The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling

The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor-driven inflammation.</p

The Role of the Proteinase Inhibitor Ovorubin in Apple Snail Eggs Resembles Plant Embryo Defense against Predation

BACKGROUND: Fieldwork has thoroughly established that most eggs are intensely predated. Among the few exceptions are the aerial egg clutches from the aquatic snail Pomacea canaliculata which have virtually no predators. Its defenses are advertised by the pigmented ovorubin perivitellin providing a conspicuous reddish coloration. The nature of the defense however, was not clear, except for a screening for defenses that identified a neurotoxic perivitellin with lethal effect on rodents. Ovorubin is a proteinase inhibitor (PI) whose role to protect against pathogens was taken for granted, according to the prevailing assumption. Through biochemical, biophysical and feeding experiments we studied the proteinase inhibitor function of ovorubin in egg defenses. METHODOLOGY/PRINCIPAL FINDINGS: Mass spectrometry sequencing indicated ovorubin belongs to the Kunitz-type serine proteinase inhibitor family. It specifically binds trypsin as determined by small angle X-ray scattering (SAXS) and cross-linking studies but, in contrast to the classical assumption, it does not prevent bacterial growth. Ovorubin was found extremely resistant to in vitro gastrointestinal proteolysis. Moreover feeding studies showed that ovorubin ingestion diminishes growth rate in rats indicating that this highly stable PI is capable of surviving passage through the gastrointestinal tract in a biologically active form. CONCLUSIONS: To our knowledge, this is the first direct evidence of the interaction of an egg PI with a digestive protease of potential predators, limiting predator's ability to digest egg nutrients. This role has not been reported in the animal kingdom but it is similar to plant defenses against herbivory. Further, this would be the only defense model with no trade-offs between conspicuousness and noxiousness by encoding into the same molecule both the aposematic warning signal and an antinutritive/antidigestive defense. These defenses, combined with a neurotoxin and probably unpalatable factors would explain the near absence of predators, opening new perspectives in the study of the evolution and ecology of egg defensive strategies

The association between parity, infant gender, higher level of paternal education and preterm birth in Pakistan: a cohort study

<p>Abstract</p> <p>Background</p> <p>High rates of antenatal depression and preterm birth have been reported in Pakistan. Self reported maternal stress and depression have been associated with preterm birth; however findings are inconsistent. Cortisol is a biological marker of stress and depression, and its measurement may assist in understanding the influence of self reported maternal stress and depression on preterm birth.</p> <p>Methods</p> <p>In a prospective cohort study pregnant women between 28 to 30 weeks of gestation from the Aga Khan Hospital for Women and Children completed the A-Z Stress Scale and the Centre for Epidemiology Studies Depression Scale to assess stress and depression respectively, and had a blood cortisol level drawn. Women were followed up after delivery to determine birth outcomes. Correlation coefficients and Wilcoxon rank sum test was used to assess relationship between preterm birth, stress, depression and cortisol. Logistic regression analysis was used to determine the key factors predictive of preterm birth.</p> <p>Results</p> <p>132 pregnant women participated of whom 125 pregnant women had both questionnaire and cortisol level data and an additional seven had questionnaire data only. Almost 20% of pregnant women (19·7%, 95% CI 13·3-27·5) experienced a high level of stress and nearly twice as many (40·9%, 95% CI 32·4-49·8%) experienced depressive symptoms. The median of cortisol level was 27·40 ug/dl (IQR 22·5-34·2). The preterm birth rate was 11·4% (95% CI 6·5-18). There was no relationship between cortisol values and stress scale or depression. There was a significant positive relationship between maternal depression and stress. Preterm birth was associated with higher parity, past delivery of a male infant, and higher levels of paternal education. Insufficient numbers of preterm births were available to warrant the development of a multivariable logistic regression model.</p> <p>Conclusions</p> <p>Preterm birth was associated with higher parity, past delivery of a male infant, and higher levels of paternal education. There was no relationship between stress, and depression, cortisol and preterm birth. There were high rates of stress and depression among this sample suggesting that there are missed opportunities to address mental health needs in the prenatal period. Improved methods of measurement are required to better understand the psychobiological basis of preterm birth.</p

Determinação da idade gestacional com base em informações do estudo Nascer no Brasil

O objetivo deste estudo foi verificar a validade de diferentes métodos de estimação da idade gestacional e propor a criação de um algoritmo para cálculo da mesma para a pesquisa Nascer no Brasil – estudo realizado em 2011-2012, com 23.940 puérperas. Utilizou-se a ultrassonografia precoce, realizada entre 7-20 semanas de gestação, como método de referência. Todas as análises foram estratificadas segundo tipo de pagamento do parto (público ou privado). Quando comparado à ultrassonografia precoce, foram encontrados coeficientes de correlação intraclasse substanciais tanto para o método idade gestacional na admissão baseado em ultrassonografia (0,95 and 0,94) quanto para o método idade gestacional relatada pela puérpera na entrevista (0,90 and 0,88), para o pagamento do parto público e privado, respectivamente. Medidas baseadas na data da última menstruação apresentaram coeficientes de correlação intraclasse menores. Este estudo sugere cautela ao se utilizar a data da última menstruação como primeiro método de estimação da idade gestacional no Brasil, fortalecendo o uso de informações oriundas de ultrassonografia precoce

Cognitive Vulnerability to Depression in Canadian and Chinese Adolescents

The goal of the current study was to compare diathesis-stress and transactional models of cognitive vulnerability to depression in samples of Canadian (n = 118) and Chinese (n = 405) adolescents. We utilized a six-month multi-wave, longitudinal design in order to examine whether (a) perceived control moderated the association between the occurrence of dependent interpersonal stressors and subsequent increases in depressive symptoms (i.e., a diathesis-stress perspective) and (b) dependent interpersonal stressors mediated the association between perceived control and subsequent increases in depressive symptoms (i.e., a transactional perspective). Results from idiographic, time-lagged, hierarchical linear modeling analyses indicated that for Canadian adolescents both diathesis-stress and transactional models were significant predictors of depressive symptomology. When examining the diathesis-stress model, boys, but not girls, who reported lower perceived control, reported higher levels of depressive symptoms following the occurrence of dependent interpersonal stress. Gender differences, however, were not present in the transactional model. In contrast, transactional, but not diathesis-stress, models were significant in Chinese adolescents, and gender differences did not emerge. Overall, these results may reflect culturally-relevant differences in the etiology of depression in Canadian and Chinese adolescents