A Thermodynamic Model for Multivalency in 14-3-3 Protein-Protein Interactions

Protein-protein interactions (PPIs) are at the core of molecular control over cellular function. Multivalency in PPI formation, such as via proteins with multiple binding sites and different valencies, requires fundamental understanding to address correlated challenges in pathologies and drug development. Thermodynamic binding models are needed to provide frameworks for describing multivalent PPIs. We established a model based on ditopic host-guest systems featuring the effective molarity, a hallmark property of multivalency, as a prime parameter governing the intramolecular binding in divalent interactions. By way of illustration, we study the interaction of the bivalent 14-3-3 protein scaffold with both the nonavalent CFTR and the hexavalent LRRK2 proteins, determining the underlying thermodynamics and providing insights into the role of individual sites in the context of the multivalent platform. Fitting of binding data reveals enthalpy-entropy correlation in both systems. Simulations of speciations for the entire phosphorylated protein domains reveal that the CFTR protein preferably binds to 14-3-3 by combinations including the strongest binding site pS768, but that other binding sites take over when this site is eliminated, leading to only a minor decrease in total affinity for 14-3-3. For LRRK2, two binding sites dominate the complex formation with 14-3-3, but the distantly located pS1444 site also plays a role in complex formation. Thermodynamic modeling of these multivalent PPIs allowed analyzing and predicting the effects of individual sites regarding their modulation via, for example, (de)phosphorylation or small-molecule targeting. The results specifically bring forward the potential of PPI stabilization, as an entry for drug discovery for multivalent PPIs.</p

The relationship between birth order and acute alcohol intoxication among Dutch adolescents

Background: Prior research demonstrated the relationship between birth order and adolescent risky behavior. The possible connection between the presence of siblings and birth order and underage alcohol abuse is unknown. Methods: Our study involves 10 years of data collection on underage alcohol intoxication in Dutch hospitals. A total of 2,234 patients were included in the current study. Results: Adolescents treated for alcohol intoxication less often have no siblings (6.7%) than the population has (14.8%). Furthermore, middle and youngest children are overrepresented in the patient population. Conclusion: The presence of older siblings is a risk factor for acute alcohol intoxication

Physical properties of Brazil nuts.

The Brazil-nut, also known as Para-nut, is widely used as food and in cosmetic industries. The seeds are rich in lipids and protein, and also present a considerable amount of selenium. Limited research has been conducted on postharvest of the Brazil nut, being an important information to design equipment related to aeration, drying, storage and transportation steps. Thus, the objective of this study was to determine the physical properties of the Brazil-nut with and without tegument. The dimensions found for the almonds with tegument were 39.35 mm in the X axis, 24.19 mm in the Y axis, and 17.88 mm in the Z axis. However for the almond without tegument the values were 31.05 mm in X, 14.38 in Y and 15.91 mm in Z axis. The sphericity was 66.40% and 51.59% for the kernels with and without seed tegument respectively. The kernels with and without tegument presented sphericity of 63.00% and 47.72% respectively. The mass of 1000 almonds was 6.13 kg for almond with teguments and 3.18 kg for almonds without teguments. Specific mass of 0.947 g.cm-3 and 1.003 g.cm-3 for the kernels with and without tegument, coupled with a porosity of 46.88% and 37.60% and, resulting on a bulk density of 0.504 g.cm-3 and 0.626 g.cm-3 for almonds with and without teguments respectively. Finally, the angle of repose for the kernels with teguments was 36.37°. A castanha-do-brasil, também conhecida como castanha-do-pará, é muito utilizada na alimentação humana e na indústria cosmética. As sementes são ricas em lipídeos e proteínas, apresentando ainda uma quantidade considerável de Selênio. Poucas pesquisas vêm sendo realizadas na pós-colheita do produto, sendo as propriedades físicas importantes para o desenvolvimento de equipamentos relacionados à aeração, secagem, armazenamento e transporte de produtos. Assim, neste trabalho, teve-se por objetivos: determinar as propriedades físicas da castanha-do-brasil com e sem tegumento. O tamanho para as amêndoas com tegumento, foi de 39,35 mm no eixo X, 24,19 mm no eixo Y e 17,88 mm no eixo Z; já para a amêndoa sem tegumento os valores foram de 31,05 mm em X, 14,38 mm em Y e 15,91 em Z. A esfericidade foi de 66,40% e 51,59%, para as amêndoas com e sem tegumento, respectivamente. 63,00% e 47,72% foram os valores de esfericidade encontrados para as amêndoas com e sem tegumento, respectivamente. A massa de 1.000 amêndoas foi de 6,13 kg para a amêndoa com tegumento e de 3,18 kg para amêndoas sem tegumento. Valores de massa específica de 0,947 g.cm-3 e de 1,003 g.cm-3 para as amêndoas com e sem tegumento, associados a uma porosidade de 46,88% e 37,60%, produziram uma massa específica aparente de 0,504 g.cm-3 e de 0,626 g.cm-3. Finalmente, o ângulo de repouso para as amêndoas com tegumento foi de 36,37°

