Propagation of Oligomeric α-Synuclein and Amyloid-β: Implications for Parkinson\u27s and Alzheimer\u27s Diseases

The aggregation of amyloidogenic proteins is a critical event in the pathology of a variety of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The proteins α-synuclein (αS) and amyloid-β (Aβ) are involved in the formation of amyloid lesions observed in PD and AD, respectively. Both PD and AD exhibit a significant amount of co-pathology in clinical settings, and the αS and Aβ proteins have been shown to interact in vitro. Recent experimental consensus has shown oligomeric species to be significant, if not primary, sources of toxicity in these diseases. In this work, the ability of oligomeric species of αS and Aβ to cross-propagate their oligomeric state was investigated. Oligomeric species of αS were generated in the presence of dopamine (DA) were characterized. Five discrete and stable dopamine-derived αS oligomers (DSOs) ranging from 2-14mers were fractionated. All isolated DSOs were formed along an off-fibril formation pathway. Their mechanism of formation was dependent on the oxidation of DA, implicating the quinone form of DA as an inducer of oligomerization. Importantly, DSOs could self-propagate through interactions with αS monomers. DSOs could also cross-propagate to Aβ42 monomers, yielding Aβ42 oligomers. In addition, Aβ42 oligomers (LFAOs) were shown to be capable of crosspropagating their oligomeric state to αS monomers. This work provides the first experimental evidence for the cross-propagation of oligomeric states among neurodegenerative proteins and provides a potential molecular explanation for the copathology causing increased disease severity in many PD and AD patients

Le contrôle de proportionnalité des sanctions disciplinaires franchit les portes des prisons

Dans un arrêt du 1er juin 2015, le Conseil d’Etat abandonne le contrôle de l’erreur manifeste sur le choix des sanctions disciplinaires infligées aux détenus pour passer – enfin – au contrôle de proportionnalité (ou maximum). La Cour européenne des droits de l’Homme n’est certainement pas étrangère à cette solution protectrice des détenus. Cependant, son influence reste inavouée puisque l’applicabilité de l’article 6 de la Convention n’est toujours pas admise par le Conseil d’Etat au procès disciplinaire pénitentiaire. Une telle position lui permet de continuer d’affirmer que le juge de l’excès de pouvoir – et non le juge du plein contentieux – est compétent pour statuer en la matière, ce qui, au regard des exigences de l’article 6, paraît contestable

Inside the Incumbency Factor's "Black Box" The Source of Electoral Advantage on the Local Level

The literature on the &ldquo;incumbency factor&rdquo; and its sources in congressional politics is some of the most pervasive in political science. However, few scholars have attempted&mdash;and none have persuasively established&mdash;the significance of the incumbency factor in lower visibility elections, such as those on the local level. Within this context, my honors thesis seeks to answer two research questions: (1) Does the incumbency factor exist on the local level? and (2) If so, what are its causal mechanisms? My findings from aggregated race-level data from the Commonwealth of Virginia and over 1,000 local candidate survey responses corroborate that this &ldquo;Black Box&rdquo; of the local incumbency factor does, in fact, exist. Furthermore, bivariate and multivariate probit and Ordinary Least Square regressions techniques revealed that the local incumbency factor is dominantly explained by quality challenger deterrence and probably contributed to by the institutional characteristics and resources of the offices at stake, though to a much lesser extent.</p

El psicólogo escolar. Sus tareas y su formación

Entre las conclusiones generales del Congreso Internacional de Pedagogía celebrado en Santander-San Sebastián en julio último, se pueden leer, en las sugestiones relativas a la tercera Sección, consagrada a los problemas de la formación de los educadores, las siguientes líneas: "'Se recomienda que en cada Centro de Enseñanza Media y en cada circunscripción de enseñanza primaria, haya un maestro o profesor especializado que se ocupe exclusivamente de las tareas de investigación psico-pedagógica.

Andrej Tarkovskij en France : le dernier exil européen du cinéaste

Depuis le Lion d'or obtenu par L'Enfance d'Ivan à Venise en 1962, l'Europe médiatise les talents du cinéaste soviétique Andreï Tarkovski. De 1966 à 1986, c'est alors le festival de Cannes qui se mobilise en faveur de films mal aimés (Andreï Roublev, Stalker) par les dirigeants d'URSS. Si Andrej Tarkovskij incarne la figure cinématographique de l'artiste russe, attaché à sa terre (les bois du Miroir) et fier de ses racines spirituelles (le pouvoir des icônes), l'Europe constitue un territoire protecteur et hospitalier. Qu'il s'agisse de journalistes (Serge Daney pour Libération), d'institutions (festival de Cannes, Ministère français de la culture) ou de personnalités du cinéma (Daniel Toscan du Plantier chez Gaumont), l'artiste est non seulement reconnu mais surtout soutenu à l'Ouest. Malgré les amples budgets de ses films soviétiques, les pressions idéologiques épuisent Tarkovskij qui finit par s'installer en Italie au milieu des années 1980. Refusant de rentrer à Moscou, le cinéaste est désormais épaulé par des comités de soutiens dans son combat pour faire sortir son fils d'URSS. Affrontant un grave cancer aux premiers jours de l'année 1986, l'artiste est soigné à Paris tandis que les autorités françaises facilitent la venue de son fils. Le réalisateur avait peu d'attaches personnelles avec la France mais c'est à Paris, parmi ses soutiens et ceux qui le tenaient pour un cinéaste de tout premier plan que Tarkovskij est enterré aux premiers jours de l'année 1987

Vers un renforcement en France du statut juridique de l’enfant issu d’une GPA effectuée à l’étranger ?

Par un arrêt en date du 12 décembre 2014, le Conseil d’Etat français a refusé de faire droit au recours initié contre la circulaire du 25 janvier 2013 relative à la délivrance des certificats de nationalité française pour les enfants né à l’étranger de parents français ayant vraisemblablement eu recours à une convention de gestation pour autrui (GPA). Ce faisant, le Conseil d’Etat détermine de manière précise les contours des droits des enfants en matière de nationalité issus de GPA à l’étranger de parents français. De plus, cet arrêt de la haute juridiction administrative permet de contrebalancer la ligne ferme de la Cour de cassation consistant à priver d’effet juridique dans l’ordre interne tout acte concernant un enfant issu d’une telle méthode procréative

Introduction

La deuxième partie du colloque est consacrée à l’égalité de genre. Force est de constater le peu d’études réalisées en droit français mobilisant le concept de genre, contrairement aux autres disciplinaires ainsi qu’au monde anglo-saxon. Pourtant, il y a matière à s’emparer du genre comme outil d’analyse du droit, comme le démontre notamment le travail de REGINE. Mais le genre mérite aussi d’avoir sa place dans l’enseignement du droit. En effet, à partir du postulat que le droit est un rapport..

463 Vibostolimab plus pembrolizumab with/without docetaxel vs docetaxel in NSCLC after platinum chemotherapy and immunotherapy

BackgroundAgents blocking interactions between the T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) and its ligands (CD112, CD155) have demonstrated preclinical antitumor activity. Anti-TIGIT humanized monoclonal antibody vibostolimab (MK-7684) showed promising antitumor activity and manageable toxicity in heavily pretreated patients across multiple tumor types, particularly when combined with the PD-1 inhibitor pembrolizumab (NCT02964013). Pembrolizumab has significantly improved OS versus chemotherapy in PD-L1–positive advanced non–small-cell lung cancer (NSCLC). However, many patients present with primary or acquired resistance to immunotherapy. This phase 2 study (NCT04725188) evaluates efficacy and safety of MK-7684A, a co-formulation of vibostolimab plus pembrolizumab, administered with/without docetaxel versus docetaxel alone in patients with previously treated metastatic NSCLC.MethodsThis randomized, placebo- and active-controlled, multicenter, partial-blind study is enrolling adults with histologically/cytologically confirmed metastatic NSCLC with PD after platinum-doublet chemotherapy and 1 prior anti–PD-(L)1 therapy. Patients must have measurable disease per RECIST v1.1, ECOG PS of 0–1, and no known active CNS metastases (previously treated brain metastases allowed if radiologically/clinically stable). Tumor tissue from archival or newly-obtained core or excisional biopsies are evaluated centrally for PD-L1 expression before randomization, and local documentation of the absence of EGFR mutations or ALK/ROS1 gene rearrangements must be provided. Patients are randomized 1:1:1 to receive intravenous vibostolimab (200 mg) plus pembrolizumab (200 mg) Q3W (open-label), vibostolimab plus pembrolizumab plus docetaxel (standard-of-care dose) Q3W (blinded), or docetaxel plus placebo Q3W (blinded). Randomization is stratified by ECOG PS (0/1), prior anti–PD-(L)1 therapy (immediate/no immediate prior therapy), and PD-L1 tumor proportion score (<50%/≥50%). Treatment continues for up to 35 cycles (approximately 2 years) of vibostolimab plus pembrolizumab, and per locally approved label for docetaxel, or until PD, unacceptable AEs, intercurrent illness, or investigator decision. Patients with SD/PR/CR may be eligible for up to 17 additional rechallenge cycles of vibostolimab plus pembrolizumab following BICR-verified radiographic PD by RECIST v1.1 after initial treatment or first course is completed or stopped for confirmed CR. Primary endpoint is PFS per RECIST v1.1 by BICR. Secondary endpoints are OS, ORR and DOR per RECIST v1.1 by BICR, and safety. Radiographic imaging occurs at baseline, Q6W through week 36, Q9W through week 54, and then Q12W until PD, start of new anticancer treatment, withdrawal of consent, or death. AEs are assessed by NCI CTCAE v5.0. Approximately 240 patients will be randomized. Enrollment began in April of 2021, and is ongoing at 42 sites in 10 countries.AcknowledgementsMedical writing assistance was provided by Rozena Varghese, PharmD, CMPP, of ICON plc (North Wales, PA, USA), funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.Trial RegistrationClinicalTrials.gov, NCT04725188Ethics ApprovalAn independent institutional review board or ethics committee approved the protocol at each study site, and the trial is being conducted in compliance with Good Clinical Practice guidelines and the Declaration of Helsinki. All patients are required to provide informed consent prior to participation in the study

Worksite Physical Activity Barriers and Facilitators: A Qualitative Study Based on the Transtheoretical Model of Change

Background: Many of the studies on worksite physical activity (PA) have investigated either the effectiveness of PA programs for employees and the work-related outcomes or health promotion interventions to increase PA. However, studies on barriers and enabling factors for participation are scarce and have generally not been theoretically grounded. The purpose of this qualitative study was to identify worksite PA barriers and facilitators from the perspective of the transtheoretical model of change (TTM).Methods: Thirty employees (15 females and 15 males; Mage = 44.70; SD = 5.20) were recruited to participate in semi-structured interviews lasting from 60 to 90 min. Participants came from several organizations that offered PA programs and were at different exercise stages of change. They were invited to describe: (a) general information on the place of PA in their daily lives and in the workplace, and the reasons for (b) worksite PA participation or (c) non-participation. The interview transcripts were analyzed both inductively and deductively with reference to the exercise stages of change.Results: Three categories of barriers and facilitators related to physical, psychological and environmental dimensions were identified. For all exercise stages of change combined, psychological and environmental barriers were significantly more reported than physical barriers, whereas physical and psychological facilitators were more cited than environmental facilitators. Further qualitative analysis suggested that these categories differed with the exercise stage of change. At the precontemplative and contemplative stages, all types of barriers predominated (e.g., physical constraints due to the workstation, fear of management disapproval, time constraints). At the preparation stage, physical, and psychological needs emerged in relation to worksite PA (e.g., need to compensate for sedentary work, stress regulation). At the action and maintenance levels, physical, psychological, and environmental facilitators were reported (e.g., enhanced physical condition, workplace well-being, social ties). At the relapse stage, specific life changes or events broke the physically active lifestyle dynamics.Conclusion: This study identified the contribution of different types of worksite PA barriers and facilitators according to the exercise stage of change. The identified facilitators are consistent with the general TTM processes of change, while being specific to the workplace. Practical strategies are discussed

Staging of nutrition disorders in non-small-cell lung cancer patients : utility of skeletal muscle mass assessment

Background An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia [skeletal muscle mass (SMM) loss], inflammation, and anorexia. The aim of this study was to stage CAX in non-small-cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters. Methods This was a cross-sectional and non-interventional multicentre study. SMM was assessed by analysing L3 computed tomography-scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ-C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ). Results Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0-1, and the tumour stage was mainly IIIB-IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre-CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K-RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre-CAX patients. Overall, 43.8% of pre-CAX patients had only sarcopenia with limited weight loss (<= 2%) and no anorexia. Conclusions This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX