Les Signaux Post Mortem (SPM) de l’apoptose endothéliale : des acteurs du remodelage vasculaire

L’immunosuppression a permis d’améliorer l’incidence du rejet aigu sans toutefois améliorer significativement le rejet chronique. Celui-ci est caractérisé par une vasculopathie du greffon (VG) similaire à une forme accélérée d’athérosclérose native accompagnée de fibrose. La pathophysiologie de la VG découle de l’hypothèse de réponse à l’insulte proposée par Russell Ross en 1977. Selon son postulat, l’endothélium stressé par des facteurs immunologiques et non immunologiques initie l’apoptose endothéliale suivi d’une réponse de réparation vasculaire via un épaississement myo-intimal aux sites d’insultes. Toutefois, lorsque les stress endothéliaux initiaux demeurent soutenus, l’apoptose endothéliale et la réponse de réparation perpétuent. Compte tenu que l’inhibition de l’apoptose endothéliale bloque le développement de la VG in vivo, notre hypothèse de travail reposait sur les répercussions paracrines de l’apoptose endothéliale sur les types cellulaires participant au remodelage vasculaire. Nous avons généré un système expérimental in vitro afin d’induire l’apoptose endothéliale en absence significative de nécrose cellulaire. À l’aide d’une approche protéomique multidimensionnelle et comparative, nous avons démontré que les cellules endothéliales apoptotiques exportent spécifiquement 27 signaux post mortem (SPM). Nous avons démontré que certains de ces SPM ont des propriétés anti-apoptotiques (TCTP et EGF), d’autre fibrogénique (CTGF), récapitulant ainsi certains phénotypes cellulaires associés au développement de la VG. Parmi les médiateurs identifiés, 16 n’avaient pas de signal de sécrétion, incluant TCTP, suggérant que des mécanismes de sécrétion non conventionnels soient favorisés durant l’apoptose. Nous avons démontré que la caspase-3 effectrice régule la voie de sécrétion non classique exosomiale associée à l’export extracellulaire de nanovésicules TCTP+VE, anti-apoptotiques et biochimiquement distinctes des corps apoptotiques. Finalement, l’ensemble des données protéomiques ont permis d’émettre l’hypothèse qu’en réponse à un stress apoptotique, la cellule exporte différents médiateurs (solubles et vésiculaires) de manière non conventionnelle nécessitant la fusion d’organelles de la voie endocytaire et autophagique avec la membrane plasmique. Ce mécanisme serait régulé durant la phase effectrice de l’apoptose permettant ainsi d’initier une réponse de réparation extracellulaire seulement lorsque le destin cellulaire a atteint un point de non retour. Ainsi, le testament protéique et nanovésiculaire légué durant l’apoptose endothéliale pourrait servir simultanément de biomarqueur de la VG et de cible thérapeutique afin de diminuer le remodelage vasculaire pathologique.Immunosuppression regiments improved steadily the incidence of acute rejection with minimal positive effects on chronic rejection. The latter is characterized by a transplant vasculopathy (TV) similar to native atherosclerosis, accompanied with fibrosis throughout the vascular wall of the allograft. The pathophysiology associated to TV arose from pionnering work of Russell Ross in 1977. He proposed the 'Response to Injury' hypothesis revealing that endothelium injury initiated by immunological and non immunological factors favors a vascular repair response through neo-intima thickening at the sites of cellular injury. However, when endothelial insult is maintained, apoptosis ensues and the vascular repair process perpetuates. Since inhibition of endothelial apoptosis prevents TV development in vivo, we hypothesized that endothelial apoptosis regulates the vascular repair process through a paracrine program active on the cellular components of the vessel wall. We have generated an in vitro experimental system to induce endothelial apoptosis in absence of necrosis. Using a multifunctional and comparative proteomic approach, we have identified 27 post mortem signals (PMS) specifically exported by apoptotic endothelial cells. Some of these PMS display anti-apoptotic function (TCTP and EGF), whereas CTGF was identified as a fibrogenic factor, recapitulating the cellular events associated to the development of TV. Interestingly, 16 of these SPM did not contain a peptide signal, suggesting that non conventional secretion mechanisms could be favored during the effector phase of apoptosis. We demonstrated that activated caspase-3 regulates the exosomal secretion pathway associated to the export of nanovesicles TCTP +ve, anti-apoptotic and biochemically different from apoptotic blebs. Finally, the overall proteomic data generated a new hypothesis suggesting that in response to apoptotic stress, the cell exports different mediators (soluble and vesicular) by non conventional mechanism through the fusion of endocytic organelles and autophagic vacuoles with the plasma membrane, releasing their content into the extracellular milieu. This mechanism should be regulated during the effector phase of apoptosis favoring a vascular repair response only when cell’s demise reaches a point of no return. Therefore, these PMS could be used both as biomarkers of apoptosis or as biopharmaceutical targets to decrease the incidence of chronic vascular repair

Psychiatric and non-psychiatric polypharmacy among older adults with schizophrenia: Trends from a population-based study between 2000 and 2016

Background: Schizophrenia is a severe psychiatric disorder associated with multiple psychiatric and non-psychiatric comorbidities. As adults with schizophrenia age, they may use many medications, i.e., have polypharmacy. While psychiatric polypharmacy is well documented, little is known about trends and patterns of global polypharmacy. This study aimed to draw a portrait of polypharmacy among older adults with schizophrenia from 2000 to 2016. Methods: This population-based cohort study was conducted using the data of the Quebec Integrated Chronic Disease Surveillance System of the National Institute of Public Health of Quebec to characterize recent trends and patterns of medication use according to age and sex. We identified all Quebec residents over 65 years with an ICD-9 or ICD-10 diagnosis of schizophrenia between 2000 and 2016. We calculated the total number of medications used by every individual each year and the age-standardized proportion of individuals with polypharmacy, as defined by the usage of 5+, 10+, 15+, and 20+ different medications yearly. We identified the clinical and socio-demographic factors associated with polypharmacy using robust Poisson regression models considering the correlation of the responses between subjects and analyzed trends in the prevalence of different degrees of polypharmacy. Results: From 2000 to 2016, the median number of medications consumed yearly rose from 8 in 2000 to 11 in 2016. The age-standardized proportion of people exposed to different degrees of polypharmacy also increased from 2000 to 2016: 5+ drugs: 76.6%–89.3%; 10+ drugs: 36.9%–62.2%; 15+: 13.3%–34.4%; 20+: 3.9%–14.4%. Non-antipsychotic drugs essentially drove the rise in polypharmacy since the number of antipsychotics remained stable (mean number of antipsychotics consumed: 1.51 in 2000 vs. 1.67 in 2016). In the multivariate regression, one of the main clinically significant factor associated with polypharmacy was the number of comorbidities (e.g., Polypharmacy-10+: RR[2 VS. 0–1] = 1.4; 99% IC:1.3–1.4, RR[3–4] = 1.7 (1.7–1.8); RR[5+] = 2.1 (2.1–2.2); Polypharmacy-15+: RR[2 VS 0–1] = 1.6; 99% IC:1.5–1.7, RR[3–4] = 2.5 (2.3–2.7); RR[5+] = 4.1 (3.8–4.5). Conclusion: There was a noticeable increase in polypharmacy exposure among older adults with schizophrenia in recent years, mainly driven by non-antipsychotic medications. This raises concerns about the growing risks for adverse effects and drug-drug interactions in this vulnerable population

Violences sexuelles en milieu universitaire au Québec : rapport de recherche de l’enquête ESSIMU

Cette recherche, intitulée « Enquête Sexualité, Sécurité et Interactions en Milieu Universitaire(ESSIMU) : Ce qu’en disent étudiant.es, enseignant.es et employé.es », a permis d’établir un portrait des violences sexuelles se déroulant en contexte universitaire au Québec. Cette enquête d’envergure provinciale regroupe 12 chercheures provenant des 6 universités suivantes : Université du Québec à Montréal, Université de Montréal, Université Laval, Université de Sherbrooke, Université du Québec en Outaouais et Université du Québec à Chicoutimi. L’équipe interdisciplinaire et interuniversitaire compte également le Regroupement québécois des centres d’aide et de lutte contre les agressions à caractère sexuel et le Service aux collectivités de l’UQAM. Afin de documenter les situations de violence sexuelle vécues en milieu universitaire (VSMU), l’équipe ESSIMU a réalisé en 2016 une vaste étude auprès de 9 284 répondant.es dans 6 universités québécoises francophones. Le questionnaire, administré en ligne, a permis de rendre compte d’un large éventail de manifestations de violence sexuelle vécues par l’ensemble de la communauté universitaire (étudiant ou travaillant à l’université). La mesure de victimisation distinguait le harcèlement sexuel (comportements verbaux et non verbaux qui traduisent des attitudes insultantes, hostiles et dégradantes), les comportements sexuels non désirés (comportements verbaux et non verbaux à caractère sexuel, offensants, non désirés ou non réciproques, incluant la tentative de viol et l’agression sexuelle) et la coercition sexuelle (chantage en retour de récompenses)

Cellular Senescence Is Immunogenic and Promotes Antitumor Immunity

Senescencia celular; Inmunidad antitumoralSenescència cel·lular; Immunitat antitumoralCellular senescence; Antitumor immunityCellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DC) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of IFN signaling, enhanced MHC class I machinery, and presentation of senescence-associated self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong antitumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent antitumor immune responses. Significance: Our study shows that senescent cells are endowed with a high immunogenic potential—superior to the gold standard of immunogenic cell death. We harness these properties of senescent cells to trigger efficient and protective CD8-dependent antitumor immune responses.We are grateful to Maria Isabel Muñoz for assistance with the animal protocols; to Kevin Kovalchik for help with data sharing; to Francesca Castoldi for help in total RNA extraction for B16F10 and IMR-90 cells; to Fredrik Fagerstrom-Billai, Susann Fält, Anastasios Damdimopoulos, and David Brodin at Bioinformatics and Expression Analysis Core Facility, Karolinska Institute (KI), for assistance in RNA-seq and analysis; to the IRB core facilities (Functional Genomics, Biostatistics/Bioinformatics and Histopathology); and to the PCB (Animal House) for general research support. I. Marin was the recipient of an FPI fellowship from the Spanish Ministry of Science (PRE2018-083381). O. Boix was the recipient of an FPI-AGAUR fellowship from the Generalitat de Catalunya. A. Garcia-Garijo was supported by a PERIS grant (SLT017/20/000131) from the Generalitat de Catalunya. J.A. López-Domínguez and M. Kovatcheva were supported by a fellowship from the Spanish Association Against Cancer (AECC). Work in the laboratory of E. Caron was funded by the Fonds de recherche du Québec – Santé (FRQS), the Cole Foundation, CHU Sainte-Justine, the Charles-Bruneau Foundation, the Canada Foundation for Innovation, the National Sciences and Engineering Research Council (#RGPIN-2020-05232), and the Canadian Institutes of Health Research (#174924). E. Garralda received funding from the Comprehensive Program of Cancer Immunotherapy and Immunology II (CAIMI-II) supported by the BBVA Foundation (grant 53/2021). The M. Abad lab received funding from the Spanish Ministry of Science and Innovation (RTI2018-102046-B-I00A and RTC-2017-6123-1) and the AECC (PRYCO211023SERR). M. Abad was the recipient of a Ramón y Cajal contract from the Spanish Ministry of Science and Innovation (RYC-2013-14747). A. Gros received funding from the Spanish Ministry of Science cofunded by the European Regional Development Fund (ERDF; RTC-2017-6123-1), from the Instituto de Salud Carlos III (MS15/00058), and from CAIMI-II (grant 53/2021) supported by the BBVA Foundation. The work in the laboratory of F. Pietrocola is supported by a KI Starting Grant, a Starting Grant from the Swedish Research Council (2019_02050_3), and grants from the Harald Jeanssons Foundation, the Loo and Hans Osterman Foundation, and Cancerfonden (21 1637 Pj). Work in the laboratory of M. Serrano was funded by the IRB and La Caixa Foundation, and by grants from the Spanish Ministry of Science cofunded by the European Regional Development Fund (SAF-2017-82613-R, RTC-2017-6123-1), the European Research Council (ERC-2014-AdG/669622), Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282), and the AECC (PRYCO211023SERR). The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734

Factors influencing black spruce reproductive potential in the northern boreal forest of Quebec

Abstract The reproductive ecology of the semi-serotinous species black spruce (Picea mariana (Mill.) BSP) in northern boreal forests remains poorly understood. There is a general lack of data on cone/seed production and viability as a function of biotic tree-level characteristics and abiotic variables. No studies currently exist to quantify these differences over a large gradient in temperature, elevation, and precipitation. Extensive physical, ecological, dendrometric, and reproductive data were collected from young to very old black spruce stands in northern Quebec. ANOVA and general linear mixed models were used to examine interannual cone production, and the relative importance of the biotic and abiotic explanatory factors in determining total cone production; length of the cone-bearing zone; filled seeds per cone; proportion of filled seeds; and seed viability. The results illustrate that the reproductive ecology of black spruce in northern cold forests is mainly explained by biotic variables such as age and diameter at breast height, and by abiotic variables related to temperature such as elevation, length of the growing season, and growing degree-days. Black spruce exhibits a lower reproductive potential in northern cold forests, making it possibly less resilient to increased fire frequency, particularly in unproductive and very young or very old stands. Résumé L'écologie de la reproduction de l'espèce semi-serotineuse, l'épinette noire (Picea mariana (Mill.) BSP) dans les forêts boréales froides est encore peu documentée. Il existe un manque général de données sur la production des cônes/graines et leur viabilité en fonction des caractéristiques biotiques au niveau de l'arbre et des variables abiotiques. Aucune étude n”existe actuellement pour quantifier ces différences sur un large gradient de température, d'altitude, et de précipitations. De nombreuses données physiques, écologiques, dendrométriques et reproductives ont été recueillies dans des peuplements d“épinette noire jeunes à très âgés dans le nord du Québec. Des ANOVA et des modèles mixtes linéaires généraux ont été utilisés pour examiner la production annuelle de cônes et l'importance relative des facteurs explicatifs biotiques et abiotiques dans la détermination de la production totale de cônes; la longueur de la cime comportant des cônes; le nombre de graines pleines par cône; la proportion de graines pleines; et leur taux de germination. Les résultats indiquent que l'écologie de la reproduction de l'épinette noire dans les forêts boréales nordiques est expliquée par des variables biotiques telles que l'âge et le DHP, et des variables abiotiques liées à la somme thermique régionale telles que l'altitude, la durée de la saison de croissance, et les degrés-jours de croissance. L'épinette noire présente un potentiel reproductif plus faible dans les forêts froides du nord, ce qui la rend moins résistante à l'augmentation de la fréquence des feux, particulièrement dans les peuplements improductifs et très jeunes ou très vieux

Cellular senescence is immunogenic and promotes anti-tumor immunity

Cellular senescence is a stress response that activates innate immune cells, but little is known about its interplay with the adaptive immune system. Here, we show that senescent cells combine several features that render them highly efficient in activating dendritic cells (DCs) and antigen-specific CD8 T cells. This includes the release of alarmins, activation of interferon signaling, enhanced MHC class I machinery, and presentation of senescence-specific self-peptides that can activate CD8 T cells. In the context of cancer, immunization with senescent cancer cells elicits strong anti-tumor protection mediated by DCs and CD8 T cells. Interestingly, this protection is superior to immunization with cancer cells undergoing immunogenic cell death. Finally, the induction of senescence in human primary cancer cells also augments their ability to activate autologous antigen-specific tumor-infiltrating CD8 lymphocytes. Our study indicates that senescent cancer cells can be exploited to develop efficient and protective CD8-dependent anti-tumor immune responses

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis