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Abstract Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.

Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate. Although IFN-γ is known to regulate T cell function and expansion during virus-specific responses, its impact on T cells with varying avidity for antigen remains unclear. Here, the authors demonstrate that IFN-γ promotes the expansion of low-avidity CD8+ T cells during the effector phase, but favours those with high avidity in the memory pool. [ABSTRACT FROM AUTHOR]

Assessment Essentials: Planning, Implementing, and Improving Assessment in Higher Education, by Catherine A. Palomba and Trudy W. Banta. San Francisco: Jossey-Bass, 1999. 405 pp. $32.95 Although assessment activities are now [...]

Disparities persist regarding the access to pediatric and congenital cardiac catheterization procedures (PCCC). Developing capacities in French overseas territories located far away from mainland France remains essential to reducing inequalities and mortality. To describe the characteristics of patients, procedures type risk categories (PTRC) and outcomes for all PCCC performed on the French island of Martinique (Caribbean). Single center observational study. We recorded prospectively all consecutives PCCC performed in the catheter laboratory of the university Hospital of Martinique from January 2007 to December 2023. Demographics, procedures characteristics, PTRC, adverse events occurrence, as well as 24-hours mortality were documented. All results were retrospectively analysed. We performed 869 PCCC in 770 consecutives patients (31.3% < 1-year-old; 9.4% aged < 1 month) living in French territories (90%) of Martinique, Guadeloupe, French Guiana, Saint-Martin, or natives from others Caribbean islands (10%). The median age and weight (IQR) were 4 years (0.6–13) and 16 kg (6.4–4.6). There were 126 urgent and 43 (4.9%) rescue procedures. PCCC were predominantly interventional (68.7%; success rate: 95.1%) covering all types of procedures, except revalvulation. The overall median PTRC was 2 (2–3) with a 24-h mortality of 1.1%. Complications occurred in 35 cases (4%), of which 18 were major, either procedure and anaesthesia-related (40%) or likely linked (40%) to the critical condition on admission at the cathlab. Overtime, the case-mix complexity continued to increase (PTRC > 3 in 25% of patients, with a median age and weight of 2.6 years and 6.5 kg, within the past 5 years). Developing permanent PCCC capabilities in French Martinique is efficient and safe. This ongoing international program is sustainable with the inclusion of patients coming from all French territories and neighbouring Caribbean islands and the continuous support of French Health Authorities. [ABSTRACT FROM AUTHOR]

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients' long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation. [ABSTRACT FROM AUTHOR]

Abstract Alcohol dehydrogenases (ADHs) are used in reductive biotransformations for the production of valuable chiral alcohols. In this study, we used a high-throughput screening approach based on the NADPH biosensor pSenSox and fluorescence-activated cell sorting (FACS) to search for variants of the NADPH-dependent ADH of Lactobacillus brevis (LbADH) with improved activity for the reduction of 2,5-hexanedione to (2R,5R)-hexanediol. In a library of approx. 1.4 × 106 clones created by random mutagenesis we identified the variant LbADHK71E. Kinetic analysis of the purified enzyme revealed that LbADHK71E had a ~ 16% lowered KM value and a 17% higher Vmax for 2,5-hexanedione compared to the wild-type LbADH. Higher activities were also observed for the alternative substrates acetophenone, acetylpyridine, 2-hexanone, 4-hydroxy-2-butanone, and methyl acetoacetate. K71 is solvent-exposed on the surface of LbADH and not located within or close to the active site. Therefore, K71 is not an obvious target for rational protein engineering. The study demonstrates that high-throughput screening using the NADPH biosensor pSenSox represents a powerful method to find unexpected beneficial mutations in NADPH-dependent alcohol dehydrogenases that can be favorable in industrial biotransformations.

The(m, k)-firm model has recently drawn a lot of attention. It provides a flexible real-time system with graceful degradation of the quality of service (QoS), thus achieving the fault tolerance in case of system overload. In this paper, we focus on the distance-based priority (DBP) algorithm as it presents the interesting feature of dynamically assigning the priorities according to the system's current state (QoS-aware scheduling). However, DBP cannot readily be used for systems requiring a deterministic(m, k)-firm guarantee since the schedulability analysis was not done in the original proposition. In this paper, a sufficient schedulability condition is given to deterministically guarantee a set of periodic or sporadic activities (jobs) sharing a common non-preemptive server. This condition is applied to two case studies showing its practical usefulness for both bandwidth dimensioning of the communication system providing graceful degradation of QoS and the task scheduling in an in-vehicle embedded system allowing fault tolerance. [ABSTRACT FROM PUBLISHER]

T cells are essential mediators of the adaptive immune system, which constantly patrol the body in search for invading pathogens. During an infection, T cells that recognise the pathogen are recruited, expand and differentiate into subtypes tailored to the infection. In addition, they differentiate into subsets required for short and long-term control of the pathogen, i.e., effector or memory. T cells have a remarkable degree of plasticity and heterogeneity in their response, however, their overall response to a given infection is consistent and robust. Much research has focused on how individual T cells are activated and programmed. However, in order to achieve a critical level of population-wide reproducibility and robustness, neighbouring cells and surrounding tissues have to provide or amplify relevant signals to tune the overall response accordingly. The characteristics of the immune response—stochastic on the individual cell level, robust on the global level—necessitate coordinated responses on a system-wide level, which facilitates the control of pathogens, while maintaining self-tolerance. This global coordination can only be achieved by constant cellular communication between responding cells, and faults in this intercellular crosstalk can potentially lead to immunopathology or autoimmunity. In this review, we will discuss how T cells mount a global, collective response, by describing the modes of T cell-T cell (T-T) communication they use and highlighting their physiological relevance in programming and controlling the T cell response. [ABSTRACT FROM AUTHOR]