Investigation of microglial diversity in a LRRK2 G2019S mouse model of Parkinson's disease.

Microglia contribute to the outcomes of various pathological conditions including Parkinson's disease (PD). Microglia are heterogenous, with a variety of states recently identified in aging and neurodegenerative disease models. Here, we delved into the diversity of microglia in a preclinical PD model featuring the G2019S mutation in LRRK2, a known pathological mutation associated with PD. Specifically, we investigated the 'dark microglia' (DM) and the 'disease-associated microglia' (DAM) which present a selective enrichment of CLEC7A expression. In the dorsal striatum - a region affected by PD pathology - extensive ultrastructural features of cellular stress as well as reduced direct cellular contacts, were observed for microglia from old LRRK2 G2019S mice versus controls. In addition, DM were more prevalent while CLEC7A-positive microglia had extensive phagocytic ultrastructural characteristics in the LRRK2 G2019S mice. Furthermore, our findings revealed a higher proportion of DM in LRRK2 G2019S mice, and an increased number of CLEC7A-positive cells with age, exacerbated by the pathological mutation. These CLEC7A-positive cells exhibited a selective enrichment of ameboid morphology and tended to cluster in the affected animals. In summary, we provide novel insights into the occurrence and features of recently defined microglial states, CLEC7A-positive cells and DM, in the context of LRRK2 G2019S PD pathology.

Nurse Preceptors' Experiences of an Online Strength-Based Nursing Course in Clinical Teaching.

Background: Online educational programs for nurse preceptors have been created based on various theoretical frameworks; however, no programs using a Strengths-Based Nursing (SBN) approach could be located. Purpose: This qualitative descriptive study explored the nurse preceptors' experiences in using a SBN approach to provide clinical teaching to nursing students after completing an online SBN clinical teaching course. Methods: Semi-structured interviews were conducted with six nurses. Data was thematically analyzed. Findings: Although their levels of familiarity with SBN varied, all preceptors acknowledged that using a SBN approach in clinical teaching benefits both students and educators. They reported that it empowered students and that it allowed them to discover their strengths. Getting to know their students helped the preceptors provide tailored learning experiences and feedback. Using the SBN approach simultaneously enhanced the preceptors' self-confidence and created opportunities for shared learning. Conclusion: Using a strengths' approach offers nurse preceptors a powerful tool to facilitate student learning and skills development in clinical practice.

Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions.

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia-neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1-CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

Timescales for pluton growth, magma-chamber formation and super-eruptions.

Generation of silicic magmas leads to emplacement of granite plutons, huge explosive volcanic eruptions and physical and chemical zoning of continental and arc crust1-7. Whereas timescales for silicic magma generation in the deep and middle crust are prolonged8, magma transfer into the upper crust followed by eruption is episodic and can be rapid9-12. Ages of inherited zircons and sanidines from four Miocene ignimbrites in the Central Andes indicate a gap of 4.6 Myr between initiation of pluton emplacement and onset of super-eruptions, with a 1-Myr cyclicity. We show that inherited zircons and sanidine crystals were stored at temperatures <470 °C in these plutons before incorporation in ignimbrite magmas. Our observations can be explained by silicic melt segregation in a middle-crustal hot zone with episodic melt ascent from an unstable layer at the top of the zone with a timescale governed by the rheology of the upper crust. After thermal incubation of growing plutons, large upper-crustal magma chambers can form in a few thousand years or less by dike transport from the hot-zone melt layer. Instability and disruption of earlier plutonic rock occurred in a few decades or less just before or during super-eruptions.

The patient advisor, an organizational resource as a lever for an enhanced oncology patient experience (PAROLE-onco): a longitudinal multiple case study protocol.

BACKGROUND: Quebec is one of the Canadian provinces with the highest rates of cancer incidence and prevalence. A study by the Rossy Cancer Network (RCN) of McGill university assessed six aspects of the patient experience among cancer patients and found that emotional support is the aspect most lacking. To improve this support, trained patient advisors (PAs) can be included as full-fledged members of the healthcare team, given that PA can rely on their knowledge with experiencing the disease and from using health and social care services to accompany cancer patients, they could help to round out the health and social care services offer in oncology. However, the feasibility of integrating PAs in clinical oncology teams has not been studied. In this multisite study, we will explore how to integrate PAs in clinical oncology teams and, under what conditions this can be successfully done. We aim to better understand effects of this PA intervention on patients, on the PAs themselves, the health and social care team, the administrators, and on the organization of services and to identify associated ethical and legal issues. METHODS/DESIGN: We will conduct six mixed methods longitudinal case studies. Qualitative data will be used to study the integration of the PAs into clinical oncology teams and to identify the factors that are facilitators and inhibitors of the process, the associated ethical and legal issues, and the challenges that the PAs experience. Quantitative data will be used to assess effects on patients, PAs and team members, if any, of the PA intervention. The results will be used to support oncology programs in the integration of PAs into their healthcare teams and to design a future randomized pragmatic trial to evaluate the impact of PAs as full-fledged members of clinical oncology teams on cancer patients' experience of emotional support throughout their care trajectory. DISCUSSION: This study will be the first to integrate PAs as full-fledged members of the clinical oncology team and to assess possible clinical and organizational level effects. Given the unique role of PAs, this study will complement the body of research on peer support and patient navigation. An additional innovative aspect of this study will be consideration of the ethical and legal issues at stake and how to address them in the health care organizations.

Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain.

Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.

Glutamate-induced excitotoxicity in Parkinson's disease: The role of glial cells.

Glutamate is the major excitatory neurotransmitter in the central nervous system. Glutamate transmission efficiency depends on the correct functionality and expression of a plethora of receptors and transporters, located both on neurons and glial cells. Of note, glutamate reuptake by dedicated transporters prevents its accumulation at the synapse as well as non-physiological spillover. Indeed, extracellular glutamate increase causes aberrant synaptic signaling leading to neuronal excitotoxicity and death. Moreover, extrasynaptic glutamate diffusion is strongly associated with glia reaction and neuroinflammation. Glutamate-induced excitotoxicity is mainly linked to an impaired ability of glial cells to reuptake and respond to glutamate, then this is considered a common hallmark in many neurodegenerative diseases, including Parkinson's disease (PD). In this review, we discuss the function of astrocytes and microglia in glutamate homeostasis, focusing on how glial dysfunction causes glutamate-induced excitotoxicity leading to neurodegeneration in PD.

The role of semantic memory in the recognition of emotional valence conveyed by written words.

The main goal of this study was to examine the role of semantic memory in the recognition of emotional valence conveyed by words. Eight participants presenting with the semantic variant of primary progressive aphasia (svPPA) and 33 healthy control participants were administered three tasks designed to investigate the formal association between the recognition of emotional valence conveyed by words and the lexical and semantic processing of these words. Results revealed that individuals with svPPA showed deficits in the recognition of negative emotional valence conveyed by words. Moreover, results evidenced that their performance in the recognition of emotional valence was better for correctly than for incorrectly retrieved lexical entries of words, while their performance was comparable for words that were correctly or incorrectly associated with semantic concepts. These results suggest that the recognition of emotional valence conveyed by words relies on the retrieval of lexical, but not semantic, representations of words.

Prediction model optimization using full model selection with regression trees demonstrated with FTIR data from bovine milk.

Predictive modeling is the development of a model that is best able to predict an outcome based on given input variables. Model algorithms are different processes that are used to define functions that transform the data within models. Common algorithms include logistic regression (LR), linear discriminant analysis (LDA), classification and regression trees (CART), naïve Bayes (NB), and k-nearest neighbor (KNN). Data preprocessing option, such as feature extraction and reduction, and model algorithms are commonly selected empirically in epidemiological studies even though these decisions can significantly affect model performance. Accordingly, full model selection (FMS) methods were developed to provide a systematic approach to select predictive modeling methods; however, current limitations of FMS, such as its dependency on user-selected hyperparameters, have prevented their routine incorporation into analyses for model performance optimization. Here we present the use of regression trees as an innovative method to apply FMS. Regression tree FMS (rtFMS) requires the development of a model for every combination of predictive modeling method options under consideration. The iterated, cross-validation performances of these models are then passed through a regression tree for selection of a final model. We demonstrate the benefits of rtFMS using a milk Fourier transform infrared spectroscopy dataset, wherein we build prediction models for two blood metabolic health parameters in dairy cows, nonesterified fatty acids (NEFA) and ß-hydroxybutyrate acid (BHBA). The goal for building NEFA and BHBA prediction models is to provide a milk-based screening tool for metabolic health in dairy cattle that can be incorporated automatically in milk analysis routines. These models could be used in conjunction with physical exams, cow side tests, and other indications to initiate medical intervention. In contrast to previously reported FMS methods, rtFMS is not a black box, is simple to implement and interpret, it does not have hyperparameters, and it illustrates the relative importance of modeling options. Additionally, rtFMS allows for indirect comparisons among models developed using different datasets. Finally, rtFMS eliminates user bias due to personal preference for certain methods and rtFMS removes the dependency on published comparisons of methods. Thus, rtFMS provides clear benefits over the empirical selection of data preprocessing options and model algorithms.

