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Abstract Background Macrophages release not only cytokines but also extracellular vesicles (EVs). which are small membrane-derived nanovesicles with virus-like properties transferring cellular material between cells. Until now, the consequences of macrophage plasticity on the release and the composition of EVs have been poorly explored. In this study, we determined the impact of high-glucose (HG) concentrations on macrophage metabolism, and characterized their derived-EV subpopulations. Finally, we determined whether HG-treated macrophage-derived EVs participate in immune responses and in metabolic alterations of skeletal muscle cells. Methods THP1-macrophages were treated with 15mM (MG15) or 30mM (MG30) glucose. Then, M1/M2 canonical markers, pro- and anti-inflammatory cytokines, activities of proteins involved in glycolysis or oxidative phosphorylation were evaluated. Macrophage-derived EVs were characterized by TEM, NTA, MRSP, and 1H-Nuclear magnetic resonance spectroscopy for lipid composition. Macrophages or C2C12 muscle cells were used as recipients of MG15 and MG30-derived EVs. The lipid profiles of recipient cells were determined, as well as proteins and mRNA levels of relevant genes for macrophage polarization or muscle metabolism. Results Untreated macrophages released small and large EVs (sEVs, lEVs) with different lipid distributions. Proportionally to the glucose concentration, glycolysis was induced in macrophages, associated to mitochondrial dysfunction, triacylglycerol and cholesterol accumulation. In addition, MG15 and MG30 macrophages had increased level of CD86 and increase release of pro-inflammatory cytokines. HG also affected macrophage sphingolipid and phospholipid compositions. The differences in the lipid profiles between sEVs and lEVs were abolished and reflected the lipid alterations in MG15 and MG30 macrophages. Interestingly, MG15 and MG30 macrophages EVs induced the expression of CD163, Il-10 and increased the contents of triacylglycerol and cholesterol in recipient macrophages. MG15 lEVs and sEVs induced insulin-induced AKT hyper-phosphorylation and accumulation of triacylglycerol in myotubes, a state observed in pre-diabetes. Conversely, MG30 lEVs and sEVs induced insulin-resistance in myotubes. Conclusions As inflammation involves first M1 macrophages, then the activation of M2 macrophages to resolve inflammation, this study demonstrates that the dialog between macrophages through the EV route is an intrinsic part of the inflammatory response. In a hyperglycemic context, EV macrophages could participate in the development of muscle insulin-resistance and chronic inflammation.

Abstract BMP-1/tolloid-like proteinases (BTPs) are major players in tissue morphogenesis, growth and repair. They act by promoting the deposition of structural extracellular matrix proteins and by controlling the activity of matricellular proteins and TGF-β superfamily growth factors. They have also been implicated in several pathological conditions such as fibrosis, cancer, metabolic disorders and bone diseases. Despite this broad range of pathophysiological functions, the putative existence of a specific endogenous inhibitor capable of controlling their activities could never be confirmed. Here, we show that procollagen C-proteinase enhancer-2 (PCPE-2), a protein previously reported to bind fibrillar collagens and to promote their BTP-dependent maturation, is primarily a potent and specific inhibitor of BTPs which can counteract their proteolytic activities through direct binding. PCPE-2 therefore differs from the cognate PCPE-1 protein and extends the possibilities to fine-tune BTP activities, both in physiological conditions and in therapeutic settings.

Abstract Background The Inner Santiago Health Study (ISHS) aimed to (i) estimate the prevalence of common mental disorders (CMD; i.e. depressive and anxiety disorders) among immigrants of Peruvian origin in Chile; (ii) determine whether such immigrants are at higher risk of CMD when compared with the native-born geographically matched population (i.e. non-immigrants); and (iii) identify factors associated with higher risk of any CMD among this immigrant group. A secondary aim was to describe access to mental health services by Peruvian immigrants meeting criteria for any CMD. Methods Findings are based on a population-based cross-sectional household mental health survey of 608 immigrant and 656 non-immigrant adults (18-64 years) residing in Santiago de Chile. Diagnoses of ICD-10 depressive and anxiety disorders and of any CMD were obtained using the Revised Clinical Interview Schedule. The relationships between demographic, economic, psychosocial, and migration-specific predictor variables, and risk of any CMD were analyzed with a series of stepwise multivariate logistic regression models. Results The one-week prevalence of any CMD was 29.1% (95% CI: 25.2-33.1) among immigrants and 34.7% (95% CI: 30.7-38.7) among non-immigrants. Depending on the statistical model used in the pooled sample, we found the prevalence of any CMD among non-immigrants to be higher (OR=1.53; 95% CI: 1.05-2.25) or similar (OR=1.34; 95% CI: 0.94-19.2) when compared with immigrants. In the multivariate stepwise regression of any CMD in immigrants only, the prevalence was higher for females, those with primary compared to higher education, in debt and exposed to discrimination. Conversely, higher levels of functional social support, sense of comprehensibility, and manageability were associated with a lower risk of any CMD in immigrants. In addition, no differences were observed between immigrants and non-immigrants reporting any CMD in mental health service utilization. Conclusion Our results evidence high levels of current CMD in this immigrant group, particularly amongst women. However, lower adjusted prevalence of any CMD in immigrants compared to non-immigrants was limited to preliminary statistical models, thus failing to provide clear support for a “healthy immigrant effect”. The study sheds new light on differences in CMD prevalence by immigrant status in Latin America by examining differential exposure to risk factors in immigrant versus non-immigrant groups.

Summary: Background: Depressive disorder is one of the leading causes of disability worldwide; however its prevalence and association with inequality and crime is poorly characterised in Latin America. This study aimed to: i. systematically review population-based studies of prevalence of ICD/DSM depressive disorder in Latin America, ii. report pooled regional, country, and sex-specific prevalence estimates, and iii. test its association with four country-level development indicators: human development (HDI), income (Gini) and gender inequality (GII), and intentional homicide rate (IHR). Methods: We conducted a systematic review and meta-analysis of population-based studies reporting primary data on the prevalence of ICD/DSM depressive disorder in Latin America from 1990 to 2023, irrespective of language. We searched PubMed, PsycINFO, Cochrane Library, SciELO (regional database), LILAC (regional database), and available grey literature. Study quality was assessed using JBI's critical appraisal tools. We generated pooled estimates using random-effects meta-analysis; heterogeneity was assessed using the I2 statistic. Meta-regression analyses were used to test associations of depression prevalence with indicators of inequality and human development. The study was registered with PROSPERO (CRD42019143054). Findings: Using data from 40 studies in Latin America, lifetime, 12-month, and current prevalence of ICD/DSM depressive disorder were calculated at 12.58% (95% CI 11.00%–14.16%); 5.30% (4.55–6.06%), and 3.12% (2.22–4.03), respectively. Heterogeneity was high across lifetime, 12-month, and current prevalence, sex, and countries. 12-month and current prevalence was associated with higher Gini and GII, 12-month prevalence with lower HDI, and current prevalence with higher IHR. Interpretation: We found a high prevalence of ICD/DSM depressive disorders in Latin America, and a statistically significant association with inequality and development indicators. The high heterogeneity found across prevalence periods and the major gaps in country representation underscore the need to escalate efforts to improve mental health access and research capabilities in Latin America. Systematic, comparable prevalence estimates would inform more effective decision-making in the region. Funding: Pfizer Independent Medical Education Grant.

This article explores the construction of the category "Woman" in the official history and social studies curricular documents distributed by the Chilean Ministry of Education to all public and charter schools in 2014. It answers two major questions: what are the characteristics and acceptable gender performances of the category "Woman" in these Chilean curricular documents? Are there differences in the expected/acceptable performances of "Woman" according to her categories of ethnicity/race or social class? I will argue that these curricular documents construct a historical narrative where two archetypal categories represent possible, oppressive gendered citizens. Students that wish to be identified as "Woman" will be able to read these categories as scripts for gender performance. The objective of this paper is to disrupt untroubled "inclusive" historical narratives. A bibliography is included.

Zinc, an essential trace element that serves as a cofactor for numerous cellular and viral proteins, plays a central role in the dynamics of HIV-1 infection. Among the viral proteins, the nucleocapsid NCp7, which contains two zinc finger motifs, is abundantly present viral particles and plays a crucial role in coating HIV-1 genomic RNA, thus concentrating zinc within virions. In this study, we investigated whether HIV-1 virus production impacts cellular zinc homeostasis and whether isotopic fractionation occurs between the growth medium, the producing cells, and the viral particles. We found that HIV-1 captures a significant proportion of cellular zinc in the neo-produced particles. Furthermore, as cells grow, they accumulate lighter zinc isotopes from the medium, resulting in a concentration of heavier isotopes in the media, and the viruses exhibit a similar isotopic fractionation to the producing cells. Moreover, we generated HIV-1 particles in HEK293T cells enriched with each of the five zinc isotopes to assess the potential effects on the structure and infectivity of the viruses. As no strong difference was observed between the HIV-1 particles produced in the various conditions, we have demonstrated that enriched isotopes can be accurately used in future studies to trace the fate of zinc in cells infected by HIV-1 particles. Comprehending the mechanisms underlying zinc absorption by HIV-1 viral particles offers the potential to provide insights for developing future treatments aimed at addressing this specific facet of the virus’s life cycle.

Abstract We have determined the lipid, protein and miRNA composition of skeletal muscle (SkM)-released extracellular vesicles (ELVs) from Ob/ob (OB) vs wild-type (WT) mice. The results showed that atrophic insulin-resistant OB-SkM released less ELVs than WT-SkM, highlighted by a RAB35 decrease and an increase in intramuscular cholesterol content. Proteomic analyses of OB-ELVs revealed a group of 37 proteins functionally connected, involved in lipid oxidation and with catalytic activities. OB-ELVs had modified contents for phosphatidylcholine (PC 34-4, PC 40-3 and PC 34-0), sphingomyelin (Sm d18:1/18:1) and ceramides (Cer d18:1/18:0) and were enriched in cholesterol, likely to alleviated intracellular accumulation. Surprisingly many ELV miRNAs had a nuclear addressing sequence, and targeted genes encoding proteins with nuclear activities. Interestingly, SkM-ELV miRNA did not target mitochondria. The most significant function targeted by the 7 miRNAs altered in OB-ELVs was lipid metabolism. In agreement, OB-ELVs induced lipid storage in recipient adipocytes and increased lipid up-take and fatty acid oxidation in recipient muscle cells. In addition, OB-ELVs altered insulin-sensitivity and induced atrophy in muscle cells, reproducing the phenotype of the releasing OB muscles. These data suggest for the first time, a cross-talk between muscle cells and adipocytes, through the SkM-ELV route, in favor of adipose tissue expansion.

TAR DNA binding protein of 43 kDa (TDP-43)-positive inclusions in neurons are a hallmark of several neurodegenerative diseases including familial amyotrophic lateral sclerosis (fALS) caused by pathogenic TARDBP variants as well as more common non-Mendelian sporadic ALS (sALS). Here we report a G376V-TDP-43 missense variant in the C-terminal prion-like domain of the protein in two French families affected by an autosomal dominant myopathy but not fulfilling diagnostic criteria for ALS. Patients from both families presented with progressive weakness and atrophy of distal muscles, starting in their fifth to seventh decade. Muscle biopsies revealed a degenerative myopathy characterized by accumulation of rimmed (autophagic) vacuoles, disruption of sarcomere integrity and severe myofibrillar disorganization. The G376V variant altered a highly conserved amino acid residue and was absent in databases on human genome variation. Variant pathogenicity was supported by in silico analyses and functional studies. The G376V mutant increased the formation of cytoplasmic TDP-43 condensates in cell culture models, promoted assembly into high molecular weight oligomers and aggregates in vitro , and altered morphology of TDP-43 condensates arising from phase separation. Moreover, the variant led to the formation of cytoplasmic TDP-43 condensates in patient-derived myoblasts and induced abnormal mRNA splicing in patient muscle tissue. The identification of individuals with TDP-43-related myopathy, but not ALS, implies that TARDBP missense variants may have more pleiotropic effects than previously anticipated and support a primary role for TDP-43 in skeletal muscle pathophysiology. We propose to include TARDBP screening in the genetic work-up of patients with late-onset distal myopathy. Further research is warranted to examine the precise pathogenic mechanisms of TARDBP variants causing either a neurodegenerative or myopathic phenotype. [ABSTRACT FROM AUTHOR]

At present, ArchDaily.com is the most visited virtual architecture platform in the world. Aware of the importance acquired in the architectural practice, the site declares itself to be the main source from which architects feed on tools, information and inspiration to develop their projects. However, it is clear that its importance is not limited to its status as reference bank for professional practice. The accumulation of visual and textual representations contributes to the idea of “good architecture”, in turn transforming this platform into an institution validating and legitimizing the understanding of the discipline, its scope and limitations, its protagonists and predominant methods applied. The following pages propose an analysis of the platform’s content in its residential architecture section, an analysis that supports a critical reflection on its wider cultural effects.

Introduction Understanding suicidal ideation and its association with childhood adversity is crucial for preventing suicide. Although the “healthy immigrant effect”, whereby immigrants are healthier than the native-born population, has been well documented across studies, little research has examined the presence of such effect on lifetime suicidal ideation (LSI) and its association to early adversity. Objectives The aim of this study was to compare the prevalence of LSI between the immigrant and native-born population in Chile and explore the association between childhood adversity and suicidal ideation in immigrants. Methods Data from two cross-sectional health surveys: the Santiago Immigrant Wellbeing Study (STRING, n=1,091; 2019) and the Chilean National Health Survey (ENS2016, n=3,432) were used. Each study used multistage probability sampling and estimates were weighted to approximate the distribution of demographic variables in each population. Outcomes included LSI measured by WHO-CIDI and an adapted version of the Adverse Childhood Experience Questionnaire. Multivariate logistic regression was employed. Results indicated that immigrants were less likely to report LSI compared with the native-born population. Moreover, male and female immigrants had lower risk of having SI than native-born counterparts. After controlling for socioeconomic status, social support, and health conditions, childhood adversities predicted an increased risk of LSI in immigrants. No gender differences were found in the effects of childhood adversity on suicidal thoughts. Conclusions Findings confirm the presence of a healthy immigrant effect in LSI and support a life course perspective, highlighting the importance of assessing early life disadvantages to understand suicidal ideation among immigrants.

La incorporación de los nuevos vehículos motorizados a la vida urbana durante las décadas iniciales del siglo XX fue un proceso conflictivo que supuso una transformación material y simbólica de la experiencia de los viajes en la ciudad. Haciendo foco en el caso de Santiago, este artículo analiza el lugar que tuvo el accidente de tránsito en este proceso. Específicamente, se busca comprender distintas formas en que el accidente impactó en la cultura urbana y en las nociones del tránsito de la época, diferenciando entre los alcances del evento particular y aquellos producidos por la imagen cada vez más arraigada de la eventualidad del accidente. El análisis sugiere que fue la cotidianeidad adquirida por el accidente, como evento y eventualidad, la que posibilitó la implementación y legitimación del nuevo sistema de circulación que permitió incorporar a los vehículos motorizados como elementos ordenadores del tránsito.

Summary: In the current COVID-19 pandemic context, proposing and validating effective treatments represents a major challenge. However, the scarcity of biologically relevant pre-clinical models of SARS-CoV-2 infection imposes a significant barrier for scientific and medical progress, including the rapid transition of potentially effective treatments to the clinical setting. We use reconstituted human airway epithelia to isolate and then characterize the viral infection kinetics, tissue-level remodeling of the cellular ultrastructure, and transcriptional early immune signatures induced by SARS-CoV-2 in a physiologically relevant model. Our results emphasize distinctive transcriptional immune signatures between nasal and bronchial HAE, both in terms of kinetics and intensity, hence suggesting putative intrinsic differences in the early response to SARS-CoV-2 infection. Most important, we provide evidence in human-derived tissues on the antiviral efficacy of remdesivir monotherapy and explore the potential of the remdesivir-diltiazem combination as an option worthy of further investigation to respond to the still-unmet COVID-19 medical need.

This study reviews and classifies the most common uses of the terms “enemy” and “enmity” within the context of traditional philosophical discourse. In order to contribute to a structured understanding of these concepts, we proceed in two steps. We first explore the auxiliary (or non-technical) uses of the terms, which we distinguish from each other according to their axiological connotations. In a second part, we review the technical uses of the concepts known to philosophy of law. Here, we distinguish between two different approaches to the concept, one of which defines it through qualitative criteria, and a second approach that uses the term as a quantifier (of intensity, strength, etc.).

Research Question: Does reproductive outcome differ among the various subgroups of poor ovarian responders according to the Bologna criteria?Design: This was a retrospective, cohort study including poor ovarian responders according to Bologna criteria, undergoing an ICSI cycle from January 2011 until December 2017. Patients were divided into four groups: (1) age ≥ 40 years and abnormal ovarian response test, (2) age ≥ 40 years, abnormal ovarian reserve test and one previous poor response to stimulation, (3) age ≥ 40 years and one previous poor response, (4) abnormal ovarian reserve test and one previous poor response.Result(s): Overall, 846 cycles in 706 Bologna poor ovarian responders were included: 310 cycles in group 1, 169 in group 2, 52 in group 3, and 315 in group 4. There were significant differences in age, antral follicle count, antimüllerian hormone, cycle cancellation rates, and number of retrieved oocytes between the four groups. Live birth and cumulative live birth rate differed significantly between groups and were highest in Group 4 [Live birth rate: 7.4% (1) vs. 4.1% (2) vs. 5.8% (3) vs. 13.4% (4), p = 0.001 and Cumulative live birth rate: 8.3% (1) vs. 4.1 % (2) vs. 9.6% (3) vs. 16.8% (4) p < 0.001]. The multivariate GEE analysis revealed that the number of MIIs and the Bologna criteria pattern were the variables which were significantly associated with cumulative live birth rate.Conclusion(s): Poor ovarian responders represent a heterogeneous population. The young subpopulation has a better clinical prognosis in terms of fresh and cumulative live birth rate.