Regulation of immunity during visceral Leishmania infection

Unicellular eukaryotes of the genus Leishmania are collectively responsible for a heterogeneous group of diseases known as leishmaniasis. The visceral form of leishmaniasis, caused by L. donovani or L. infantum, is a devastating condition, claiming 20,000 to 40,000 lives annually, with particular incidence in some of the poorest regions of the world. Immunity to Leishmania depends on the development of protective type I immune responses capable of activating infected phagocytes to kill intracellular amastigotes. However, despite the induction of protective responses, disease progresses due to a multitude of factors that impede an optimal response. These include the action of suppressive cytokines, exhaustion of specific T cells, loss of lymphoid tissue architecture and a defective humoral response. We will review how these responses are orchestrated during the course of infection, including both early and chronic stages, focusing on the spleen and the liver, which are the main target organs of visceral Leishmania in the host. A comprehensive understanding of the immune events that occur during visceral Leishmania infection is crucial for the implementation of immunotherapeutic approaches that complement the current anti-Leishmania chemotherapy and the development of effective vaccines to prevent disease.The research leading to these results has received funding from the European Community’s Seventh Framework Programme under grant agreement No.602773 (Project KINDRED). VR is supported by a post-doctoral fellowship granted by the KINDReD consortium. RS thanks the Foundation for Science and Technology (FCT) for an Investigator Grant (IF/00021/2014). This work was supported by grants to JE from ANR (LEISH-APO, France), Partenariat Hubert Curien (PHC) (program Volubilis, MA/11/262). JE acknowledges the support of the Canada Research Chair Program

Immobilienwirtschaft aktuell 2022: Beiträge zur immobilienwirtschaftlichen Forschung

Dieser Band enthält zehn aktuelle Beiträge zur Schweizer Immobilienwirtschaft. Die Arbeiten bieten raschen und einfachen Zugriff auf aktuelle Erkenntnisse aus den Themengebieten "Immobilieninvestment", "Immobilienmanagement", "Projektentwicklung" sowie "Urban Management". Die Publikation Immobilienwirtschaft aktuell erscheint jährlich und wird vom Center for Urban & Real Estate Management (CUREM) herausgegeben. Sie enthält die Zusammenfassungen der besten Abschlussarbeiten des Masters of Advanced Studies in Real Estate. Ziel ist die Förderung der akademischen und zugleich praxisnahen Diskussion immobilienrelevanter Themen in der Schweiz. Die vollständigen Abschlussarbeiten stehen auf www.curem.uzh.ch zum kostenlosen Download zur Verfügung. CUREM ist Teil der Wirtschaftswissenschaftlichen Fakultät an der Universität Zürich und widmet sich der immobilienwirtschaftlichen Forschung und Weiterbildung. Ziel ist die Förderung einer professionellen Immobilienwirtschaft in der Schweiz. Nebst dem RICS akkreditierten, berufsbegleitenden Studiengang zum "Master of Advanced Studies in Real Estate" und dem "Certificate of Advanced Studies in Urban Management" führt CUREM verschiedene Kompaktkurse, Expertenworkshops und Fachveranstaltungen durch

"Être à bonne école": pour un dialogue bilatéral qui mette en mouvement praticien·nes et chercheur·es

La recherche qui demande à dialoguer avec la pratique ? C’est l’invitation que lance une dizaine de chercheurs et de chercheuses en éducation à la HEP | PH de Fribourg à toutes celles et tous ceux qu’intéressent les apports scientifiques à la profession enseignante. Dans le dossier qui suit, ces chercheurs et ces chercheuses, souvent aussi enseignant·e·s, présentent leurs recherches et les thèses qui en ont découlé. Langage, grammaire, orthographe, évaluation, identité professionnelle, inclusion scolaire, émotions … les domaines abordés sont larges. Comment le terrain accueille-t- il leur travail

Na+-K+-ATPase is not involved in the warming-up phenomenon in generalized myotonia.

