In vivo imaging of prostate cancer using an anti-PSMA scFv fragment as a probe

AbstractWe aimed to evaluate a fluorescent-labeled single chain variable fragment (scFv) of the anti-PSMA antibody as a specific probe for the detection of prostate cancer by in vivo fluorescence imaging. An orthotopic model of prostate cancer was generated by injecting LNCaP cells into the prostate lobe. ScFvD2B, a high affinity anti-PSMA antibody fragment, was labeled using a near-infrared fluorophore to generate a specific imaging probe (X770-scFvD2B). PSMA-unrelated scFv-X770 was used as a control. Probes were injected intravenously into mice with prostate tumors and fluorescence was monitored in vivo by fluorescence molecular tomography (FMT). In vitro assays showed that X770-scFvD2B specifically bound to PSMA and was internalized in PSMA-expressing LNCaP cells. After intravenous injection, X770-scFvD2B was detected in vivo by FMT in the prostate region. On excised prostates the scFv probe co-localized with the cancer cells and was found internalized in PSMA-expressing cells. The PSMA-unrelated scFv used as a control did not label the prostate cancer cells. Our data demonstrated that scFvD2B is a high affinity contrast agent for in vivo detection of PSMA-expressing cells in the prostate. NIR-labeled scFvD2B could thus be further developed as a clinical probe for imaging-guided targeted biopsies

High rate, fast timing Glass RPC for the high η\eta CMS muon detectors

The HL-LHC phase is designed to increase by an order of magnitude the amount of data to be collected by the LHC experiments. To achieve this goal in a reasonable time scale the instantaneous luminosity would also increase by an order of magnitude up to $6 \cdot 10^{34}$ cm$^{-2}$s$^{-1}$. The region of the forward muon spectrometer ($|\eta| > 1.6$) is not equipped with RPC stations. The increase of the expected particles rate up to 2 kHz/cm$^2$ ( including a safety factor 3 ) motivates the installation of RPC chambers to guarantee redundancy with the CSC chambers already present. The actual RPC technology of CMS cannot sustain the expected background level. A new generation Glass-RPC (GRPC) using low resistivity glass (LR) is proposed to equip at least the two most far away of the four high eta muon stations of CMS. The design of small size prototypes and the studies of their performances under high rate particles flux is presented.Comment: 5 pages, 5 figures, proceeding for the conference VCI 201

La colère chez les éducateurs de la PJJ : une émotion inutile mais légitime face à la transgression d’un jeune

Le travail éducatif auprès d’adolescents en conflit avec la loi peut être source de frustration et de colère. L’interprétation par les éducateurs du sens des comportements d’opposition est possiblement liée à leur réaction émotionnelle. Cette étude vise à explorer l’attitude des éducateurs de la Protection judiciaire de la jeunesse (PJJ) envers la colère. En présentant à des éducateurs stagiaires (N = 85) un scénario fictif qui relate une situation de transgression où un éducateur ressent de la colère, cette étude s’intéresse à l’évaluation de l’utilité et de la légitimité de la colère du professionnel ainsi qu’à la manière d’interpréter le comportement de l’adolescent (attributions causales contrôlables versus incontrôlables et internes versus externes).Les résultats indiquent qu’une large majorité des éducateurs jugent que la colère est inutile et qu’une légère majorité d’entre eux jugent qu’elle est pourtant légitime. Par ailleurs, les éducateurs tendent plutôt à percevoir les causes du comportement de l’adolescent comme étant internes mais incontrôlables, ce qui fournit une explication indulgente à la transgression, qui semble pouvoir être liée à l’attitude envers la colère. À la lumière de ces résultats et dans le contexte du travail émotionnel à accomplir par les éducateurs, ces attributions causales indulgentes peuvent être interprétées comme des stratégies cognitives de régulation de la colère. Enfin, la légitimité accordée à la colère pourrait traduire une revendication d’autonomie émotionnelle par les éducateurs ou une attitude favorable à la colère malgré des connaissances sur son inutilité.Educational work with teenagers that are likely to enter into conflict may be a source of frustration and anger. The youth workers’ interpretation of the meaning of opposition behaviors is possibly linked to their emotional reactions.The purpose of this study is to explore the juvenile justice educators’ attitudes towards anger. By presenting to juvenile justice trainee educators (N= 85) a fictive scenario that recounts a conflict situation in which an educator feels angry, this study is interested in the evaluation of usefulness and legitimacy of the youth worker’s anger as well as the way to interpret the teenager’s behavior (controllable causal attributions vs uncontrollable and internal vs external ones).The results show that a large majority of the youth workers judge that anger is useless and a small majority of them estimate that anger is, however, legitimate. Moreover, youth workers are more likely to perceive the adolescent’s behavior as internal but uncontrollable, what provides an indulgent explanation to the transgression that seems to be able to be linked to the attitude towards anger.In light of these results and in the context of the emotional work to be done by juvenile justice educators, those indulgent causal attributions can be interpreted as cognitive strategies of anger regulation. Finally, the legitimacy given to anger could translate a claim of emotional autonomy by youth workers or an attitude favorable to anger despite the knowledge of its uselessness.La labor educativa entre los adolescentes en conflicto con la ley puede ser fuente de frustración e ira. La interpretación por parte de los educadores del sentido de los comportamientos de oposición está probablemente vinculada a su reacción emocional. Este estudio pretende explorar la actitud de los educadores de la Protección Judicial de la Juventud (PJJ) respecto a la ira. Presentando a los educadores en período de prácticas (N = 85) un escenario ficticio que relata una situación de transgresión donde un educador siente ira, este estudio se interesa por la evaluación de la utilidad y la legitimidad de la ira del profesional, así como por la manera de interpretar el comportamiento del adolescente (atribuciones causales controlables frente a incontrolables e internas frente a externas).Los resultados indican que una amplia mayoría de los educadores consideran inútil la ira y que una minoría considera que, a pesar todo, es legítima. Además, los educadores tienden a percibir las causas del comportamiento del adolescente como internas pero incontrolables, lo que ofrece una explicación indulgente para la transgresión que parece poder estar asociada a la actitud ante la ira. A la vista de estos resultados y dentro del contexto del trabajo emocional que los educadores deben realizar, estas atribuciones causales indulgentes pueden interpretarse como estrategias cognitivas de regulación de la ira. Por último, la legitimidad reconocida a la ira podría revelar una reivindicación de autonomía emocional por parte de los educadores o una actitud favorable ante la ira a pesar de ser conscientes de su inutilidad

La reconstitution de l'offre dans les opérations de renouvellement urbain de 2000 à 2004

Contexte :Cette démarche fait suite à une première analyse conduite en 2002 - 2003, par le Certu et quatre cete, ayant abouti à l’élaboration d'un ouvrage intitulé : « Renouvellement urbain - Enseignements de 15 opérations de démolition/reconstruction " . Ce document, destiné aux acteurs du renouvellement urbain et en particulier aux DDE, a souligné la difficulté de reconstituer une offre sociale à l'échelle des agglomérations . Il a également pointé la nécessité d'une meilleure utilisation des PLH pour décliner des politiques de re-développement de l'offre plus équilibrées au sein des Communautés d'Agglomération. C'est pourquoi la DGUHC a souhaité qu'une nouvelle investigation soit réalisée autour de cette double question. Résumé : Au travers des analyses de sites concernant dix agglomérations, l'objectif poursuivi est :- d'analyser la définition, le contenu et la mise en œuvre des politiques de reconstitution de l'offre dans les opérations de renouvellement urbain, à l'échelle de l'agglomération. n - d'apprécier l'articulation entre la reconstitution de l'offre des opérations de renouvellement urbain et les politiques locales de l'habitat. - de favoriser la connaissance des pratiques au regard de la problématique formulée, en premier lieu dans le réseau de l'Équipement, mais aussi auprès des collectivités ou auprès d'autres acteurs du renouvellement urbain. L'étude a été conduite dans un contexte très évolutif en matière de réglementations, de financements et de stratégies institutionnelles avec, d'une part, la création de l'Agence Nationale de la Rénovation Urbaine et, d'autre part, la délégation de compétence aux collectivités locales en matière d'attribution d'aides à la pierre, ouverte par la loi du 13 août 2004 relative aux libertés et responsabilités locales . Elle n'a donc pas vocation à édicter des éléments de doctrine, elle rend compte d'intentions locales, dresse un certain nombre de constats, et tente d'en tirer de premiers enseignements dans le cadre de processus opérationnels, souvent à des stades très amon

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background Late–onset Alzheimer's disease (AD) is heritable with 20 genes showing genome wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease we extended these genetic data in a pathway analysis. Methods The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (p = 3.27×10-12 after multiple testing correction for pathways), regulation of endocytosis (p = 1.31×10-11), cholesterol transport (p = 2.96 × 10-9) and proteasome-ubiquitin activity (p = 1.34×10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected p 0.002 – 0.05). Conclusions The immune response, regulation of endocytosis, cholesterol transport and protein ubiquitination represent prime targets for AD therapeutics

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues