolchildren's physical fitness objectively measured in a maximal multistage 20 m shuttle run test. Associations between objectively measured and self-reported physical fitness and between self-reported physical fitness and infection status were determined. Spearman rank correlation coefficient, uni- and multivariable linear regression models adjusting for children's age and sex, ambient air temperature and humidity, Fisher's test, chi^2 and t-test statistics were used for statistical analysis. RESULTS: The prevalence of Schistosoma haematobium, Plasmodium spp., Schistosoma mansoni, hookworm and Ascaris lumbricoides in 167 children with complete parasitological results was 84.4%, 74.9%, 54.5%, 14.4% and 1.2%, respectively. High infection intensities and multiple species parasite infections were common. In the 137 children with complete data also from the shuttle run test, we found statistically significant correlations between objectively measured and self-reported physical fitness. However, no statistically significant correlation between the children's parasitic infection status and self-reported physical fitness was identified. An attrition analysis revealed considerably lower self-reported physical fitness scores of parasitized children who were excluded from shuttle run testing due to medical concerns in comparison to parasitized children who were able to successfully complete the shuttle run test. CONCLUSIONS: Our QoL questionnaire proofed valid to assess children's physical fitness in the current study area. Reasons why no differences in self-reported physical fitness in children with different parasitic infections were found are manifold, but do not preclude the use of QoL questionnaires in the elicitation of DWs. Indeed, the questionnaire was particularly useful in assessing physical fitness of those children, who were - supposedly due to parasitic infections - unable to complete the shuttle run test. Hence, we encourage others to use QoL questionnaires to determine not only physical fitness, but also more subtle morbidities

Salience-based selection: attentional capture by distractors less salient than the target

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience

Exercising control at the urban scale: Towards a theory of spatial organisation and surveillance

The purpose of this chapter is to explore how urban spaces are implicated in the control and surveillance of users in a culture saturated by the notion of the self as a consuming body or entity. Using the work of Foucault on disciplinary cultures, Lefebvre in relation to the production of space, and other seminal theorists such as Baudrillard, Bauman, Shields, and Walzer, a model for analysing the three dimensions of social spatialisation is proposed and illustrated by reference to contemporary public spaces, and specifically spaces of mundane leisure such as shopping malls and high streets. The chapter deals with how the public realm as a controlling space has been theorised in terms of opposition to such controlling tendencies—from the flaneur, through the self-constructed narratives of De Certeau’s walker to the digitally ‘enhanced’ individual today, appropriating space via technology and their own projects in tinder and so on, and other potentially subversive media

Robust averaging protects decisions from noise in neural computations

An ideal observer will give equivalent weight to sources of information that are equally reliable. However, when averaging visual information, human observers tend to downweight or discount features that are relatively outlying or deviant (‘robust averaging’). Why humans adopt an integration policy that discards important decision information remains unknown. Here, observers were asked to judge the average tilt in a circular array of high-contrast gratings, relative to an orientation boundary defined by a central reference grating. Observers showed robust averaging of orientation, but the extent to which they did so was a positive predictor of their overall performance. Using computational simulations, we show that although robust averaging is suboptimal for a perfect integrator, it paradoxically enhances performance in the presence of “late” noise, i.e. which corrupts decisions during integration. In other words, robust decision strategies increase the brain’s resilience to noise arising in neural computations during decision-making

Re A (A Child) and the United Kingdom Code of Practice for the Diagnosis and Confirmation of Death: Should a Secular Construct of Death Override Religious Values in a Pluralistic Society?

