Low-grade systemic inflammation stimulates microglial turnover and accelerates the onset of Alzheimer's-like pathology.

Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aß accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.

Kairos study protocol: a multidisciplinary approach to the study of school timing and its effects on health, well-being and students' performance.

Recent evidence from chronobiology, chssronomedicine and chronopsychology shows that the organisation of social time (e.g., school schedules) generally does not respect biological time. This raises concerns about the impact of the constant mismatch between students' social and internal body clocks on their health, well-being and academic performance. The present paper describes a protocol used to investigate the problem of (de) synchronisation of biological times (chronotypes) in childhood and youth in relation to school times. It studies the effects of student chronotype vs. school schedule matches/mismatches on health behaviours (e.g., how many hours students sleep, when they sleep, eat, do physical activity, spend time outdoors in daylight) and learning (verbal expression, spatial structuring, operations) and whether alert-fatigue levels mediate this effect alignments/misalignments on learning (verbal expression, spatial structuring, operations) and their mediation by alert-fatigue levels. The novelty of our protocol lies in its multidisciplinary and mixed methodology approach to a relevant and complex issue. It draws on up-to-date knowledge from the areas of biology, medicine, psychology, pedagogy and sociology. The methods employed include a varied repertoire of techniques from hormonal analysis (cortisol and melatonin), continuous activity and light monitoring, self-registration of food intake, sleep timings, exercise and exposure to screens, alongside with systematic application of cognitive performance tests (e.g., memory, reasoning, calculation, attention) and self-reported well-being. This comprehensive and interdisciplinary protocol should support evidence-based education policy measures related to school time organisation. Appropriate and healthier school timetables will contribute to social change, healthier students and with more efficient learning. The results of studies using a similar methodology in other countries would ensure replication and comparability of results and contribute to knowledge to support policy making.

Changes in the network structure of well-being components in adolescents in the school context: A 2-year longitudinal study.

Disentangling the connections between subjective and psychological well-being may help practitioners identify effective targets of intervention to promote mental health in school settings. Based on theoretical foundations of well-being, the present study utilized psychometric network analysis to explore prospective associations between the subjective and psychological well-being of adolescents over 2 years. To this end, a cross-sectional network was estimated at Time 1 (n = 560) and Time 2 (n = 281), followed by a longitudinal network incorporating individual changes across time points in each component (n = 235). The networks included different indicators of subjective (e.g., life satisfaction, positive affect, negative affect) and psychological well-being measured by means of self-reported questionnaires. The results revealed direct connections between indicators of subjective and psychological well-being over time. Positive affect, especially feeling happy and satisfied, exhibited most of these connections. Only one negative longitudinal association emerged, which involved negative affect (e.g., feeling worried) and psychological well-being. The suitability of the network approach to represent the structure of subjective and psychological well-being can be used to widen research on adolescents' well-being. Considering the longitudinal associations identified, the present study makes an exploratory hypothesis to propose specific connectors between subjective and psychological well-being as potential targets for interventions aimed at promoting adolescents' mental health.

Mediation effect of emotional self-regulation in the relationship between physical activity and subjective well-being in Chilean adolescents.

Adolescents' subjective well-being and physical activity have been found to be correlated in previous studies. However, the underlying mechanisms of this relationship, especially the potential contribution of emotional self-regulation, have received little attention. This study aims to investigate the extent to which emotional self-regulation mediates the association between adolescent physical activity habits and their subjective well-being. The study involved 9585 adolescents who completed a cross-sectional survey. Participants were aged between 10 and 19 years old and attended primary and secondary schools in all 16 regions of Chile. The survey utilized a self-report questionnaire to measure physical activity habits, subjective well-being, and emotional self-regulation. Sociodemographic variables, such as age, gender, and socioeconomic level, were also considered in the analysis. The results showed that physical activity habits, emotional regulation, and subjective well-being were positively correlated. Among these factors, the strongest association was found between subjective well-being and emotional self-regulation. The mediation analysis revealed a partial mediation effect of emotional self-regulation between physical activity habits and subjective well-being. In other words, physical activity habits affect subjective well-being to the extent that these habits affect emotional self-regulation. These findings provide valuable insights into the mechanisms underlying the link between physical activity habits and subjective well-being among adolescents. They also offer useful information for the development of public programs and policies aimed at promoting physical activity habits and subjective well-being in young people.

A Qualitative Approach to Exploring the Impact of the Gay Identity Formation Process.

Background: Most gay men experience difficulty in coming to terms with their sexual orientation, with their health, wellbeing, and quality of life potentially affected by unpleasant experiences often associated with the formation of their gay identity. It is therefore important for nurses to understand the needs of gay men so that they can accompany them and provide quality care during and after the identity formation process. Objective: The aim of the study was to explore and describe the identity formation and coming out experiences of gay men. Methods: A qualitative design with a constructivist naturalist approach was used. Data were collected through in-depth semi-structured interviews with five gay men with experience of the gay identity formation process, and data were analyzed using a thematic analysis method. Results: The results show that the men needed support, as they reported feeling different and alone during the identity formation and coming out process, and that their mental health was affected. Fear of rejection, negative reactions, and disappointing people were the reasons that led the men not to disclose their sexual orientation to family, while those who had come out defined a feeling of liberation. Conclusions: The gay identity formation process has potential impacts on health, wellbeing, and quality of life. Nurses need cultural competence training to be able to understand the needs of gay men, accompany them in the identity formation process, and provide individualized and non-heteronormative care. Nurses also need to participate in dismantling a heterosexist social structure.

The relationship between subjective well-being and food: a qualitative study based on children's perspectives.

PURPOSE: Despite the lack of consensus regarding which life satisfaction domains should be included in the study of children's subjective well-being (SWB), some domains are frequently considered, such as satisfaction with health. However, some others, such as satisfaction with food, are barely taken into account, despite the impact eating habits have on children's health and well-being. We adopt a qualitative approach to explore the role food plays in children's SWB, providing for a more in-depth analysis of children's perceptions and evaluations on a still insufficiently known domain of life satisfaction. METHOD: Sixteen discussion groups were held with 112 Spanish students (10-12 years old) from six schools. The transcripts were analy sed and themes reflecting the key concepts were defined using reflexive thematic analysis. RESULTS: Five themes emerged from the children's discourses on the relationship between food and SWB: health, pleasure, emotions, commensality-i.e., eating together-and food-empowerment-thus offering new insights from children's perspectives. CONCLUSION: Almost all of the participants established a relationship between their SWB and their eating behaviour, meaning that, within the challenges facing public health, SWB must be taken into account when promoting healthy eating programmes for children. Also, group discussion is found to be a very powerful tool for exploring topics with subjective connotations among child populations.

Dysregulated Expression of Transposable Elements in TDP-43M337V Human Motor Neurons That Recapitulate Amyotrophic Lateral Sclerosis In Vitro.

Amyotrophic lateral sclerosis (ALS) is a disease that progressively annihilates spinal cord motor neurons, causing severe motor decline and death. The disease is divided into familial and sporadic ALS. Mutations in the TAR DNA binding protein 43 (TDP-43) have been involved in the pathological emergence and progression of ALS, although the molecular mechanisms eliciting the disease are unknown. Transposable elements (TEs) and DNA sequences capable of transposing within the genome become dysregulated and transcribed in the presence of TDP-43 mutations. We performed RNA-Seq in human motor neurons (iMNs) derived from induced pluripotent stem cells (iPSCs) from TDP-43 wild-type-iMNs-TDP-43WT-and mutant-iMNs-TDP-43M337V-genotypes at 7 and 14 DIV, and, with state-of-the-art bioinformatic tools, analyzed whether TDP-43M337V alters both gene expression and TE activity. Our results show that TDP-43M337V induced global changes in the gene expression and TEs levels at all in vitro stages studied. Interestingly, many genetic pathways overlapped with that of the TEs activity, suggesting that TEs control the expression of several genes. TEs correlated with genes that played key roles in the extracellular matrix and RNA processing: all the regulatory pathways affected in ALS. Thus, the loss of TE regulation is present in TDP-43 mutations and is a critical determinant of the disease in human motor neurons. Overall, our results support the evidence that indicates TEs are critical regulatory sequences contributing to ALS neurodegeneration.

Physical activity habits and their relationship with sociodemographic factors in Chilean adolescents.

