Influences of Excluded Volume of Molecules on Signaling Processes on Biomembrane

We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i) monotonically increasing; ii) increasing then decreasing in a bell-shaped curve; or iii) increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor.Comment: 31 pages, 10 figure

A1C as a Diagnostic Criteria for Diabetes in Low- and Middle-Income Settings: Evidence from Peru

OBJECTIVES: To determine the prevalence of type 2 diabetes mellitus, in three groups of Peruvian adults, using fasting glucose and glycosylated hemoglobin (A1C). METHODOLOGY/PRINCIPAL FINDINGS: This study included adults from the PERU MIGRANT Study who had fasted ≥ 8 h. Fasting glucose ≥ 126 mg/dL and A1C ≥ 6.5% were used, separately, to define diabetes. Subjects with a current diagnosis of diabetes were excluded. 964 of 988 subjects were included in this analysis. Overall, 0.9% (95%CI 0.3-1.5) and 3.5% (95%CI 2.4-4.7) had diabetes using fasting glucose and A1C criteria, respectively. Compared to those classified as having diabetes using fasting glucose, newly classified subjects with diabetes using A1C (n = 25), were older, poorer, thinner and more likely to come from rural areas. Of these, 40% (10/25) had impaired fasting glucose (IFG). CONCLUSIONS: This study shows that the use of A1C as diagnostic criteria for type 2 diabetes mellitus identifies people of different characteristics than fasting glucose. In the PERU MIGRANT population using A1C to define diabetes tripled the prevalence; the increase was more marked among poorer and rural populations. More than half the newly diagnosed people with diabetes using A1C had normal fasting glucose

Drinking Water with Uranium below the U.S. EPA Water Standard Causes Estrogen Receptor–Dependent Responses in Female Mice

Background: The deleterious impact of uranium on human health has been linked to its radioactive and heavy metal-chemical properties. Decades of research has defined the causal relationship between uranium mining/milling and onset of kidney and respiratory diseases 25 years later. Objective: We investigated the hypothesis that uranium, similar to other heavy metals such as cadmium, acts like estrogen. Methods: In several experiments, we exposed intact, ovariectomized, or pregnant mice to depleted uranium in drinking water [ranging from 0.5 μg/L (0.001 μM) to 28 mg/L (120 μM). Results: Mice that drank uranium-containing water exhibited estrogenic responses including selective reduction of primary follicles, increased uterine weight, greater uterine luminal epithelial cell height, accelerated vaginal opening, and persistent presence of cornified vaginal cells. Coincident treatment with the antiestrogen ICI 182,780 blocked these responses to uranium or the synthetic estrogen diethylstilbestrol. In addition, mouse dams that drank uranium-containing water delivered grossly normal pups, but they had significantly fewer primordial follicles than pups whose dams drank control tap water. Conclusions: Because of the decades of uranium mining/milling in the Colorado plateau in the Four Corners region of the American Southwest, the uranium concentration and the route of exposure used in these studies are environmentally relevant. Our data support the conclusion that uranium is an endocrine-disrupting chemical and populations exposed to environmental uranium should be followed for increased risk of fertility problems and reproductive cancers

The health of people classified as lesbian, gay and bisexual attending family practitioners in London: a controlled study

BACKGROUND: The morbidity of gay, lesbian or bisexual people attending family practice has not been previously assessed. We compared health measures of family practice attendees classified as lesbian, gay and bisexual. METHODS: We conducted a cross-sectional, controlled study conducted in 13 London family practices and compared the responses of 26 lesbian and 85 bisexual classified women, with that of 934 heterosexual classified women and 38 gay and 23 bisexual classified men with that of 373 heterosexual classified men. Our outcomes of interest were: General health questionnaire; CAGE questionnaire; short form12; smoking status; sexual experiences during childhood; number of sexual partners and sexual function and satisfaction. RESULTS: In comparison to people classified as heterosexuals: men classified as gay reported higher levels of psychological symptoms (OR 2.48, CI 1.05–5.90); women classified as bisexual were more likely to misuse alcohol (OR 2.73, 1.70–4.40); women classified as bisexual (OR 2.53, 1.60–4.00) and lesbian (OR 3.13, 1.41–6.97) and men classified as bisexual (OR 2.48, 1,04, 5.86) were more likely to be smokers and women classified as bisexual (OR 3.27, 1.97–5.43) and men classified as gay (OR 4.86, 2.28–10.34) were much more likely to report childhood sexual experiences in childhood. Psychological distress was associated with reporting sexual experiences in childhood in men classified as gay and bisexual and women classified as heterosexual. Men classified as bisexual (OR 5.00, 1.73–14.51) and women classified as bisexual (OR 2.88, 1.24- 6.56) were more likely than heterosexuals to report more than one sexual partner in the preceding four weeks. Lesbian, gay and bisexual classified people encountered no more sexual function problems than heterosexuals but men classified as bisexual (OR 2.74, 1.12–6.70) were more dissatisfied with their sex lives. CONCLUSION: Bisexual and lesbian classified people attending London general practices were more likely to be smokers and gay classified men were at increased risk of psychological distress in comparison to heterosexual classified people. Increased awareness of the sexuality of people seen in primary care can provide opportunities for health promotion

The Cyclic AMP Cascade Is Altered in the Fragile X Nervous System

Fragile X syndrome (FX), the most common heritable cause of mental retardation and autism, is a developmental disorder characterized by physical, cognitive, and behavioral deficits. FX results from a trinucleotide expansion mutation in the fmr1 gene that reduces levels of fragile X mental retardation protein (FMRP). Although research efforts have focused on FMRP's impact on mGluR signaling, how the loss of FMRP leads to the individual symptoms of FX is not known. Previous studies on human FX blood cells revealed alterations in the cyclic adenosine 3′, 5′-monophosphate (cAMP) cascade. We tested the hypothesis that cAMP signaling is altered in the FX nervous system using three different model systems. Induced levels of cAMP in platelets and in brains of fmr1 knockout mice are substantially reduced. Cyclic AMP induction is also significantly reduced in human FX neural cells. Furthermore, cAMP production is decreased in the heads of FX Drosophila and this defect can be rescued by reintroduction of the dfmr gene. Our results indicate that a robust defect in cAMP production in FX is conserved across species and suggest that cAMP metabolism may serve as a useful biomarker in the human disease population. Reduced cAMP induction has implications for the underlying causes of FX and autism spectrum disorders. Pharmacological agents known to modulate the cAMP cascade may be therapeutic in FX patients and can be tested in these models, thus supplementing current efforts centered on mGluR signaling

Rapid niche expansion by selection on functional genomic variation after ecosystem recovery

It is well recognized that environmental degradation caused by human activities can result in dramatic losses of species and diversity. However, comparatively little is known about the ability of biodiversity to re-emerge following ecosystem recovery. Here, we show that a European whitefish subspecies, the gangfisch Coregonus lavaretus macrophthalmus, rapidly increased its ecologically functional diversity following the restoration of Lake Constance after anthropogenic eutrophication. In fewer than ten generations, gangfisch evolved a greater range of gill raker numbers (GRNs) to utilize a broader ecological niche. A sparse genetic architecture underlies this variation in GRN. Several co-expressed gene modules and genes showing signals of positive selection were associated with GRN and body shape. These were enriched for biological pathways related to trophic niche expansion in fishes. Our findings demonstrate the potential of functional diversity to expand following habitat restoration, given a fortuitous combination of genetic architecture, genetic diversity and selection

Parameter estimate of signal transduction pathways

BACKGROUND: The "inverse" problem is related to the determination of unknown causes on the bases of the observation of their effects. This is the opposite of the corresponding "direct" problem, which relates to the prediction of the effects generated by a complete description of some agencies. The solution of an inverse problem entails the construction of a mathematical model and takes the moves from a number of experimental data. In this respect, inverse problems are often ill-conditioned as the amount of experimental conditions available are often insufficient to unambiguously solve the mathematical model. Several approaches to solving inverse problems are possible, both computational and experimental, some of which are mentioned in this article. In this work, we will describe in details the attempt to solve an inverse problem which arose in the study of an intracellular signaling pathway. RESULTS: Using the Genetic Algorithm to find the sub-optimal solution to the optimization problem, we have estimated a set of unknown parameters describing a kinetic model of a signaling pathway in the neuronal cell. The model is composed of mass action ordinary differential equations, where the kinetic parameters describe protein-protein interactions, protein synthesis and degradation. The algorithm has been implemented on a parallel platform. Several potential solutions of the problem have been computed, each solution being a set of model parameters. A sub-set of parameters has been selected on the basis on their small coefficient of variation across the ensemble of solutions. CONCLUSION: Despite the lack of sufficiently reliable and homogeneous experimental data, the genetic algorithm approach has allowed to estimate the approximate value of a number of model parameters in a kinetic model of a signaling pathway: these parameters have been assessed to be relevant for the reproduction of the available experimental data

East London Experience with Enteric Fever 2007-2012

The clinical presentation and epidemiology for patients with enteric fever at two hospitals in East London during 2007-2012 is described with the aim to identify preventive opportunities and to reduce the cost of treatment.A retrospective analysis of case notes from patients admitted with enteric fever during 2007 to 2012 with a microbiologically confirmed diagnosis was undertaken. Details on clinical presentation, travel history, demographic data, laboratory parameters, treatment, patient outcome and vaccination status were collected.Clinical case notes were available for 98/129 (76%) patients including 69 Salmonella enterica serovar Typhi (S. Typhi) and 29 Salmonella enterica serovar Paratyphi (S. Paratyphi). Thirty-four patients (35%) were discharged from emergency medicine without a diagnosis of enteric fever and then readmitted after positive blood cultures. Seventy-one of the 98 patients (72%) were UK residents who had travelled abroad, 23 (23%) were foreign visitors/new entrants to the UK and four (4%) had not travelled abroad. Enteric fever was not considered in the initial differential diagnosis for 48/98 (49%) cases. The median length of hospital stay was 7 days (range 0-57 days). The total cost of bed days for managing enteric fever was £454,000 in the two hospitals (mean £75,666/year). Median time to clinical resolution was five days (range 1-20). Seven of 98 (7%) patients were readmitted with relapsed or continued infection. Six of the 71 (8%) patients had received typhoid vaccination, 34 (48%) patients had not received vaccination, and for 31 cases (44%) vaccination status was unknown.Further interventions regarding education and vaccination of travellers and recognition of the condition by emergency medicine clinicians in travellers to South Asia is required

Determination of Specific Electrocatalytic Sites in the Oxidation of Small Molecules on Crystalline Metal Surfaces

The identification of active sites in electrocatalytic reactions is part of the elucidation of mechanisms of catalyzed reactions on solid surfaces. However, this is not an easy task, even for apparently simple reactions, as we sometimes think the oxidation of adsorbed CO is. For surfaces consisting of non-equivalent sites, the recognition of specific active sites must consider the influence that facets, as is the steps/defect on the surface of the catalyst, cause in its neighbors; one has to consider the electrochemical environment under which the “active sites” lie on the surface, meaning that defects/steps on the surface do not partake in chemistry by themselves. In this paper, we outline the recent efforts in understanding the close relationships between site-specific and the overall rate and/or selectivity of electrocatalytic reactions. We analyze hydrogen adsorption/desorption, and electro-oxidation of CO, methanol, and ammonia. The classical topic of asymmetric electrocatalysis on kinked surfaces is also addressed for glucose electro-oxidation. The article takes into account selected existing data combined with our original works.M.J.S.F. is grateful to PNPD/CAPES (Brazil). J.M.F. thanks the MCINN (FEDER, Spain) project-CTQ-2016-76221-P

A systematic review evaluating the psychometric properties of measures of social inclusion

Introduction: Improving social inclusion opportunities for population health has been identified as a priority area for international policy. There is a need to comprehensively examine and evaluate the quality of psychometric properties of measures of social inclusion that are used to guide social policy and outcomes. Objective: To conduct a systematic review of the literature on all current measures of social inclusion for any population group, to evaluate the quality of the psychometric properties of identified measures, and to evaluate if they capture the construct of social inclusion. Methods: A systematic search was performed using five electronic databases: CINAHL, PsycINFO, Embase, ERIC and Pubmed and grey literature were sourced to identify measures of social inclusion. The psychometric properties of the social inclusion measures were evaluated against the COSMIN taxonomy of measurement properties using pre-set psychometric criteria. Results: Of the 109 measures identified, twenty-five measures, involving twenty-five studies and one manual met the inclusion criteria. The overall quality of the reviewed measures was variable, with the Social and Community Opportunities Profile-Short, Social Connectedness Scale and the Social Inclusion Scale demonstrating the strongest evidence for sound psychometric quality. The most common domain included in the measures was connectedness (21), followed by participation (19); the domain of citizenship was covered by the least number of measures (10). No single instrument measured all aspects within the three domains of social inclusion. Of the measures with sound psychometric evidence, the Social and Community Opportunities Profile-Short captured the construct of social inclusion best. Conclusions: The overall quality of the psychometric properties demonstrate that the current suite of available instruments for the measurement of social inclusion are promising but need further refinement. There is a need for a universal working definition of social inclusion as an overarching construct for ongoing research in the area of the psychometric properties of social inclusion instruments