Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses

T-lymphocyte activation displays a remarkable combination of speed, sensitivity, and discrimination in response to peptide–major histocompatibility complex (pMHC) ligand engagement of clonally distributed antigen receptors (T cell receptors or TCRs). Even a few foreign pMHCs on the surface of an antigen-presenting cell trigger effective signaling within seconds, whereas 1 × 10(5)–1 × 10(6) self-pMHC ligands that may differ from the foreign stimulus by only a single amino acid fail to elicit this response. No existing model accounts for this nearly absolute distinction between closely related TCR ligands while also preserving the other canonical features of T-cell responses. Here we document the unexpected highly amplified and digital nature of extracellular signal-regulated kinase (ERK) activation in T cells. Based on this observation and evidence that competing positive- and negative-feedback loops contribute to TCR ligand discrimination, we constructed a new mathematical model of proximal TCR-dependent signaling. The model made clear that competition between a digital positive feedback based on ERK activity and an analog negative feedback involving SH2 domain-containing tyrosine phosphatase (SHP-1) was critical for defining a sharp ligand-discrimination threshold while preserving a rapid and sensitive response. Several nontrivial predictions of this model, including the notion that this threshold is highly sensitive to small changes in SHP-1 expression levels during cellular differentiation, were confirmed by experiment. These results combining computation and experiment reveal that ligand discrimination by T cells is controlled by the dynamics of competing feedback loops that regulate a high-gain digital amplifier, which is itself modulated during differentiation by alterations in the intracellular concentrations of key enzymes. The organization of the signaling network that we model here may be a prototypic solution to the problem of achieving ligand selectivity, low noise, and high sensitivity in biological responses

African Linguistics in Central and Eastern Europe, and in the Nordic Countries

Non peer reviewe

Language endangerment and language documentation in Africa

Non peer reviewe

PFAPA, un syndrome de fièvre récurrente

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

Perception of medical education by learners and teachers during the COVID-19 pandemic: a cross-sectional survey of online teaching

International audienceCOVID-19 lockdowns have deeply impacted teaching programs. Online teaching has suddenly become the main form of medical education, a form that may be used as long as the pandemic continues. We aimed at analyzing how online teaching was perceived by both teachers and learners to help determine how to adapt curricula in the next few years. An anonymous cross-sectional survey of medical students, pediatric residents, neonatal fellows, and their respective teachers was conducted between June and August 2020 to assess feelings about quality, attendance, equivalence, and sustainability of online teaching programs. 146 Students and 26 teachers completed the survey. 89% of students agreed that the offered online teaching was an appropriate way of teaching during the pandemic. Less than half of learners and teachers felt they have received or provided a training of an equivalent level and quality as in usual courses. About one-third thought that this online teaching should continue after the crisis ends. Medical school students had significantly more mixed opinions on online teaching than residents and fellows did. Attendance of learners significantly improved with synchronous online classes (p < 0.001), and among more advanced learners (p < 0.002). Our study is the first of this kind to assess simultaneously the feelings of learners at different levels (medical students, residents, and fellows) and their respective teachers of pediatric on programs taught online. It showed that online programs were perceived as appropriate ways of teaching during the COVID pandemic. Further studies are, however, needed to assess the efficacy of such teaching methods on medical skills and communication capabilities

Cost-effectiveness of infant hypoallergenic formulas to manage cow’s milk protein allergy in France