Physical activity plays an important role in the well-being and development of adolescents. Physical activity habits expressed in terms of frequency and duration are consistently associated with sociodemographic factors such as age, gender, and socioeconomic status. However, there is less evidence of the relationship between the type and context of physical activity in adolescents. The aim of this article is to analyze physical activity habits and their relationship with sociodemographic factors in Chilean adolescents. The cross-sectional study consisted of 7,263 adolescents aged between 10 and 20 years old, students from both public and private schools in all regions of Chile. Physical activity habits were examined by means of a self-report questionnaire. The age groups were classified according to the three stages of adolescence (early: 10 to 13, middle: 14 to 16, and late: 17 to 20 years old). Socioeconomic level was established based on the school vulnerability index (SVI) of the school attended by each adolescent. In the study it was obvious to the level of physical activity for the adolescents was below the international recommendations. A statistically significant association can also be found between the sociodemographic factors studied and the physical activity habits reported by the young people. The multivariate regression analysis established that the risk of not achieving the physical activity recommendations was 2.8 times higher in females than in males, 2.4 times higher in the older age groups (14-16 and 17-20 years old) compared to the 10-13-year age range and 1.1 times in the medium and high vulnerability groups than in the low socioeconomic vulnerability group. These findings highlight the importance of considering all these factors holistically whenever designing programs or public policies that promote the development of healthy physical activity habits in adolescents.

The Mental Health of Patients With Psychotic Disorder From a Positive, Multidimensional and Recovery Perspective.

Positive mental health (PMH) and mental illness are distinct, yet interrelated, constructs. However, this relationship has yet to be adequately established. We aimed to evaluate the level of PMH and its relationship with sociodemographic and clinical determinants as well as to explore the relationship between PMH and the positive constructs of recovery, subjective wellbeing (SWB), insight and functioning in patients with psychotic disorder. A multicenter, descriptive, cross-sectional and correlational study with a sample of 347 patients with psychotic disorder was conducted. The following assessment instruments were used: Positive Mental Health Questionnaire, Maryland Assessment of Recovery in Serious Mental Illness scale, Insight Scale, Personal Wellbeing Index-Adult version (PWI-A), Overall Life Satisfaction (OLS) and Global Assessment of Functioning scale. The mean global level of PMH was 116.16 (range of 39-156, SD = 19.39). Significant differences were found in PMH in relation to sociodemographic (sex, civil status and employment situation) and clinical variables (family history of mental disorders, number of prescribed antipsychotics, treatment with anxiolytics, treatment with antidepressants and suicide attempts). PMH was significantly and positively correlated with recovery (r = 0.760), SWB (PWI-A: r = 0.728 and OLS: r = 0.602) and functioning (r = 0.243), and negatively with insight (r = -0.335). These results can lead to a major change in mental health care. If actions are taken to increase PMH, then recovery, SWB and functioning will also increase. At the same time, interventions should be carried out to boost insight, since increasing PMH could decrease insight, all resulting in better quality of life for patients with psychotic disorder.

Activation of Transposable Elements in Human Skeletal Muscle Fibers upon Statin Treatment.

High cholesterol levels have been linked to a high risk of cardiovascular diseases, and preventative pharmacological care to lower cholesterol levels is critically important. Statins, which are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are drugs used to reduce the endogenous cholesterol synthesis, thus minimizing its pathophysiological effects. Despite the proven benefits, statins therapy is known to cause a number of skeletal muscle disorders, including myalgia, myopathy and myositis. The mechanisms underlying such statin-induced side effects are unknown. Recently, a group of genes and molecular pathways has been described to participate in statin-induced myopathy, caused by either simvastatin or rosuvastatin, although the mechanism by which changes in gene regulation occur was not studied. Transposable Elements (TEs), repetitive elements that move within the genome, are known to play regulatory roles in gene expression; however, their role in statin-induced muscle damage has not been studied. We analyzed the expression of TEs in human skeletal fiber cells treated with either simvastatin or rosuvastatin, as well as their respective controls, and identified TEs that change their expression in response to the treatment. We found that simvastatin resulted in >1000 differentially expressed (DE) TEs, whereas rosuvastatin resulted in only 27 DE TEs. Using network analysis tools, we predicted the impact of the DE TEs on the expression of genes and found that amongst the genes potentially modulated by TEs, there are some previously associated to statin-linked myopathy pathways (e.g., AKT3). Overall, our results indicate that TEs may be a key player in the statin-induced muscle side effects.

Spatially Resolved Expression of Transposable Elements in Disease and Somatic Tissue with SpatialTE.

Spatial transcriptomics (ST) is transforming the way we can study gene expression and its regulation through position-specific resolution within tissues. However, as in bulk RNA-Seq, transposable elements (TEs) are not being studied due to their highly repetitive nature. In recent years, TEs have been recognized as important regulators of gene expression, and thus, TE expression analysis in a spatially resolved manner could further help to understand their role in gene regulation within tissues. We present SpatialTE, a tool to analyze TE expression from ST datasets and show its application in somatic and diseased tissues. The results indicate that TEs have spatially regulated expression patterns and that their expression profiles are spatially altered in ALS disease, indicating that TEs might perform differential regulatory functions within tissue organs. We have made SpatialTE publicly available as open-source software under an MIT license.

The Moderating Role of Sociodemographic Factors in the Relationship between Physical Activity and Subjective Well-Being in Chilean Children and Adolescents.

BACKGROUND: The relationship between physical activity habits and well-being is widely recognized; however, the interaction that these variables have with sociodemographic factors throughout life is only partially addressed in the literature, particularly in children and adolescents. The aim of this article is to analyze the moderating effect of sociodemographic factors and the possible interaction of these moderations in the relationship between physical activity and subjective well-being in children and adolescents. METHODS: This cross-sectional study considered a sample of 9572 children and adolescents from 10 to 19 years of age, students of primary and secondary schools in all regions of Chile. Subjective well-being and physical activity habits were measured using self-report questionnaires. Socioeconomic level was established from the school vulnerability index (SVI) of each student's school. RESULTS: Simple moderation analyses revealed that the higher the age and the lower the SVI, the stronger the relationship between physical activity habits and subjective well-being. From a double moderation analysis, it could be observed that the age of the subjects is the most relevant moderator in the relationship between physical activity habits and perceived well-being in young people. CONCLUSIONS: This study highlights the importance of considering these factors and their interaction when generating programs or public policies to improve physical activity habits and well-being in children and adolescents.

Differential regulation of transposable elements (TEs) during the murine submandibular gland development.

The submandibular gland (SG) is a relatively simple organ formed by three cell types: acinar, myoepithelial, and an intricate network of duct-forming epithelial cells, that together fulfills several physiological functions from assisting food digestion to acting as an immune barrier against pathogens. Successful SG organogenesis is the product of highly controlled and orchestrated genetic and transcriptional programs. Mounting evidence links Transposable Elements (TEs), originally thought to be selfish genetic elements, to different aspects of gene regulation in mammalian development and disease. To our knowledge, the role of TEs during murine SG organogenesis has not been studied. Using novel bioinformatic tools and publicly available RNA-Seq datasets, our results indicate that a significant number of genic and intergenic TEs are differentially expressed during the SG development. Furthermore, changes in expression of specific TEs correlated with that of genes involved in cellular division and differentiation, critical aspects for SG maturation. Altogether, we propose that TEs modulate gene networks that operate during SG development.

Locus-specific analysis of Transposable Elements during the progression of ALS in the SOD1G93A mouse model.

Transposable Elements (TEs) are ubiquitous genetic elements with the ability to move within a genome. TEs contribute to a large fraction of the repetitive elements of a genome, and because of their nature, they are not routinely analyzed in RNA-Seq gene expression studies. Amyotrophic Lateral Sclerosis (ALS) is a lethal neurodegenerative disease, and a well-accepted model for its study is the mouse harboring the human SOD1G93A mutant. In this model, landmark stages of the disease can be recapitulated at specific time points, making possible to understand changes in gene expression across time. While there are several works reporting TE activity in ALS models, they have not explored their activity through the disease progression. Moreover, they have done it at the expense of losing their locus of expression. Depending on their genomic location, TEs can regulate genes in cis and in trans, making locus-specific analysis of TEs of importance in order to understand their role in modulating gene expression. Particularly, the locus-specific role of TEs in ALS has not been fully elucidated. In this work, we analyzed publicly available RNA-Seq datasets of the SOD1G93A mouse model, to understand the locus-specific role of TEs. We show that TEs become up-regulated at the early stages of the disease, and via statistical associations, we speculate that they can regulate several genes, which in turn might be contributing to the genetic dysfunction observed in ALS.

Factors Favoring and Hindering Volunteering by Older Adults and Their Relationship with Subjective Well-Being: A Mixed-Method Approach.

A mixed methodology was used through the triangulation of quantitative and qualitative data to determine older adults' perspectives regarding volunteering and identify what factors can contribute to promoting it, with special emphasis on the role that their own well-being plays in this behavior. The results reveal that satisfaction with life as a whole contributes positively to volunteer behavior and satisfaction with the groups one belongs to contributes negatively. The volunteers were less satisfied than non-volunteers with interpersonal relationships and with the groups they belong to. Knowing the opinion of the older adults with regard to volunteering and understanding how this prosocial behavior relates to their own well-being is very useful for developing strategic plans that allow future volunteers to be captured.

Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aß pathology.

The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased ßgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aß, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aß pathology in AD.

Peer Relatedness, School Satisfaction, and Life Satisfaction in Early Adolescence: A Non-recursive Model.

Cumulative evidence suggests that, for children and adolescents, peer relatedness is an essential component of their overall sense of belonging, and correlates with subjective well-being and school-based well-being. However, it remains unclear what the underlying mechanism explaining these relationships is. Therefore, this study examines whether there is a reciprocal effect between school satisfaction and overall life satisfaction (Hypothesis 1), and whether the effect of peer relatedness on life satisfaction is mediated by school satisfaction (Hypothesis 2). A non-recursive model with instrumental variables was tested with econometric and structural equation modeling methodologies, using a cross-sectional sample of n = 5,619 Chilean early adolescents (49.2% girls), aged 10, 11, and 12 (46.13, 44.99, and 8.88% respectively). Results were highly consistent across methods and supported the hypotheses. First, the findings confirmed a significant reciprocal influence between school satisfaction and overall life satisfaction, with a greater impact from school to life satisfaction. Second, the effect of peer relatedness on overall life satisfaction was fully mediated by school satisfaction. The study further suggests the importance of considering reciprocal effects among domain-specific satisfaction and overall life satisfaction and illustrates the application of non-recursive models for this purpose.

Subjective Well-Being in Early Adolescence: Observations from a Five-Year Longitudinal Study.

This article aims to redress the lack of longitudinal studies on adolescents' subjective well-being (SWB) and highlight the relevance of knowledge deriving from such research in designing public policies for improving their health and wellbeing in accordance with the stage of development they are in. To achieve this, the evolution of SWB during early adolescence (in adolescents aged between 10 and 14 in the first data collection) was explored over a five year period, considering boys and girls together and separately. This involved comparing different SWB scales and contrasting results when considering the year of data collection versus the cohort (year of birth) participants belonged to. The methodology comprised a generalized linear mixed model using the INLA (Integrated Nested Laplace Approximation) estimation within a Bayesian framework. Results support the existence of a decreasing-with-age trend, which has been previously intuited in cross-sectional studies and observed in only a few longitudinal studies and contrasts with the increasing-with-age tendency observed in late adolescence. This decrease is also found to be more pronounced for girls, with relevant differences found between instruments. The decreasing-with-age trend observed when the year of data collection is taken into account is also observed when considering the cohort, but the latter provides additional information. The results obtained suggest that there is a need to continue studying the evolution of SWB in early adolescence with samples from other cultures; this, in turn, will make it possible to establish the extent to which the observed decreasing-with-age trend among early adolescents is influenced by cultural factors.

Coarse-Grained Parameters for Divalent Cations within the SIRAH Force Field.

Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges in achieving an accurate structural and dynamical description of many biological assemblies, particularly to coarse-grained (CG) models. Although the reduced computational cost of CG methods often makes them the technique of choice for the study of large biomolecular systems, the parameterization of metal ions is still very crude or not available for the vast majority of CG force fields. Here, we show that incorporating statistical data retrieved from the Protein Data Bank (PDB) to set specific Lennard-Jones interactions can produce structurally accurate CG molecular dynamics simulations using the SIRAH force field. We provide a set of interaction parameters for calcium, magnesium, and zinc ions, which cover more than 80% of the metal-bound structures reported in the PDB. Simulations performed on several proteins and DNA systems show that it is possible to preclude the use of topological constraints by modifying specific Lennard-Jones interactions.

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain.

Chronic pain is a common detrimental condition that affects around 20% of the world population. The current drugs to treat chronic pain states, especially neuropathic pain, have a limited clinical efficiency and present significant adverse effects that complicates their regular use. Recent studies have proposed new therapeutic strategies focused on the pharmacological modulation of G-protein-coupled receptors, transporters, enzymes, and ion channels expressed on the nociceptive pathways. The present work intends to summarize recent advances on the pharmacological modulation of pentameric ligand-gated ion channels, which plays a key role in pain processing. Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABAA and glycine receptors, reverse chronic pain-related behaviors in preclinical assays. Collectively, these evidences strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans.