Nucleocytoplasmic transport: a thermodynamic mechanism

The nuclear pore supports molecular communication between cytoplasm and nucleus in eukaryotic cells. Selective transport of proteins is mediated by soluble receptors, whose regulation by the small GTPase Ran leads to cargo accumulation in, or depletion from the nucleus, i.e., nuclear import or nuclear export. We consider the operation of this transport system by a combined analytical and experimental approach. Provocative predictions of a simple model were tested using cell-free nuclei reconstituted in Xenopus egg extract, a system well suited to quantitative studies. We found that accumulation capacity is limited, so that introduction of one import cargo leads to egress of another. Clearly, the pore per se does not determine transport directionality. Moreover, different cargo reach a similar ratio of nuclear to cytoplasmic concentration in steady-state. The model shows that this ratio should in fact be independent of the receptor-cargo affinity, though kinetics may be strongly influenced. Numerical conservation of the system components highlights a conflict between the observations and the popular concept of transport cycles. We suggest that chemical partitioning provides a framework to understand the capacity to generate concentration gradients by equilibration of the receptor-cargo intermediary.Comment: in press at HFSP Journal, vol 3 16 text pages, 1 table, 4 figures, plus Supplementary Material include

Effect of phosphorus on the attenuation of lead and chromium

This study analyses the adsorption of Pb(II) and Cr(III) in soils. These metals are commonly found together in nature in urban wastes or industrial spillages, and the theoretical approach of the work was to evaluate the response of the soil to continuous Cr and Pb spillages to soil in terms of several physicochemical parameters. The influence of an anthropogenic input of phosphorus was evaluated. Continuous flow experiments were run in duplicates in acrylic columns (25 cm × 3.2 cm). The influent Cr(III) and Pb(II) solutions of 10 mg l−1 and 25 mg l−1 at pH 5 were pumped upward through the bottom of the columns to ensure saturation flow conditions. Also, successive experiments were run with the above concentrations of Cr(III) and Pb(II) and NaH2PO4, keeping metal to phosphorus ratio of 1:0, 1:0.1 and 1:1. Modelling parameters included Freundlich and Langmuir equations, together with the Two-site adsorption model using CXTFIT code. Results obtained allowed concluding that Pb(II) adsorption presents a certain degree of irreversibility and the continued spillages over soil increment the fraction which is not easily desorbed. Cr(III) desorption was almost complete, evidencing its high mobility in nature. The presence of an anthropogenic input of phosphorus leads to a marked increase of both Pb(II) and Cr(III) adsorption in soils. Z-potential measurements allow to discard the electrostatic attraction of Cr(III) and Pb(II) with the surface charged soil as the dominant process of metal sorption. Instead, CheaqsPro simulation allows to identify PbH2PO4 +, PbHPO4 (aq) and CrHPO4 + as the dominant species which regulate Cr(III) and Pb(II) transport in soils.Fundação para a Ciência e a Tecnologi

Breastfeeding and weaning practices among Hong Kong mothers: a prospective study

<p>Abstract</p> <p>Background</p> <p>Breastfeeding provides optimal and complete nutrition for newborn babies. Although new mothers in Hong Kong are increasingly choosing to breastfeed their babies, rates of exclusive breastfeeding are low and duration remains short. The purpose of this study was to describe the breastfeeding and weaning practices of Hong Kong mothers over the infant's first year of life to determine the factors associated with early cessation.</p> <p>Methods</p> <p>A cohort of 1417 mother-infant pairs was recruited from the obstetric units of four public hospitals in Hong Kong in the immediate post-partum period and followed prospectively for 12 months or until weaned. We used descriptive statistics to describe breastfeeding and weaning practices and multiple logistic regression to investigate the relationship between maternal characteristics and breastfeeding cessation.</p> <p>Results</p> <p>At 1 month, 3 months, 6 months and 12 months only 63%, 37.3%, 26.9%, and 12.5% of the infants respectively, were still receiving any breast milk; approximately one-half of breastfeeding mothers were exclusively breastfeeding. Younger mothers, those with a longer duration of residence in Hong Kong, and those returning to work postpartum were more likely to wean before 1 month. Mothers with higher education, previous breastfeeding experience, who were breastfed themselves and those who were planning to exclusively breastfeed and whose husbands preferred breastfeeding were more likely to continue breastfeeding beyond 1 month. The introduction of infant formula before 1 month and returning to work postpartum were predictive of weaning before 3 months.</p> <p>Conclusions</p> <p>Breastfeeding promotion programs have been successful in achieving high rates of breastfeeding initiation but the focus must now shift to helping new mothers exclusively breastfeed and sustain breastfeeding for longer.</p

The Terneuzen Birth Cohort. Longer exclusive breastfeeding duration is associated with leaner body mass and a healthier diet in young adulthood

<p>Abstract</p> <p>Background</p> <p>Breastfeeding (BF) is protective against overweight and is associated with dietary behaviour. The aims of our study were to assess the relationship between exclusive BF duration and BMI, waist circumference (WC) and waist-hip ratio (WHR) at adulthood, and to study whether dietary behaviour could explain the relationship between BF duration and the proxies of fat mass.</p> <p>Methods</p> <p>In 2004-2005, 822 subjects from the Terneuzen Birth Cohort (n = 2,604), aged 18-28 years, filled in postal questionnaires including sociodemographic factors and aspects of dietary behaviour (dietary pattern, and consumption of fruit and vegetables, snacks, sweetened beverages and alcohol); 737 subjects also underwent anthropometric measurements of weight, height, and waist and hip circumference. The relationship between exclusive BF duration and dietary outcomes was investigated by logistic regression analysis. The relationships of BF duration with the anthropometric measures were investigated by linear regression analyses. All results were corrected for age, gender and possible confounders. Finally, regression analyses were performed to investigate if diet factors had a mediating effect on the relationship between BF duration and fat mass.</p> <p>Results</p> <p>A significant inverse dose-response relationship of BF duration was found for BMI (β-0.13, SE 0.06), WC (β-0.39, SE 0.18) and WHR (β-0.003, SE 0.001), after correction for age, gender and confounders. The odds ratio (OR) of exclusive BF duration in months for a breakfast frequency of at least 5 times a week was 1.16 (95%CI 1.06-1.27), and for snack consumption of less than twice a week was 1.15 (95%CI 1.06-1.25). Both ORs were corrected for age, gender and confounders. For other dietary outcomes, the results point in the same direction, i.e. a positive relationship with BF duration, but these were not statistically significant. A mediating effect of the diet factors on the association between BF and anthropometric outcomes was not shown.</p> <p>Conclusions</p> <p>Exclusive BF duration had a significant inverse dose-response relationship with BMI, WC and WHR at young adulthood. BF duration was positively related to a healthier diet at adulthood, but this did not explain the protective effect of BF against body fat. Our results underline the recommendation of the WHO to exclusively breastfeed for 6 months or longer.</p

Intramolecular Cohesion of Coils Mediated by Phenylalanine–Glycine Motifs in the Natively Unfolded Domain of a Nucleoporin

The nuclear pore complex (NPC) provides the sole aqueous conduit for macromolecular exchange between the nucleus and the cytoplasm of cells. Its diffusion conduit contains a size-selective gate formed by a family of NPC proteins that feature large, natively unfolded domains with phenylalanine–glycine repeats (FG domains). These domains of nucleoporins play key roles in establishing the NPC permeability barrier, but little is known about their dynamic structure. Here we used molecular modeling and biophysical techniques to characterize the dynamic ensemble of structures of a representative FG domain from the yeast nucleoporin Nup116. The results showed that its FG motifs function as intramolecular cohesion elements that impart order to the FG domain and compact its ensemble of structures into native premolten globular configurations. At the NPC, the FG motifs of nucleoporins may exert this cohesive effect intermolecularly as well as intramolecularly to form a malleable yet cohesive quaternary structure composed of highly flexible polypeptide chains. Dynamic shifts in the equilibrium or competition between intra- and intermolecular FG motif interactions could facilitate the rapid and reversible structural transitions at the NPC conduit needed to accommodate passing karyopherin–cargo complexes of various shapes and sizes while simultaneously maintaining a size-selective gate against protein diffusion

Overweight at age two years in a multi-ethnic cohort (ABCD study): the role of prenatal factors, birth outcomes and postnatal factors

<p>Abstract</p> <p>Background</p> <p>Childhood overweight/obesity is a major public health problem worldwide which disproportionally affects specific ethnic groups. Little is known about whether such differences already exist at an early age and which factors contribute to these ethnic differences. Therefore, the present study assessed possible ethnic differences in overweight at age 2 years, and the potential explanatory role of prenatal factors, birth outcomes and postnatal factors.</p> <p>Methods</p> <p>Data were derived from a multi-ethnic cohort in the Netherlands (the ABCD study). Weight and height data of 3,156 singleton infants at age 2 years were used. Five ethnic populations were distinguished: Dutch native (n = 1,718), African descent (n = 238), Turkish (n = 162), Moroccan (n = 245) and other non-Dutch (n = 793). Overweight status was defined by the International Obesity Task Force guidelines. The explanatory role of prenatal factors, birth outcomes and postnatal factors in ethnic disparities in overweight (including obesity) was assessed by logistic regression analysis.</p> <p>Results</p> <p>Compared to the native Dutch (7.1%), prevalence of overweight was higher in the Turkish (19.8%) and Moroccan (16.7%) group, whereas the prevalence was not increased in the African descent (9.2%) and other non-Dutch (8.8%) group. Although maternal pre-pregnancy body mass index partly explained the ethnic differences, the odds ratio (OR) of being overweight remained higher in the Turkish (OR: 2.66; 95%CI: 1.56-4.53) and Moroccan (OR: 2.11; 95%CI: 1.31-3.38) groups after adjusting for prenatal factors. The remaining differences were largely accounted for by weight gain during the first 6 months of life (postnatal factor). Maternal height, birth weight and gender were independent predictors for overweight at age 2 years, but did not explain the ethnic differences.</p> <p>Conclusion</p> <p>Turkish and Moroccan children in the Netherlands have 2- to 3-fold higher odds for being overweight at age 2 years, which is largely attributed to maternal pre-pregnancy BMI and weight gain during the first 6 months of life. Further study on the underlying factors of this early weight gain is required to tackle ethnic differences in overweight among these children.</p

Instrumentos de avaliação do aleitamento materno e seu uso na prática clínica

RESUMO Objetivos Identificar instrumentos de avaliação da amamentação e sua aplicação na prática clínica, validação e adaptação transcultural. Método Revisão integrativa, realizada em seis bases de dados e em uma biblioteca eletrônica, entre agosto/2014-dezembro/2015, sem limitação temporal. Resultados Foram identificados 19 instrumentos de avaliação do AM. Destes, 12 foram validados e cinco foram adaptados transculturalmente. Quanto à aplicação, destacam-se seu uso para a avaliação do risco de desmame (BAPT) e a percepção/comportamento da mulher em amamentar (BSES-SF e IIFAS). Conclusão A identificação dos instrumentos disponíveis e de suas indicações para a avaliação do AM pode auxiliar profissionais na escolha pelo instrumento a ser utilizado, qualificando a assistência materno-infantil

The Ccr4-Not Complex Interacts with the mRNA Export Machinery

The Ccr4-Not complex is a key eukaryotic regulator of gene transcription and cytoplasmic mRNA degradation. Whether this complex also affects aspects of post-transcriptional gene regulation, such as mRNA export, remains largely unexplored. Human Caf1 (hCaf1), a Ccr4-Not complex member, interacts with and regulates the arginine methyltransferase PRMT1, whose targets include RNA binding proteins involved in mRNA export. However, the functional significance of this regulation is poorly understood.Here we demonstrate using co-immunoprecipitation approaches that Ccr4-Not subunits interact with Hmt1, the budding yeast ortholog of PRMT1. Furthermore, using genetic and biochemical approaches, we demonstrate that Ccr4-Not physically and functionally interacts with the heterogenous nuclear ribonucleoproteins (hnRNPs) Nab2 and Hrp1, and that the physical association depends on Hmt1 methyltransferase activity. Using mass spectrometry, co-immunoprecipitation and genetic approaches, we also uncover physical and functional interactions between Ccr4-Not subunits and components of the nuclear pore complex (NPC) and we provide evidence that these interactions impact mRNA export.Taken together, our findings suggest that Ccr4-Not has previously unrealized functional connections to the mRNA processing/export pathway that are likely important for its role in gene expression. These results shed further insight into the biological functions of Ccr4-Not and suggest that this complex is involved in all aspects of mRNA biogenesis, from the regulation of transcription to mRNA export and turnover

Malignant hyperthermia

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stresses such as vigorous exercise and heat. The incidence of MH reactions ranges from 1:5,000 to 1:50,000–100,000 anesthesias. However, the prevalence of the genetic abnormalities may be as great as one in 3,000 individuals. MH affects humans, certain pig breeds, dogs, horses, and probably other animals. The classic signs of MH include hyperthermia to marked degree, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH, specifically elevation of end-expired carbon dioxide, provides the clinical diagnostic clues. In humans the syndrome is inherited in autosomal dominant pattern, while in pigs in autosomal recessive. The pathophysiologic changes of MH are due to uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Elucidation of the genetic changes has led to the introduction, on a limited basis so far, of genetic testing for susceptibility to MH. As the sensitivity of genetic testing increases, molecular genetics will be used for identifying those at risk with greater frequency. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. Thanks to the dramatic progress in understanding the clinical manifestation and pathophysiology of the syndrome, the mortality from MH has dropped from over 80% thirty years ago to less than 5%