Like No Other?:A Family-Specific Network Approach to Parenting Adolescents

Numerous theories suggest that parents and adolescents influence each other in diverse ways; however, whether these influences differ between subgroups or are unique to each family remains uncertain. Therefore, this study explored whether data-driven subgroups of families emerged that exhibited a similar daily interplay between parenting and adolescent affective well-being. To do so, Subgrouping Group Iterative Multiple Model Estimation (S-GIMME) was used to estimate family-specific dynamic network models, containing same- and next-day associations among five parenting practices (i.e., warmth, autonomy support, psychological control, strictness, monitoring) and adolescent positive and negative affect. These family-specific networks were estimated for 129 adolescents (M age = 13.3, SD age = 1.2, 64% female, 87% Dutch), who reported each day on parenting and their affect for 100 consecutive days. The findings of S-GIMME did not identify data-driven subgroups sharing similar parenting-affect associations. Instead, each family displayed a unique pattern of temporal associations between the different practices and adolescent affect. Thus, the ways in which parenting practices were related to adolescents’ affect in everyday life were family specific.</p

Like No Other?:A Family-Specific Network Approach to Parenting Adolescents

Numerous theories suggest that parents and adolescents influence each other in diverse ways; however, whether these influences differ between subgroups or are unique to each family remains uncertain. Therefore, this study explored whether data-driven subgroups of families emerged that exhibited a similar daily interplay between parenting and adolescent affective well-being. To do so, Subgrouping Group Iterative Multiple Model Estimation (S-GIMME) was used to estimate family-specific dynamic network models, containing same- and next-day associations among five parenting practices (i.e., warmth, autonomy support, psychological control, strictness, monitoring) and adolescent positive and negative affect. These family-specific networks were estimated for 129 adolescents (M age = 13.3, SD age = 1.2, 64% female, 87% Dutch), who reported each day on parenting and their affect for 100 consecutive days. The findings of S-GIMME did not identify data-driven subgroups sharing similar parenting-affect associations. Instead, each family displayed a unique pattern of temporal associations between the different practices and adolescent affect. Thus, the ways in which parenting practices were related to adolescents’ affect in everyday life were family specific.</p

Associations between Socio-Economic Status and Unfavorable Social Indicators of Child Wellbeing; a Neighbourhood Level Data Design

Background: Living in deprivation is related to ill health. Differences in health outcomes between neighbourhoods may be attributed to neighbourhood socio-economic status (SES). Additional to differences in health, neighbourhood differences in child wellbeing could also be attributed to neighbourhood SES. Therefore, we aimed to investigate the association between neighbourhood deprivation, and social indicators of child wellbeing. Methods: Aggregated data from 3565 neighbourhoods in 390 municipalities in the Netherlands were eligible for analysis. Neighbourhood SES scores and neighbourhood data on social indicators of child wellbeing were used to perform repeated measurements, with one year measurement intervals, over a period of 11 years. Linear mixed models were used to estimate the associations between SES score and the proportion of unfavorable social indicators of child wellbeing. Results: After adjustment for year, population size, and clustering within neighbourhoods and within a municipality, neighbourhood SES was inversely associated with the proportion of ‘children living in families on welfare’ (estimates with two cubic splines: −3.59 [CI: −3.99; −3.19], and −3.00 [CI: −3.33; −2.67]), ‘delinquent youth’ (estimate −0.26 [CI: −0.30; −0.23]) and ‘unemployed youth’ (estimates with four cubic splines: −0.41 [CI: −0.57; −0.25], −0.58 [CI: −0.73; −0.43], −1.35 [−1.70; −1.01], and −0.96 [1.24; −0.70]). Conclusions: In this study using repeated measurements, a lower neighbourhood SES was significantly associated with a higher prevalence of unfavorable social indicators of child wellbeing. This contributes to the body of evidence that neighbourhood SES is strongly related to child health and a child’s ability to reach its full potential in later life. Future studies should consist of larger longitudinal datasets, potentially across countries, and should attempt to take the interpersonal variation into account with more individual-level data on SES and outcomes