ABSTRACTBackground Clinician’s choice of hypoallergenic formulas in the first-line management of cow’s milk protein allergy (CMPA) should be informed by evidence on clinical efficacy and cost-effectiveness.Objective We compare the cost-effectiveness of amino acid-based formula (AAF), extensively hydrolyzed casein formula with Lactobacillus rhamnosus Gorbach Goldin (EHCF+LGG), extensively hydrolyzed whey formula (EHWF), and rice hydrolyzed formula (RHF) in non-breastfed children in France.Methods Immunotolerance and atopic manifestations’ prevalence were based on a prospective non-randomized study with a 36-month follow-up. Resource utilization was sourced from a survey of French clinicians, and unit costs were based on national data. Costs and health consequences were discounted at 2.5% annually. Results were reported using the Collective and French National Health Insurance perspectives.Results Children receiving EHCF+LGG were predicted to require less healthcare resources, given their reduced prevalence of CMPA symptoms at 3 years. In the base case, EHCF+LGG led to savings of at least €674 per child compared to AAF, EHWF, and RHF at 3 years, from both perspectives. Nutrition had the highest economic burden in CMPA, driven by hypoallergenic formulas and dietetic replacements costs. Results were robust to one-way and probabilistic sensitivity analyses.Conclusions EHCF+LGG was associated with more symptom-free time, higher immune tolerance, and lower costs

Interrompre une grossesse en réanimation sans recueil du consentement de la patiente : enjeux éthiques et médico-légaux

International audienceIn France, the voluntary interruption of a pregnancy for medical reasons can be requested by the woman, whatever the term of the pregnancy, if it is attested that the continuation of the pregnancy seriously endangers her health. The termination of the pregnancy is then subject to the collegial opinion of a Pluridisciplinary Centre for Prenatal Diagnosis, which must give a favourable decision after analysing the situation. Following, it is the woman who takes the final decision. Respect for the autonomy of the pregnant woman is therefore a fundamental principle in prenatal diagnosis and termination of pregnancy in French law.In this article, we analyse a situation that raises complex ethical and decision-making issues where the termination of pregnancy is required when the patient is neither able to formulate a request nor to consent, due to her pathology requiring hospitalization in intensive care.If the continuation of the pregnancy poses a serious threat to the patient's health, urgency may be an acceptable argument for acting without the patient's consent. This urgency is understood here as the fact that, without a rapid decision, the clinical situation has little chance of improving or even deteriorating. In this context, we discuss the arguments for terminating the pregnancy and the importance of consulting the parents and spouse, so as not to exclude relatives from the decision-making process. Finally, our analysis questions the limits of medical secrecy in intensive care when a dialogue and an exchange of information with relatives appears essential, in particular when the patient cannot participate in the decision and when there are complex decisions to be made.En France, l'interruption volontaire d'une grossesse pour motif médical peut être demandée par la femme quel que soit le terme de la grossesse, s'il est attesté que la poursuite de celle-ci met gravement en péril sa santé. L’interruption de grossesse est alors soumise à l’avis collégial d’un Centre Pluridisciplinaire de Diagnostic Prénatal qui doit rendre une décision favorable après analyse de la situation. Suite à cet avis, c’est la femme qui prend la décision finale. Le respect de l’autonomie de la femme enceinte est donc un principe fondamental en matière de diagnostic prénatal et d’interruption de grossesse dans la loi française. Nous analysons dans cet article une situation qui soulève des problématiques d’ordre éthique et décisionnel complexes dans le cas où l’interruption de grossesse se pose mais où la patiente n’est ni à même de formuler une demande ni à même de consentir, du fait de sa pathologie nécessitant une hospitalisation en réanimation. Dès lors que le maintien de la grossesse met en péril grave la santé de la patiente, l’urgence peut apparaitre comme un argument recevable pour agir sans consentement de la patiente. Cette urgence s’entend ici par le fait que, sans une décision rapide, la situation clinique a peu de chance de s’améliorer, voire risque de se dégrader. Nous discutons dans ce contexte les arguments qui permettent de réaliser l’interruption et l’importance de consulter les parents et le conjoint, afin de ne pas exclure les proches du processus décisionnel. Notre analyse interroge enfin les limites du secret médical en réanimation quand un dialogue et un échange d’informations avec les proches apparait essentiel, en particulier dès lors que le patient ne peut participer à la décision et qu’il y a des décisions complexes à prendre

Safety and cost effectiveness of supervised ambulatory drug provocation tests in children with mild non‐immediate reactions to beta‐lactams

International audienc

Safety and cost effectiveness of supervised ambulatory drug provocation tests in children with mild non‐immediate reactions to beta‐lactams

International audienc