The determination of death by neurological criteria remains controversial scientifically, culturally, and legally, worldwide. In the United Kingdom, although the determination of death by neurological criteria is not legally codified, the Code of Practice of the Academy of Medical Royal Colleges is customarily used for neurological (brainstem) death determination and treatment withdrawal. Unlike some states in the US, however, there are no provisions under the law requiring accommodation of and respect for residents’ religious rights and commitments when secular conceptions of death based on medical codes and practices conflict with a traditional concept well-grounded in religious and cultural values and practices. In this article, we analyse the medical, ethical, and legal issues that were generated by the recent judgement of the High Court of England and Wales in Re: A (A Child) [2015] EWHC 443 (Fam). Mechanical ventilation was withdrawn in this case despite parental religious objection to a determination of death based on the code of practice. We outline contemporary evidence that has refuted the reliability of tests of brainstem function to ascertain the two conjunctive clinical criteria for the determination of death that are stipulated in the code of practice: irreversible loss of capacity for consciousness and somatic integration of bodily biological functions

Identification of host proteins interacting with Toxoplasma gondii GRA15 (TgGRA15) by yeast two-hybrid system

Background Toxoplasma gondii, an obligate intracellular protozoan parasite, possesses the remarkable ability to co-opt host cell machinery in order to maintain its intracellular survival. This parasite can modulate signaling pathways of its host through the secretion of polymorphic effector proteins localized in the rhoptry and dense granule organelles. One of such effectors is T. gondii type II-specific dense granule protein 15, TgGRA15, which activates NF-κB pathway. The aim of the present study was to identify the host interaction partner proteins of TgGRA15. Methods We screened a yeast two-hybrid mouse cDNA library using TgGRA15 as the bait. TgGRA15 (PRU strain, Type II) was cloned into the pGBKT7 vector and expressed in the Y2HGold yeast strain. Then, the bait protein expression was validated by western blotting analysis, followed by auto-activation and toxicity tests in comparison with control (Y2HGold yeast strain transformed with empty pGBKT7 vector). Results This screening led to the identification of mouse Luzp1 and AW209491 as host binding proteins that interact with TgGRA15. Luzp1 contains three nuclear localizing signals and is involved in regulating a subset of host non-coding RNA genes. Conclusions These findings reveal, for the first time, new host cell proteins interacting with TgGRA15. The identification of these cellular targets and the understanding of their contribution to the host-pathogen interaction may serve as the foundation for novel therapeutic and prevention strategies against T. gondii infection

Early menopause, association with tobacco smoking, coffee consumption and other lifestyle factors: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Early onset of menopause is a risk factor for several health problems. The objective was primarily to investigate the association between early menopause and current, past active and passive smoking. A second aim was to investigate the association between coffee and alcohol consumption and early menopause.</p> <p>Methods</p> <p>The present population-based cross-sectional study included a sub-sample of 2123 postmenopausal women born in 1940–41 who participated in the Oslo Health Study. Early menopause was defined as menopause occurring at an age of less than 45 years. We applied logistic regression analyses (crude and adjusted odds ratio (OR)) to examine the association between early menopause and selected lifestyle factors.</p> <p>Results</p> <p>Current smoking was significantly associated with early menopause (adj. OR, 1.59; 95% CI, 1.11–2.28). Stopping smoking more than 10 years before menopause considerably reduced the risk of early menopause (adj. OR, 0.13; 95% CI, 0.05–0.33). Total exposure to smoking (the product of number of cigarettes per day and time as a smoker) was positively related to early menopause and, at the highest doses, nearly doubled the odds (adj. OR, 1.93; 95% CI, 1.12–3.30). These data suggest a possible dose-response relationship between total exposure to smoking and early menopause, but no dose-response relationship was detected for the other variables examined. We found no significant association of coffee or alcohol consumption with early menopause. Of the lifestyle factors tested, high educational level (adj. OR, 0.50; 95% CI, 0.34–0.72) and high social participation (adj. OR, 0.60, 95% CI, 0.39–0.98) were negatively associated with early menopause.</p> <p>Conclusion</p> <p>This cross-sectional study shows an association between current smoking and early menopause. The data also suggest that the earlier a woman stops smoking the more protected she is from early menopause. Early menopause was not significantly associated with passive smoking, or alcohol or coffee consumption.</p