The ß-adrenoceptor blocker propranolol ameliorates compulsive-like gambling behaviour in a rodent slot machine task: implications for iatrogenic gambling disorder.

Previous work has shown that chronic administration of the dopamine D2/3 receptor agonist ropinirole invigorates performance on a rodent slot machine task (rSMT). This behavioural change appears superficially similar to the iatrogenic gambling disorder (GD) observed in a sub-set of patients with Parkinson's disease (PD), and has been associated with increased activation of the intra-cellular signalling proteins GSK3ß and CREB in the striatum. Here, we wanted to determine whether this response to ropinirole could be attenuated by targeting these signalling proteins, and if the loss of dopaminergic innervation characteristic of PD would alter ropinirole's effects on the rSMT. Male Long Evans rats were trained on the rSMT. Dopaminergic terminals innervating the dorsolateral striatum were then lesioned bilaterally using the neurotoxin 6-hydroxydopamine hydrochloride (6-OHDA). Subsequently animals were implanted with osmotic mini-pumps delivering ropinirole. Lastly, animals were given dietary lithium (Li+ ), to inhibit the activation of GSK3ß, or injections of the ß-adrenoceptor antagonist propranolol, which potently inhibits CREB as a secondary mechanism of action, and any changes in ropinirole-induced increases in compulsive-like engagement in the rSMT evaluated. Chronic ropinirole increased the number of trials animals completed, reproducing our original finding. This increase in task engagement was not altered in animals with 6-OHDA lesions, a putative model of early PD. In addition, the effects of ropinirole were not attenuated by administration of Li+ , but were ameliorated by propranolol. These data suggest that propranolol may represent a potential pharmacotherapy for the treatment of iatrogenic gambling.

The short-term effects of a mass reach physical activity campaign: an evaluation using hierarchy of effects model and intention profiles.

BACKGROUND: Mass reach physical activity campaigns are designed to deliver physical-activity related messages to a large population across different media including print, television, radio, and websites. Few evaluations have examined the short-term effects of a mass reach campaign on participants who were engaged with the campaign. The current research examined the short-term effects of the ParticipACTION 150 Play List, a mass reach physical activity campaign, on participants who registered with the campaign website. METHODS: Participants (N = 7801) completed a registration questionnaire measuring demographic information, awareness and recall of physical activity and sport advertising, and self-reported number of activities tried or planned to try from the 150 Play List. A follow-up survey was completed by 1298 participants from the original sample. Additional questions assessed experience with the 150 Play List and attitudes towards campaign advertisements. RESULTS: Approximately 14.5% of participants cited the ParticipACTION 150 Play List and 23.6% mentioned a 'getting active' message when recalling advertisements. Those who named the 150 Play List or getting active reported more activities tried and more activities planned than those who did not. They were also more likely to say they had tried a new activity and planned ongoing participation. It was also found that participants with a disability were more likely to have tried a new activity compared to those not in a minority group. Other correlates of trying new activities at follow-up were younger age, more positive reported experience with the 150 Play List, and more favourable attitudes towards campaign advertisements. Those who did not intend continued participation, or who were unsure at baseline and then decided against continued participation at follow-up, reported they were less sedentary or encouraging others to be active. CONCLUSIONS: This research addresses the gap in evidence regarding the efficacy of mass reach physical activity campaigns by informing whether a year-long campaign like the 150 Play List can be effective in influencing the behavior of those engaged with the campaign. The results reinforce the idea that 'top of mind' awareness should be measured. Investigating intention profiles can help inform campaign impacts and continuation intentions.

Inequality in physical activity, sedentary behaviour, sleep duration and risk of obesity in children: a 12-country study.

OBJECTIVE: Studies examining associations between movement behaviours (i.e. physical activity, sedentary behaviour and sleep duration) and obesity focus on average values of these movement behaviours, despite important within-country and between-country variability. A better understanding of movement behaviour inequalities is important for developing public health policies and behaviour-change interventions. The objective of this ecologic analysis at the country level was to determine if inequality in movement behaviours is a better correlate of obesity than average movement behaviour volume in children from all inhabited continents of the world. METHODS: This multinational, cross-sectional study included 6,128 children 9-11 years of age. Moderate-to-vigorous physical activity (MVPA), total sedentary time (SED) and sleep period time were monitored over 7 consecutive days using waist-worn accelerometry. Screen time was self-reported. Inequality in movement behaviours was determined using Gini coefficients (ranging from 0 [complete equality] to 1 [complete inequality]). RESULTS: The largest inequality in movement behaviours was observed for screen time (Gini of 0.32; medium inequality), followed by MVPA (Gini of 0.21; low inequality), SED (Gini of 0.07; low inequality) and sleep period time (Gini of 0.05; low inequality). Average MVPA (h d-1) was a better correlate of obesity than MVPA inequality (r = -0.77 vs. r = 0.00, p = 0.03). Average SED (h d-1) was also a better correlate of obesity than SED inequality (r = 0.52 vs. r = -0.32, p = 0.05). Differences in associations for screen time and sleep period time were not statistically significant. MVPA in girls was found to be disproportionally lower in countries with more MVPA inequality. CONCLUSIONS: Findings from this study show that average MVPA and SED should continue to be used in population health studies of children as they are better correlates of obesity than inequality in these behaviours. Moreover, the findings suggest that MVPA inequality could be greatly reduced through increases in girls' MVPA alone.

Identifying poor metabolic adaptation during early lactation in dairy cows using cluster analysis.

Currently, cows with poor metabolic adaptation during early lactation, or poor metabolic adaptation syndrome (PMAS), are often identified based on detection of hyperketonemia. Unfortunately, elevated blood ketones do not manifest consistently with indications of PMAS. Expected indicators of PMAS include elevated liver enzymes and bilirubin, decreased rumen fill, reduced rumen contractions, and a decrease in milk production. Cows with PMAS typically are higher producing, older cows that are earlier in lactation and have greater body condition score at the start of lactation. It was our aim to evaluate commonly used measures of metabolic health (input variables) that were available [i.e., blood ß-hydroxybutyrate acid, milk fat:protein ratio, blood nonesterified fatty acids (NEFA)] to characterize PMAS. Bavarian farms (n = 26) with robotic milking systems were enrolled for weekly visits for an average of 6.7 wk. Physical examinations of the cows (5-50 d in milk) were performed by veterinarians during each visit, and blood and milk samples were collected. Resulting data included 790 observations from 312 cows (309 Simmental, 1 Red Holstein, 2 Holstein). Principal component analysis was conducted on the 3 input variables, followed by K-means cluster analysis of the first 2 orthogonal components. The 5 resulting clusters were then ascribed to low, intermediate, or high PMAS classes based on their degree of agreement with expected PMAS indicators and characteristics in comparison with other clusters. Results revealed that PMAS classes were most significantly associated with blood NEFA levels. Next, we evaluated NEFA values that classify observations into appropriate PMAS classes in this data set, which we called separation values. Our resulting NEFA separation values [<0.39 mmol/L (95% confidence limits = 0.360-0.410) to identify low PMAS observations and ≥0.7 mmol/L (95% confidence limits = 0.650-0.775) to identify high PMAS observations] were similar to values determined for Holsteins in conventional milking settings diagnosed with hyperketonemia and clinical symptoms such as anorexia and a reduction in milk yield, as reported in the literature. Future studies evaluating additional clinical and laboratory data, breeds, and milking systems are needed to validate these finding. The aim of future studies would be to build a PMAS prediction model to alert producers of cows needing attention and help evaluate on-farm metabolic health management at the herd level.

Thresholds of physical activity associated with obesity by level of sedentary behaviour in children.

