Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination

Mutations in the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) were previously found to be associated with hypogammaglobulinemia in humans. It has been shown that proliferation inducing ligand (APRIL) elicits class switch recombination (CSR) by inducing recruitment ofMyD88 to a TACI highly conserved cytoplasmic domain (THC). We have identified a patient with hypogammaglobulinemia carrying a missense mutation (S231R) predicted to affect the THC. Aiming to evaluate the relevance of this novel mutation of TACI in CSR induction, we tested the ability of TACI, TLR9, or/and CD40 ligands to trigger CSR in naive B cells and B-cell lines carrying S231R. IgG secretion was impaired when triggered by TACI or/and TLR9 ligands on S231R-naive B cells. Likewise, these stimuli induced less expression of activation-induced cytidine deaminase, I(γ)1-C(μ), and I(γ)1-C(μ), while induction by optimal CD40 stimulation was indistinguishable from controls. These cells also showed an impaired cooperation between TACI and TLR9 pathways, as well as a lack of APRIL-mediated enhancement of CD40 activation in suboptimal conditions. Finally, after APRIL ligation, S231R-mutated TACI failed to colocalize withMyD88. Collectively, these results highlight the requirement of an intact MyD88-binding site in TACI to trigger CSR.Fil: Almejún, María Belén. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cols, Montserrat. Mount Sinai School of Medicine. Department of Medicine; Estados UnidosFil: Zelazko, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Oleastro, Matías. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; ArgentinaFil: Cerutti, Andrea. Mount Sinai School of Medicine. Department of Medicine; Estados UnidosFil: Oppezzo, Pablo. Instituto Pasteur. Unidad de Proteínas Recombinantes; UruguayFil: Cunningham Rundles, Charlotte. Mount Sinai School of Medicine. Department of Medicine; Estados UnidosFil: Danielian, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Laboratorio de Investigación; Argentin

The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia

Although the zeta-associated protein of 70 kDa (ZAP-70) is overexpressed in patients with chronic lymphocytic leukemia (CLL) displaying unmutated IGVH genes and poor prognosis, a previous microarray study from our group identified overexpression of LPL and ADAM29 genes among unmutated and mutated CLL, respectively. To assess the prognostic value of these genes, we quantified their expression by real-time quantitative polymerase chain reaction (PCR) in a cohort of 127 patients with CLL and correlated this with clinical outcome, IGVH mutational status, and ZAP-70 protein expression. IGVH mutational status, ZAP-70, and the LPL and ADAM29 mRNA ratios (L/A ratio) were predictive of event-free survival for the whole cohort and for patients with stage A disease. in patients in stage B and C, the L/A ratio was an independent prognostic factor, whereas ZAP-70 did not predict survival. Simultaneous usage of the L/A ratio and ZAP-70 expression allowed an almost perfect (99%) assessment of the IGVH status in the 80% of patients with concordant results (L/A(+), ZAP-70(+) or L/A(-), ZAP-70(-)). LPL and ADAM29 gene expression could also be determined by a simple competitive multiplex reverse transcription PCR assay. Overall, quantification of LPL and ADAM29 gene expression is a strong prognostic indicator in CLL, providing better prognostic assessment than ZAP-70 in advanced stages of the disease.Hop La Pitie Salpetriere, Serv Hematol Biol, F-75013 Paris, FranceInst Pasteur, Unite Immunohematol & Immunopathol, F-75724 Paris, FranceUniversidade Federal de São Paulo, Disciplina Hematol & Hemoterapia, São Paulo, BrazilInst Pasteur, Dept Ecosyst & Epidemiol Malad Infect, Paris, FranceHop La Pitie Salpetriere, Serv Immunol, Paris, FranceInst Pasteur, Ctr Rech Vaccinale & Biomed, Paris, FranceUniversidade Federal de São Paulo, Disciplina Hematol & Hemoterapia, São Paulo, BrazilWeb of Scienc

Lipoprotein lipase expression in chronic lymphocytic leukemia: new insights into leukemic progression

Lipoprotein lipase (LPL) is a central enzyme in lipid metabolism. Due to its catalytic activity, LPL is involved in metabolic pathways exploited by various solid and hematologic malignancies to provide an extra energy source to the tumor cell. We and others described a link between the expression of LPL in the tumor cell and a poor clinical outcome of patients suffering Chronic Lymphocytic Leukemia (CLL). This leukemia is characterized by a slow accumulation of mainly quiescent clonal CD5 positive B cells that infiltrates secondary lymphoid organs, bone marrow and peripheral blood. Despite LPL being found to be a reliable molecular marker for CLL prognosis, its functional role and the molecular mechanisms regulating its expression are still matter of debate. Herein we address some of these questions reviewing the current state of the art of LPL research in CLL and providing some insights into where currently unexplored questions may lead t

Effects of Sleep Deprivation on Blood Glucose, Food Cravings, and Affect in a Non-Diabetic:An N-of-1 Randomized Pilot Study

Sleep deprivation is a prevalent and rising health concern, one with known effects on blood glucose (BG) levels, mood, and calorie consumption. However, the mechanisms by which sleep deprivation affects calorie consumption (e.g., measured via self-reported types of craved food) are unclear, and may be highly idiographic (i.e., individual-specific). Single-case or “n-of-1” randomized trials (N1RT) are useful in exploring such effects by exposing each subject to both sleep deprivation and baseline conditions, thereby characterizing effects specific to that individual. We had two objectives: (1) To test and generate individual-specific N1RT hypotheses of the effects of sleep deprivation on next-day BG level, mood, and food cravings in two non-diabetic individuals; (2) To refine and guide a future n-of-1 study design for testing and generating such idiographic hypotheses for personalized management of sleep behavior in particular, and for chronic health conditions more broadly. We initially did not find evidence for idiographic effects of sleep deprivation, but better-refined post hoc findings indicate that sleep deprivation may have increased BG fluctuations, cravings, and negative emotions. We also introduce an application of mixed-effects models and pancit plots to assess idiographic effects over time

La relevancia de las organizaciones civiles en la configuración de la "inseguridad vial" como problema público

Esta presentación intentará responder en que medida y cómo contribuyen las distintas organizaciones y agrupaciones de la sociedad civil orientadas a la temática vial a la construcción del problema público de la “inseguridad vial” en nuestro país. Para ello, se revisara bibliografía que enmarca este trabajo de investigación en relación a la definición de la “inseguridad vial” como problema público; luego, se caracterizaran las principales organizaciones orientadas a la “inseguridad vial”, presentando objetivos, actividades que llevan a cabo, interlocutores, a la vez que se brindaran elementos que contribuyan a dar cuenta la forma en que se diferencian entre ellas analizando distintas variables y sus puntos de contacto y diferencias con otro tipo organizaciones ligadas por ejemplo, a derechos humanos y violencia institucional.Jornadas realizadas junto con el I Encuentro Latinoamericano de Metodología de las Ciencias Sociales.Facultad de Humanidades y Ciencias de la Educació

The Antigen Receptor as a Driver of B-Cell Lymphoma Development and Evolution

The expression of a functional antigen receptor is necessary for cell survival of normal B lymphocytes and most B-cell neoplasms alike. When the genetic modifications of the B-cell receptor locus fail to produce a functional antigen receptor or result in deleterious mutations of a previously expressed receptor, the affected B cell will undergo apoptosis. The three physiological mechanisms that generate the B-cell receptor, VDJ recombination, somatic hypermutation, and class switch recombination, can induce double-strand DNA breaks and can specifically contribute to lymphomagenesis. On the other hand, the B-cell receptor activation and signaling pathways, which provide strong survival and proliferation signals to normal B cells, can support the growth and evolution of malignant lymphocytes. As a result, an otherwise structurally normal B-cell receptor can behave, from the functional perspective, as a true oncogene. In this chapter, we provide an in-depth discussion of the most recently discovered recurrent mechanisms involving the B-cell receptor in lymphoma pathogenesis. The discussion is structured around two major topics: (1) the genetic mechanisms that create a functional antigen receptor and their errors leading to oncogenic events, and (2) the pathogenic activation of the B-cell receptor signaling cascade. Finally, we will briefly comment on novel emerging therapies targeting the B-cell receptor at different levels

Perceived Fitness and Exercise Intensity Can Predict Exercise Enjoyment

The goal of the study was to investigate the potential interplay of environmental, physiological, and psychological factors with exercise enjoyment. Eighty female undergraduate students at a private, West Coast university participated in the study. Participants were randomly assigned to one of three experimental conditions: control (C), in which the participant exercised alone; talking (T), in which the participant exercised with two confederates who provided “small talk” conversation; and no talking (NT), in which the participant was told she/he had been randomly selected not to wear headphones while the two confederates would wear them. Although experimental group assignment was unrelated to exercise enjoyment, we found that perceived fitness and average speed predicted 27.6% of the variance in exercise session enjoyment and that perceived fitness significantly predicted enjoyment as did mean speed. Neither condition nor perceived exertion were significant predictors of enjoyment. Because exercise enjoyment is a predictor of exercise program adherence, perceived fitness and actual effort during an exercise session should be further explored

Understanding Group Engagement in Online Peer Support Groups: Influence of Structured Elements and Organic Interactions

Online peer support groups (OPSGs) have been widely used in health and wellbeing interventions, but their effectiveness varies, influenced by the level of group engagement and the quality of interactions. This study explores the impact of structured elements, such as prompts and tasks, incorporated into OPSG design on peer support quality and group engagement. We analyse chat messages from two OPSGs aimed at reducing workplace sitting through exercise breaks. Despite identical study designs and similar participant demographics, the two OPSGs exhibited significant differences in group engagement, underscoring the importance of understanding group composition, organic interactions, and other factors influencing engagement. The findings emphasise the need for thoughtful OPSG design, including developing structured elements, to foster communication and improve the quality of interactions. Based on our findings, we discuss strategies to promote supportive exchange, focusing on the role of prompts, group cohesion, and social presence to enhance the effectiveness of OPSGs