DJ-1 depletion slows down immunoaging in T-cell compartments

Decline in immune function during aging increases susceptibility to different aging related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T-cell subpopulations, still remain largely elusive. Here we show that loss of DJ-1 encoded by PARK7 /DJ-1, causing early-onset familial Parkinson’s disease (PD), unexpectedly delayed immunoaging in both human and mice. Compared with two gender-matched unaffected sibling carriers of similar ages, the index PD patient with DJ-1 deficiency showed a decline in many critical immunoaging features, including almost doubled frequencies of non-senescent T cells. The observation of a ‘younger’ immune system in the index patient was further consolidated by the results in aged DJ-1 knockout mice. Our data from bone marrow chimera models and adoptive transfer experiments demonstrated that DJ-1 regulates several immunoaging features via hematopoietic-intrinsic and naïve-CD8-intrinsic mechanisms. Our finding suggests an unrecognized critical role of DJ-1 in regulating immunoaging, discovering a potent target to interfere with immunoaging- and aging-associated diseases

DJ‐1 depletion prevents immunoaging in T‐cell compartments.

Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases

Early-to-mid idiopathic Parkinson’s disease shows a more cytotoxic but declined CD8-regulatory peripheral immune profile

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Brain neuroinflammation plays a role in PD pathogenesis. However, the involvement of the peripheral immune system has not been systematically investigated. Here we analyzed >700 combinatorial immunological features in fresh blood of 28 early-to-mid-stage PD patients and 24 matched controls. We found an enhanced cytotoxic immune profile in idiopathic PD patients (iPD), with a higher frequency of terminally-differentiated effector CD8 T (TEMRA), late-differentiated CD8+ natural killer T cells and neutrophils. This immune profile was intensified by elevated serum granzyme A, reduced percentages of CD8+FOXP3+ regulatory T cells and group 2 innate lymphoid cells with immunosuppressive or tolerance-inducing functions. The frequency of CD8 TEMRA was negatively correlated with disease duration, suggesting a contribution to PD pathogenesis. Our work provides a comprehensive map on disturbed peripheral adaptive and innate immune cells in early-to-mid iPD, proposing easily-accessible candidates for early diagnosis and treatments

Mitochondria interaction networks show altered topological patterns in Parkinson's disease.

Mitochondrial dysfunction is linked to pathogenesis of Parkinson's disease (PD). However, individual mitochondria-based analyses do not show a uniform feature in PD patients. Since mitochondria interact with each other, we hypothesize that PD-related features might exist in topological patterns of mitochondria interaction networks (MINs). Here we show that MINs formed nonclassical scale-free supernetworks in colonic ganglia both from healthy controls and PD patients; however, altered network topological patterns were observed in PD patients. These patterns were highly correlated with PD clinical scores and a machine-learning approach based on the MIN features alone accurately distinguished between patients and controls with an area-under-curve value of 0.989. The MINs of midbrain dopaminergic neurons (mDANs) derived from several genetic PD patients also displayed specific changes. CRISPR/CAS9-based genome correction of alpha-synuclein point mutations reversed the changes in MINs of mDANs. Our organelle-interaction network analysis opens another critical dimension for a deeper characterization of various complex diseases with mitochondrial dysregulation

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

INVESTIGATING T CELLS IN THE CONTEXT OF NEUROIMMUNOLOGY: MOLECULAR AND CELLULAR MECHANISMS DURING A STRESS RESPONSE AND A PATIENT-BASED STUDY IN PARKINSON'S DISEASE

For a long time, the nervous system and the immune system have been studied as isolated entities, but a growing body of evidence shows that there is an extensive crosstalk between both systems. In fact, neurons and immune cells share certain functional features and reside in close proximity within the tissues, enabling them to effectively communicate. T cells are crucial for mounting and controlling almost any kind of immune response. However, when dysregulated, T cells fail to protect the host from invading pathogens or can cause damage to surrounding tissues, leading to autoimmunity-related pathology. In the first part of this cumulative thesis, we aimed at identifying novel genes regulating CD4 T cell responses and identified VIMP, one of the 25 human proteins containing the 21st amino acid selenocysteine, as a gene having anti-inflammatory functions. Furthermore, T cells express various neurotransmitter receptors allowing the integration of neuronal signal for an appropriate response. In the second part, we showed a CD4-T-cell-intrinsic mechanism through which stress hormones mediate their control over the immune system. We identified a previously unrecognized pathway regulating CD4 T cell differentiation that involves the circadian clock gene Per1 and mTORC1 signalling. Finaly, T cells involvement in different neuropathologies has been reported in the past few decades. Emerging evidence indicates the involvement of the immune system and in particular T cells in the pathogenesis of Parkinson’s disease (PD), the 2nd most common neurodegenerative disease. In the 3rd part of the thesis we systematically characterized the immunological status of early-to-mid stage PD patients and matched healthy controls, and identified a distinct peripheral immunological fingerprint in PD patients, especially in the CD8 T-cell compartment. The findings of the studies described in this cumulative thesis advance our understanding of the regulatory nodes of CD4 T cells during a stress response and fill the knowledge gap on the early involvement of CD8 T cells and other immune subsets in neurodegenerative diseases in the case of PD

La taxation des activités financières : modalités et objectifs

Longtemps considérée comme hétérodoxe, la proposition de taxer les activités financières est revenue en force à la suite de la crise. Début 2011, plusieurs états ont déjà adopté des mesures de ce type ou s'apprêtent à le faire, et les propositions de taxe internationale reviennent régulièrement. Les projets, examinés par Gunther Capelle-Blancard et Christophe Destais, diffèrent cependant de la taxe sur les transactions financières que défendaient avant la crise les mouvements altermondialistes. L'objectif n'est plus tant de réduire la volatilité des mouvements de capitaux que de prévenir les crises, d'inciter la sphère financière à plus de prudence ou de compenser l'écart de rémunération avec les autres secteurs d'activité. Au-delà, l'instauration de taxes de ce genre pourrait apporter un double dividende si elles se substituent à des prélèvements économiquement moins efficaces

Taxing Financial Activities: a Renewal of the Debate

Financial activities tax;Financial Regulation;Financial crisis

Innover dans l'habitat social : le modèle économique et social d'habitat contributif

RÉSUMÉ: En 2017, avec l'appui d'un consortium d'innovation fort d'une quinzaine de partenaires (industriels, économiste, sociologues, architectes), Pas-de-Calais habitat s'est engagé dans la conception et l'expérimentation d'un nouveau modèle de gestion locative en habitat social, qui porte en germe une redéfinition des statuts, des rôles et des identités des locataires comme du bailleur, et repose sur les dynamiques de proximité et de coordination des acteurs. Dans un contexte de détresse sociale d'une part importante des locataires, ce modèle implique un positionnement d'un nouveau genre qui bouscule les missions et les métiers du bailleur. Le bailleur devient producteur et fournisseur d'énergie, animateur de nouvelles dynamiques territoriales, incitateur à la création d’activités économiques et sociales collaboratives, et catalyseur de l'implication citoyenne pour l'amélioration des conditions et de la qualité de vie dans l'habitat. Le modèle vise à faire passer les habitants du statut de « simples locataires » consommateurs de services à celui de « contributeurs » dans la gestion de l'énergie à l'échelle domestique, mais aussi dans la co-conception et la co-production de nouvelles offres de services à destination des habitants. Expérimenté sur 5 sites pilotes, cette expérience est emblématique des enjeux auxquels sont confrontés les bailleurs français, qui imposent de trouver de nouveaux modes d'intervention auprès des populations fragilisées. -- Mots clés : Logement social, innovation, économie contributive, énergie, services à la personne. -- ABSTRACT: In 2017, with the support of an "innovation consortium" of about fifteen partners (industrialists, economists, sociologists, architects), Pas-de-Calais Habitat embarked on the design and experimentation of a new social housing rental management model, which will redefine the status, roles and identities of both tenants and landlords, and will be based on the dynamics of proximity and coordination of the players. In a context of social distress for a significant proportion of tenants, this model implies a new type of positioning that disrupts the landlord's missions and professions. The lessor becomes an energy producer and supplier, a facilitator of new territorial dynamics, an incentive to create collaborative economic and social activities, and a catalyst for citizen involvement to improve living conditions and quality of life in housing. The model aims to transform residents from "mere tenants" who consume services to "contributors" in domestic energy management, but also in the co-design and co-production of new service offers for residents. Experienced on 5 pilot sites, this experience is emblematic of the challenges facing French lessors, which require new methods of intervention with vulnerable populations. -- Keywords : Social housing, innovation, contributing economy, energy, personal care services

Quand la finance ne sert plus la croissance

Forthcomin