BACKGROUND: It is unknown whether moderate-to-vigorous physical activity (MVPA) thresholds for obesity should be adapted depending on level of sedentary behaviour in children. OBJECTIVE: The objective of the study is to determine the MVPA thresholds that best discriminate between obese and non-obese children, by level of screen time and total sedentary time in 12 countries. METHODS: This multinational, cross-sectional study included 6522 children 9-11 years of age. MVPA and sedentary time were assessed using waist-worn accelerometry, while screen time was self-reported. Obesity was defined according to the World Health Organization reference data. RESULTS: Receiver operating characteristic curve analyses showed that the best thresholds of MVPA to predict obesity ranged from 53.8 to 73.9 min d-1 in boys and from 41.7 to 58.7 min d-1 in girls, depending on the level of screen time. The MVPA cut-offs to predict obesity ranged from 37.9 to 75.9 min d-1 in boys and from 32.5 to 62.7 min d-1 in girls, depending on the level of sedentary behaviour. The areas under the curve ranged from 0.57 to 0.73 ('fail' to 'fair' accuracy), and most sensitivity and specificity values were below 85%, similar to MVPA alone. Country-specific analyses provided similar findings. CONCLUSIONS: The addition of sedentary behaviour levels to MVPA did not result in a better predictive ability to classify children as obese/non-obese compared with MVPA alone.

The adiposity of children is associated with their lifestyle behaviours: a cluster analysis of school-aged children from 12 nations.

BACKGROUND: The relationship between children's adiposity and lifestyle behaviour patterns is an area of growing interest. OBJECTIVES: The objectives of this study are to identify clusters of children based on lifestyle behaviours and compare children's adiposity among clusters. METHODS: Cross-sectional data from the International Study of Childhood Obesity, Lifestyle and the Environment were used. PARTICIPANTS: the participants were children (9-11 years) from 12 nations (n = 5710). MEASURES: 24-h accelerometry and self-reported diet and screen time were clustering input variables. Objectively measured adiposity indicators were waist-to-height ratio, percent body fat and body mass index z-scores. ANALYSIS: sex-stratified analyses were performed on the global sample and repeated on a site-wise basis. Cluster analysis (using isometric log ratios for compositional data) was used to identify common lifestyle behaviour patterns. Site representation and adiposity were compared across clusters using linear models. RESULTS: Four clusters emerged: (1) Junk Food Screenies, (2) Actives, (3) Sitters and (4) All-Rounders. Countries were represented differently among clusters. Chinese children were over-represented in Sitters and Colombian children in Actives. Adiposity varied across clusters, being highest in Sitters and lowest in Actives. CONCLUSIONS: Children from different sites clustered into groups of similar lifestyle behaviours. Cluster membership was linked with differing adiposity. Findings support the implementation of activity interventions in all countries, targeting both physical activity and sedentary time.

Sources of variability in childhood obesity indicators and related behaviors.

The purpose of this study was to describe sources of variability in obesity-related variables in 6022 children aged 9-11 years from 12 countries. The study design involved recruitment of students, nested within schools, which were nested within study sites. Height, weight and waist circumference (WC) were measured and body mass index (BMI) was calculated; sleep duration and total and in-school moderate-to-vigorous physical activity (MVPA) and sedentary time were measured by accelerometry; and diet scores were obtained by questionnaire. Variance in most variables was largely explained at the student level: BMI (91.9%), WC (93.5%), sleep (75.3%), MVPA (72.5%), sedentary time (76.9%), healthy diet score (88.3%), unhealthy diet score (66.2%), with the exception of in-school MVPA (53.8%) and in-school sedentary time (25.1%). Variance explained at the school level ranged from 3.3% for BMI to 29.8% for in-school MVPA, and variance explained at the site level ranged from 3.2% for WC to 54.2% for in-school sedentary time. In general, more variance was explained at the school and site levels for behaviors than for anthropometric traits. Given the variance in obesity-related behaviors in primary school children explained at school and site levels, interventions that target policy and environmental changes may enhance obesity intervention efforts.

Neonatal maternal separation opposes the facilitatory effect of castration on the respiratory response to hypercapnia of the adult male rat: Evidence for the involvement of the medial amygdala.

Respiratory manifestations of panic disorder (PD) include a greater respiratory instability and enhanced responsiveness to CO2 compared to normal individuals. Although the prevalence of PD is approximately three times greater in women compared to men, the origins of this sexual dimorphism remain poorly understood. Similar to PD patients, adult female rats previously subjected to neonatal maternal separation (NMS) show an increase in their ventilatory response to CO2 . Because this effect of NMS is not observed in males, we hypothesised that testosterone prevents NMS-induced hyper-responsiveness to CO2 . Pups subjected to NMS were placed in an incubator for 3 h d-1 from postnatal days 3-12. Control pups remained undisturbed. At adulthood (8-10 weeks of age), rats were then subjected either to sham surgery or castration. Fourteen days later, breathing was measured at rest (room air) and during acute exposure to hypercapnia (5 and 10% CO2 for 10 minutes each) using plethysmography. To gain insight into the mechanisms involved, c-fos expression was used as an indicator of neuronal activation. Brains were collected following air or CO2 exposure for quantification of c-fos positive cells by immunohistochemistry in selected regions, including the paraventricular nucleus of the hypothalamus, the dorsomedial hypothalamus and the amygdalar complex. Castration produced a 100% increase of hyperventilatory response to 10% CO2 in control rats. Unexpectedly, castration had no effect on the hyperventilatory response of NMS rats. The intensity of the hypercapnic response was inversely correlated with c-fos expression in the medial amygdala. We conclude that testosterone prevents the hyper-responsiveness to CO2 , whereas NMS attenuates sensitivity to hormone withdrawal. We propose that an inhibitory influence from the medial amygdala contributes to this effect.

TC-PTP regulates the IL-7 transcriptional response during murine early T cell development.

Cytokines play a critical role in directing the discrete and gradual transcriptional changes that define T cell development. The interleukin-7 receptor (IL-7R), via its activation of the JAK-STAT pathway, promotes gene programs that change dynamically as cells progress through T cell differentiation. The molecular mechanism(s) directing differential gene expression downstream of the IL-7R are not fully elucidated. Here, we have identified T cell protein tyrosine phosphatase (TC-PTP), also known as PTPN2, as a negative regulator of IL-7R-STAT signaling in T cell progenitors, contributing to both the quantitative and qualitative nature of STAT-gene targeting. Novel genetic strategies used to modulate TC-PTP expression demonstrate that depletion of TC-PTP expression heightens the phosphorylation of STAT family members, causing aberrant expression of an interferon-response gene profile. Such molecular re-programming results in deregulation of early development checkpoints culminating in inefficient differentiation of CD4+CD8+ double positive cells. TC-PTP is therefore shown to be required to safeguard the dynamic transcriptome necessary for efficient T cell differentiation.

Associations between meeting combinations of 24-h movement guidelines and health-related quality of life in children from 12 countries.

OBJECTIVES: To examine whether meeting vs not meeting movement/non-movement guidelines (moderate-to-vigorous physical activity [MVPA], screen time, sleep duration), and combinations of these recommendations, are associated with health-related quality of life (HRQoL) in children from 12 countries in five major geographic regions of the world and explore whether the associations vary by study site. STUDY DESIGN: Observational, multinational cross-sectional study. METHODS: This study included 6106 children aged 9-11 years from sites in Australia, Brazil, Canada, China, Colombia, Finland, India, Kenya, Portugal, South Africa, the United Kingdom, and the United States. Participants completed the KIDSCREEN-10 to provide a global measure of their HRQoL. Sleep duration and MVPA were assessed using 24-h accelerometry. Screen time was assessed through self-report. Meeting the recommendations was defined as ≥60 min/day for MVPA, ≤2 h/day for screen time, and between 9 and 11 h/night for sleep duration. Age, sex, highest parental education, unhealthy diet pattern score, and body mass index z-score were included as covariates in statistical models. RESULTS: In the full sample, children meeting the screen time recommendation, the screen time + sleep recommendation, and all three recommendations had significantly better HRQoL than children not meeting any of these guidelines. Differences in HRQoL scores between sites were also found within combinations of movement/non-movement behaviors. For example, while children in Australia, Canada, and USA self-reported better HRQoL when meeting all three recommendations, children in Kenya and Portugal reported significantly lower HRQoL when meeting all three recommendations (relative to not meeting any). CONCLUSIONS: Self-reported HRQoL is generally higher when children meet established movement/non-movement recommendations. However, differences between study sites also suggest that interventions aimed at improving lifestyle behaviors and HRQoL should be locally and culturally adapted.