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.

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.

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.

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.

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.

Subjective Well-Being Decreasing With Age: New Research on Children Over 8.

An increasing number of scientific publications have provided data from different countries suggesting subjective well-being (SWB) continuously decreases during adolescence. A review of these publications reveals authors have used dissimilar scales in diverse countries. Using data from the international Children's Worlds project (N = 48,040), involving 15 countries, a comparative analysis was performed to determine how mean scores evolve with different SWB scales from the age of 8 onwards. The results support the hypothesis that the tendency of SWB to decrease with age starts at around 10 years of age in most countries, while also confirming that different psychometric scales display different levels of sensitivity to diverse sociocultural contexts and more than one should be used in any research on children and adolescents' SWB.

Prevalent presence of periodic actin-spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species.

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal- and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.

Mitochondrial Complex I Activity is Conditioned by Supercomplex I-III2-IV Assembly in Brain Cells: Relevance for Parkinson's Disease.

The assembly of complex I (CI) with complexes III (CIII) and IV (CIV) of the mitochondrial respiratory chain (MRC) to configure I-III- or I-III-IV-containing supercomplexes (SCs) regulates mitochondrial energy efficiency and reactive oxygen species (mROS) production. However, whether the occurrence of SCs impacts on CI specific activity remains unknown to our knowledge. To investigate this issue, here we determined CI activity in primary neurons and astrocytes, cultured under identical antioxidants-free medium, from two mouse strains (C57Bl/6 and CBA) and Wistar rat, i.e. three rodent species with or without the ability to assemble CIV into SCs. We found that CI activity was 6- or 1.8-fold higher in astrocytes than in neurons, respectively, from rat or CBA mouse, which can form I-III2-IV SC; however, CI activity was similar in the cells from C57Bl/6 mouse, which does not form I-III2-IV SC. Interestingly, CII-III activity, which was comparable in neurons and astrocytes from mice, was about 50% lower in astrocytes when compared with neurons from rat, a difference that was abolished by antioxidants- or serum-containing media. CIV and citrate synthase activities were similar under all conditions studied. Interestingly, in rat astrocytes, CI abundance in I-III2-IV SC was negligible when compared with its abundance in I-III-containing SCs. Thus, CIV-containing SCs formation may determine CI specific activity in astrocytes, which is important to understand the mechanism for CI deficiency observed in Parkinson's disease.

Astrocyte pathology and the absence of non-cell autonomy in an induced pluripotent stem cell model of TDP-43 proteinopathy.

Glial proliferation and activation are associated with disease progression in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia. In this study, we describe a unique platform to address the question of cell autonomy in transactive response DNA-binding protein (TDP-43) proteinopathies. We generated functional astroglia from human induced pluripotent stem cells carrying an ALS-causing TDP-43 mutation and show that mutant astrocytes exhibit increased levels of TDP-43, subcellular mislocalization of TDP-43, and decreased cell survival. We then performed coculture experiments to evaluate the effects of M337V astrocytes on the survival of wild-type and M337V TDP-43 motor neurons, showing that mutant TDP-43 astrocytes do not adversely affect survival of cocultured neurons. These observations reveal a significant and previously unrecognized glial cell-autonomous pathological phenotype associated with a pathogenic mutation in TDP-43 and show that TDP-43 proteinopathies do not display an astrocyte non-cell-autonomous component in cell culture, as previously described for SOD1 ALS. This study highlights the utility of induced pluripotent stem cell-based in vitro disease models to investigate mechanisms of disease in ALS and other TDP-43 proteinopathies.

Intricate interplay between astrocytes and motor neurons in ALS.

ALS results from the selective and progressive degeneration of motor neurons. Although the underlying disease mechanisms remain unknown, glial cells have been implicated in ALS disease progression. Here, we examine the effects of glial cell/motor neuron interactions on gene expression using the hSOD1(G93A) (the G93A allele of the human superoxide dismutase gene) mouse model of ALS. We detect striking cell autonomous and nonautonomous changes in gene expression in cocultured motor neurons and glia, revealing that the two cell types profoundly affect each other. In addition, we found a remarkable concordance between the cell culture data and expression profiles of whole spinal cords and acutely isolated spinal cord cells during disease progression in the G93A mouse model, providing validation of the cell culture approach. Bioinformatics analyses identified changes in the expression of specific genes and signaling pathways that may contribute to motor neuron degeneration in ALS, among which are TGF-ß signaling pathways.

Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability.

Transactive response DNA-binding (TDP-43) protein is the dominant disease protein in amyotrophic lateral sclerosis (ALS) and a subgroup of frontotemporal lobar degeneration (FTLD-TDP). Identification of mutations in the gene encoding TDP-43 (TARDBP) in familial ALS confirms a mechanistic link between misaccumulation of TDP-43 and neurodegeneration and provides an opportunity to study TDP-43 proteinopathies in human neurons generated from patient fibroblasts by using induced pluripotent stem cells (iPSCs). Here, we report the generation of iPSCs that carry the TDP-43 M337V mutation and their differentiation into neurons and functional motor neurons. Mutant neurons had elevated levels of soluble and detergent-resistant TDP-43 protein, decreased survival in longitudinal studies, and increased vulnerability to antagonism of the PI3K pathway. We conclude that expression of physiological levels of TDP-43 in human neurons is sufficient to reveal a mutation-specific cell-autonomous phenotype and strongly supports this approach for the study of disease mechanisms and for drug screening.

Accelerated high-yield generation of limb-innervating motor neurons from human stem cells.

Human pluripotent stem cells are a promising source of differentiated cells for developmental studies, cell transplantation, disease modeling, and drug testing. However, their widespread use even for intensely studied cell types like spinal motor neurons is hindered by the long duration and low yields of existing protocols for in vitro differentiation and by the molecular heterogeneity of the populations generated. We report a combination of small molecules that within 3 weeks induce motor neurons at up to 50% abundance and with defined subtype identities of relevance to neurodegenerative disease. Despite their accelerated differentiation, motor neurons expressed combinations of HB9, ISL1, and column-specific markers that mirror those observed in vivo in human embryonic spinal cord. They also exhibited spontaneous and induced activity, and projected axons toward muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons (FOXP1(+)/LHX3(-)). Access to high-yield cultures of human limb-innervating motor neuron subtypes will facilitate in-depth study of motor neuron subtype-specific properties, disease modeling, and development of large-scale cell-based screening assays.

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.

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.

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.

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.

Activation of innate and humoral immunity in the peripheral nervous system of ALS transgenic mice.

During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1(G93A) and SOD1(G37R) transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.

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.

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.