Contains fulltext : 50049.pdf (publisher's version ) (Closed access)The initial temporary weakness that occurs in autosomal-recessive generalized myotonia diminishes with repetitive contractions. Physiological understanding of this phenomenon is incomplete. The underlying hypothesis of our study was that the "warming-up" phenomenon relates to the exercise-related activation of Na(+)-K(+)-ATPase. Three patients performed isometric exercise of the brachioradialis muscle on two separate days. Randomly, on one of these days the contraction was preceded by a 30-min infusion of the Na(+)-K(+)-ATPase inhibitor ouabain into the brachial artery of the exercising arm (0.4 mug.min(-1).dl(-1)). Force was measured simultaneously with electrical muscle activity using high-density surface electromyography (HD-sEMG). A transient rapid decline in force occurred after initiation of exercise, accompanied by electrophysiological changes indicating sarcolemmal conduction block. Ouabain infusion did not affect the recovery from transient paresis or the accompanying electromyographic changes, indicating that the warming-up phenomenon in generalized myotonia is not mediated by Na(+)-K(+)-ATPase

The importance of an integrated genotype-phenotype strategy to unravel the molecular bases of titinopathies

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SARS-CoV-2 Nsp3 unique domain SUD interacts with guanine quadruplexes and G4-ligands inhibit this interaction

International audienceThe multidomain non-structural protein 3 (Nsp3) is the largest protein encoded by coronavirus (CoV) genomes and several regions of this protein are essential for viral replication. Of note, SARS-CoV Nsp3 contains a SARS-Unique Domain (SUD), which can bind Guanine-rich non-canonical nucleic acid structures called G-quadruplexes (G4) and is essential for SARS-CoV replication. We show herein that the SARS-CoV-2 Nsp3 protein also contains a SUD domain that interacts with G4s. Indeed, interactions between SUD proteins and both DNA and RNA G4s were evidenced by G4 pull-down, Surface Plasmon Resonance and Homogenous Time Resolved Fluorescence. These interactions can be disrupted by mutations that prevent oligonucleotides from folding into G4 structures and, interestingly, by molecules known as specific ligands of these G4s. Structural models for these interactions are proposed and reveal significant differences with the crystallographic and modeled 3D structures of the SARS-CoV SUD-NM/G4 interaction. Altogether, our results pave the way for further studies on the role of SUD/G4 interactions during SARS-CoV-2 replication and the use of inhibitors of these interactions as potential antiviral compounds

The HIV-1 clade C promoter is particularly well adapted to replication in the gut in primary infection.

International audienceOBJECTIVE: Coinfection of rhesus macaques with human/simian immunodeficiency virus chimeras harbouring the minimal core-promoter/enhancer elements from HIV-1 clade B, C and E viral prototypes (STR-B, STR-C and STR-E) revealed a remarkable dichotomy in terms of spatio-temporal viral replication. The clade C chimera (STR-C) predominated in primary infection. The present study was aimed at identifying the origin of STR-C plasma viraemia at this infection phase. DESIGN: By competing isogenic viruses differing only in their promoters, it was possible to identify subtle phenotypical differences in viral replication kinetics and compartmentalization in vivo. METHODS: Two rhesus macaques were coinfected by the three STR chimeras and the relative colonization of different compartments, particularly blood and stool, was determined for each chimera. Moreover, growth competition experiments in thymic histocultures enriched in interleukin (IL)-7 were performed and relative percentages of chimeras were estimated in supernatants and thymocytes lysates at different time points. RESULTS: It is demonstrated here that at the peak of primary infection, preferential replication of STR-C was supported by the gut-associated lymphoid tissue (GALT), an IL-7 rich microenvironment. This was shown by the correlation of the RNA viral genotype in blood and stools, compartments directly draining virions from the GALT. Thymic histocultures confirmed that replication of STR-C is particularly susceptible to this cytokine, compared to its STR-B and STR-E counterparts. CONCLUSIONS: These data show that the GALT cytokine network may well favour HIV-1 clade C replication during primary infection. This could result in enhanced transmission

T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes

Abstract Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes

"Exigua pars est vitae qua vivimus. Ceterum quidem omne spatium non vita sed tempus est” : divagazioni semantiche (e lessicali) su spatium e sui suoi esiti romanzi

diasistema latino, attestato in tutta la discretio della lingua che ci è dato conoscere dai testi, spatium manifesta una sorta di liminarità concettuale con tempus che solo a partire da un certo momento si scioglie nella complementarità dell’estensione spaziale e di quella temporale. Muovendo da questi presupposti, questo contributo cercherà di evidenziare la complessa stratificazione semantica di questa lessia di basilare importanza giacché connessa con categorie fondanti per l’esperienza umana tanto dal punto di vista cognitivo, tanto da quello linguistico e pragmatico. Esaurito l’excursus interno al latino si guarderà allora alla continuazione romanza, per cercare di capire se e in quale parte del lessico permangano tracce di quell’originaria complessità di spatium risolta probabilmente prima a livello “lessicografico” che semantico-concettuale