Regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins

Scaffolding proteins that direct the assembly of multiple kinases into a spatially localized signaling complex are often essential for the maintenance of an appropriate biological response. Although scaffolds are widely believed to have dramatic effects on the dynamics of signal propagation, the mechanisms that underlie these consequences are not well understood. Here, Monte Carlo simulations of a model kinase cascade are used to investigate how the temporal characteristics of signaling cascades can be influenced by the presence of scaffold proteins. Specifically, we examine the effects of spatially localizing kinase components on a scaffold on signaling dynamics. The simulations indicate that a major effect that scaffolds exert on the dynamics of cell signaling is to control how the activation of protein kinases is distributed over time. Scaffolds can influence the timing of kinase activation by allowing for kinases to become activated over a broad range of times, thus allowing for signaling at both early and late times. Scaffold concentrations that result in optimal signal amplitude also result in the broadest distributions of times over which kinases are activated. These calculations provide insights into one mechanism that describes how the duration of a signal can potentially be regulated in a scaffold mediated protein kinase cascade. Our results illustrate another complexity in the broad array of control properties that emerge from the physical effects of spatially localizing components of kinase cascades on scaffold proteins.Comment: 12 pages, 6 figure

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Barriers related to screening examinations for prostate cancer

With the aim of describing barriers to screening for prostate cancer, a domicile survey was carried out covering 160 men of a Family Health Strategy (FHS) area. Slightly over half had undergone the examination. Regarding beliefs related to the disease, 95% of the men believed there is a cure if detected early, 29.4% mentioned the possibility of a normal life while ill, 56.3% believed it may be asymptomatic, 36.1% agreed/disagreed that the treatment is worse than the disease and 34.4% agreed that the examination affects masculinity and that if you are well it is not necessary to perform it. Regarding barriers, 15% reported that the physician had never requested it, 10.9% did not consider it important and 16.9% were afraid to take the examination. While not the sole determinant, the dissemination of adequate knowledge regarding the examination can constitute a key strategy for the formation of a positive attitude in relation to early detection.Con el objetivo de describir barreras sobre rastreo del cáncer de próstata, se realizó una encuesta domiciliar abarcando 160 hombres de una área de la Estrategia de Salud de la Familia (ESF). Poco más de la mitad ya había realizado el examen. En relación a las creencias sobre la enfermedad, 95% de ellos creen en la cura si es detectado precozmente, 29,4% refirieron la posibilidad de vida normal a pesar de estar enfermo, 56,3% creen que puede ser asintomático, 36,1% está de acuerdo/no está de acuerdo que el tratamiento es peor que la enfermedad y 34,4% está de acuerdo que el examen afecta la masculinidad y si estuviese bien no sería necesario hacerlo. En cuanto a las barreras, 15% informaron que el médico nunca lo solicitó, 10,9% no lo encuentran importante y 16,9% tiene miedo de hacer el examen. A pesar de que no es el único determinante, diseminar los conocimientos adecuados sobre el examen puede constituirse en una estrategia fundamental para la formación de una actitud positiva en relación a la detección precoz.Com o objetivo de descrever barreiras sobre rastreamento do câncer de próstata, realizou-se inquérito domiciliar, abrangendo 160 homens, de uma área da Estratégia de Saúde da Família (ESF). Pouco mais da metade já havia realizado o exame. Em relação às crenças sobre a doença, 95% deles acreditam na cura se detectado precocemente, 29,4% referiram possibilidade de vida normal embora doente, 56,3% acreditam que pode ser assintomático, 36,1% concordam/discordam que o tratamento é pior que a doença e 34,4% concordam que o exame afeta a masculinidade e, se estiver bem, não é necessário fazê-lo. Quanto às barreiras, 15% informaram que o médico nunca solicitou, 10,9% não acham importante e 16,9% têm medo de fazer o exame. Embora não seja o único determinante, disseminar conhecimentos adequados sobre o exame pode se constituir em estratégia fundamental para a formação de atitude positiva em relação à detecção precoce

Sociodemographic gradients in breast and cervical cancer screening in Korea: the Korean National Cancer Screening Survey (KNCSS) 2005-2009

<p>Abstract</p> <p>Background</p> <p>Cancer screening rates in Korea for five cancer types have increased steadily since 2002. With regard to the life-time cancer screening rates in 2009 according to cancer sites, the second highest was breast cancer (78.1%) and the third highest was cervical cancer (76.1%). Despite overall increases in the screening rate, disparities in breast and cervical cancer screening, based on sociodemographic characteristics, still exist.</p> <p>Methods</p> <p>Data from 4,139 women aged 40 to74 years from the 2005 to 2009 Korea National Cancer Screening Survey were used to analyze the relationship between sociodemographic characteristics and receiving mammograms and Pap smears. The main outcome measures were ever having had a mammogram and ever having had a Pap smear. Using these items of information, we classified women into those who had had both types of screening, only one screening type, and neither screening type. We used logistic regression to investigate relationships between screening history and sociodemographic characteristics of the women.</p> <p>Results</p> <p>Being married, having a higher education, a rural residence, and private health insurance were significantly associated with higher rates of breast and cervical cancer screening after adjusting for age and sociodemographic factors. Household income was not significantly associated with mammograms or Pap smears after adjusting for age and sociodemographic factors.</p> <p>Conclusions</p> <p>Disparities in breast and cervical cancer screening associated with low sociodemographic status persist in Korea.</p

Khat and alcohol use and risky sex behaviour among in-school and out-of-school youth in Ethiopia

BACKGROUND: Khat (an evergreen plant with amphetamine-like properties) and alcohol are widely consumed among the youth of Ethiopia. However, their relationship to risky sexual behaviour is not well described. This study was conducted to describe the magnitude of risky sexual behaviour (unprotected sex and early initiation of sexual activity) and its association with Khat and alcohol consumption in Ethiopian youths. METHODS: A probabilistic national sample of 20,434 in-school and out-of-school youths aged between 15 and 24 years of age was selected and interviewed regarding their sexual behavior and substance use. RESULTS: Over 20% of out-of-school youth had unprotected sex during the 12-month period prior to interview compared to 1.4% of in-school youth. Daily Khat intake was also associated with unprotected sex: adjusted OR (95% CI) = 2.26 (1.92, 2.67). There was a significant and linear association between alcohol intake and unprotected sex, with those using alcohol daily having a three fold increased odds compared to those not using it: adj. OR (95% CI) = 3.05 (2.38, 3.91). Use of substances other than Khat was not associated with unprotected sex, but was associated with initiation of sexual activity: adj. OR (95% CI) = 2.54 (1.84, 3.51). CONCLUSION: A substantial proportion of out-of-school youth engage in risky sex. The use of Khat and alcohol and other substances is significantly and independently associated with risky sexual behaviour among Ethiopian youths

Do faces capture the attention of individuals with Williams syndrome or Autism? Evidence from tracking eye movements

The neuro-developmental disorders of Williams syndrome (WS) and autism can reveal key components of social cognition. Eye‐tracking techniques were applied in two tasks exploring attention to pictures containing faces. Images were i) scrambled pictures containing faces or ii) pictures of scenes with embedded faces. Compared to individuals who were developing typically, participants with WS and autism showed atypicalities of gaze behaviour. Individuals with WS showed prolonged face gaze across tasks, relating to the typical WS social phenotype. Participants with autism exhibited reduced face gaze, linking to a lack of interest in socially relevant information. The findings are interpreted in terms of wider issues regarding socio‐cognition and attention mechanisms

Membrane Recruitment of Scaffold Proteins Drives Specific Signaling

Cells must give the right response to each stimulus they receive. Scaffolding, a signaling process mediated by scaffold proteins, participates in the decoding of the cues by specifically directing signal transduction. The aim of this paper is to describe the molecular mechanisms of scaffolding, i.e. the principles by which scaffold proteins drive a specific response of the cell. Since similar scaffold proteins are found in many species, they evolved according to the purpose of each organism. This means they require adaptability. In the usual description of the mechanisms of scaffolding, scaffold proteins are considered as reactors where molecules involved in a cascade of reactions are simultaneously bound with the right orientation to meet and interact. This description is not realistic: (i) it is not verified by experiments and (ii) timing and orientation constraints make it complex which seems to contradict the required adaptability. A scaffold protein, Ste5, is used in the MAPK pathway of Saccharomyces Cerevisiae for the cell to provide a specific response to stimuli. The massive amount of data available for this pathway makes it ideal to investigate the actual mechanisms of scaffolding. Here, a complete treatment of the chemical reactions allows the computation of the distributions of all the proteins involved in the MAPK pathway when the cell receives various cues. These distributions are compared to several experimental results. It turns out that the molecular mechanisms of scaffolding are much simpler and more adaptable than previously thought in the reactor model. Scaffold proteins bind only one molecule at a time. Then, their membrane recruitment automatically drives specific, amplified and localized signal transductions. The mechanisms presented here, which explain how the membrane recruitment of a protein can produce a drastic change in the activity of cells, are generic and may be commonly used in many biological processes