Examining children's physiological functioning is an important direction for understanding the links between interparental conflict and child adjustment. Utilizing growth mixture modeling, the ...present study examined children's cortisol reactivity patterns in response to a marital dispute. Analyses revealed three different patterns of cortisol responses, consistent with both a sensitization and an attenuation hypothesis. Child-rearing disagreements and perceived threat were associated with children exhibiting a rising cortisol pattern, whereas destructive conflict was related to children displaying a flat pattern. Physiologically rising patterns were also linked with emotional insecurity and internalizing and externalizing behaviors. Results supported a sensitization pattern of responses as maladaptive for children in response to marital conflict, with evidence also linking an attenuation pattern with increased family risk. The findings of the present study support children's adrenocortical functioning as one mechanism through which interparental conflict is related to children's coping responses and psychological adjustment.
The separation of CO/N2 mixtures is a challenging problem in the petrochemical sector due to the very similar physical properties of these two molecules, such as size, molecular weight and boiling ...point. To solve this and other challenging gas separations, one requires a holistic approach. The complexity of a screening exercise for adsorption-based separations arises from the multitude of existing porous materials, including metal–organic frameworks. Besides, the multivariate nature of the performance criteria that needs to be considered when designing an optimal adsorbent and a separation process – i.e. an optimal material requires fulfillment of several criteria simultaneously – makes the screening challenging. To address this, we have developed a multi-scale approach combining high-throughput molecular simulation screening, data mining and advanced visualization, as well as process system modelling, backed up by experimental validation. We have applied our recent advances in the engineering of porous materials' morphology to develop advanced monolithic structures. These conformed, shaped monoliths can be used readily in industrial applications, bringing a valuable strategy for the development of advanced materials. This toolbox is flexible enough to be applied to multiple adsorption-based gas separation applications.
We studied the effects of a cold pressor test on the plasma catecholamine levels of ten patients undergoing coronary angiography, to determine whether the pressor changes were related to adrenergic ...activity. To investigate the relative contribution of adrenal medullary catecholamine release, we subjected two adrenalectomised volunteers to the same test. Arterial blood was assayed for dopamine (DA), adrenaline (A) and noradrenaline (NA). We found significant rises in the levels of all three catecholamines in the angiography patients, accompanied by a significant elevation in arterial blood pressure. In both the adrenalectomised patients a rise in blood pressure was seen but no significant rise in plasma catecholamines could be demonstrated. We postulate that although adrenal medullary catecholamine release occurs in response to the cold pressor test, the blood pressure elevation is independent of such adrenal activity. Sampling radial arterial blood may not reflect changes in plasma levels of peripherally released NA.
BackgroundCardiopulmonary exercise testing (CPET), the gold‐standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual‐paced 400 m ...long distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF. The purpose of this study was to develop and validate an estimating equation to estimate VO2peak from average 400 m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA).MethodsAt baseline, women (58%) and men age 70 years and older enrolled in SOMMA (N = 820, 76.2 ± 4.9 years, 86% Non‐Hispanic White) completed a 400 m LDCW (400 m WS = 400 m/completion time in seconds) and symptom‐limited maximal CPET (Modified Balke Protocol). VO2peak (mL/kg/min) was considered the highest 30‐second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7‐day wrist‐worn accelerometer), physical function (Short Physical Performance Battery, range 0–12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0–50), and Borg Rating of Perceived Exertion (RPE, range 6–20) at completion of the 400 m LDCW. Stepwise linear regression was used. Internal validation was completed using data‐splitting method (70%; 30%).ResultsMean VO2peak was 20.2 ± 4.8 mL/kg/min and mean 400 m WS was 1.06 ± 0.2 m/s. Each 0.05 m/s increment in 400 m WS was associated with a 0.40 mL/kg/min higher VO2peak after covariate adjustment. An estimating equation including 400 m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (−0.26) and strong correlation (r = 0.71) between predicted and measured VO2peak values. Bland–Altman plot and regression analyses indicated predicted VO2peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among the highly fit.ConclusionsUsual‐paced 400 m LDCW strongly correlates with direct measures of CRF during CPET in older adults with lower fitness and can be used to test both fitness and function.
Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene ...function and the potential toxicity of therapeutic inhibitors targeting these genes
. Gain-of-kinase-function variants in LRRK2 are known to significantly increase the risk of Parkinson's disease
, suggesting that inhibition of LRRK2 kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns
, the biological consequences of LRRK2 inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in LRRK2 observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD)
, 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in LRRK2. Experimental validation of three variants, combined with previous work
, confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in LRRK2 reduce LRRK2 protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
Abstract Although frequent heavy drinking has been associated with decreased odds of quitting smoking, the extent to which smoking cessation is associated with decreased alcohol consumption is less ...clear. The present study examined over a 2-year period whether individuals who quit smoking for at least 6 months, compared to those making a quit attempt but continuing to smoke and to those not making any attempt to quit smoking, showed greater reductions in drinking frequency, average weekly quantity of alcohol consumption, and frequency of heavy drinking. Data were drawn from the International Tobacco Control Four Country Survey, a prospective cohort study of smokers in Australia, Canada, the UK, and the US. A total of 3614 participants provided alcohol data at one study wave and were re-interviewed 2 years later regarding smoking and alcohol use. Consistent with prior studies, individuals who drank heavily (4+/5+ drinks for women and men, respectively) more than once a week had especially low rates of quitting smoking. There was little evidence, however, that those who achieved sustained smoking cessation made greater reductions in drinking compared to those who continued to smoke. These results were consistent across countries and sexes and did not differ significantly by heaviness of smoking. Results indicate that quitting smoking, in and of itself, does not lead to meaningful changes in alcohol use. Therefore, interventions and policies directed towards increasing smoking cessation are unlikely to affect rates of hazardous drinking unless they include specific elements that address alcohol consumption.
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