The CARB-X Portfolio of Nontraditional Antibacterial Products.

The growing prevalence of antibiotic-resistant bacterial pathogens and the lack of new medicines to treat the infections they cause remain a significant global threat. In recent years, this ongoing unmet need has encouraged more research groups to focus on the discovery and development of nontraditional antibacterial agents, ranging from anti-virulence strategies to bacteriophage and ways to modulate the microbiome. The Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) is a global nonprofit public-private partnership dedicated to accelerating antibacterial-related research.

Impact of a multicomponent hand hygiene-related intervention on the infectious risk in nursing homes: A cluster randomized trial.

Background: The aim of this study was to assess the impact of a multifaceted hand hygiene (HH) program on the infectious risk in nursing homes (NHs).

Methods: This was a 2-arm cluster randomized trial; French NHs were allocated randomly to the intervention (13 NHs) or control (13 NHs) groups. The intervention consisted of implementing a bundle of HH-related measures over 1 year, including increased availability of alcohol-based handrub, HH promotion, staff education, and local work groups.

[Caregivers and residents, raising awareness of the influenza vaccine].

Influenza epidemics in nursing homes can lead to serious complications with a high level of lethality. It has been shown that an active policy of awareness campaigns with obligatory information materials and easy access to influenza immunisation increases the rate of vaccination coverage.

[Internal and external assessment of nursing home residents' satisfaction].

Quality improvement procedures and measuring the satisfaction of nursing home residents is a major priority. A study assessed the differences between the results of a survey conducted by internal staff and of one carried out by an external service provider to evaluate the satisfaction of the residents of a nursing home.

A role for the bacterial GATC methylome in antibiotic stress survival.

Antibiotic resistance is an increasingly serious public health threat. Understanding pathways allowing bacteria to survive antibiotic stress may unveil new therapeutic targets. We explore the role of the bacterial epigenome in antibiotic stress survival using classical genetic tools and single-molecule real-time sequencing to characterize genomic methylation kinetics.

Bactericidal Antibiotics Induce Toxic Metabolic Perturbations that Lead to Cellular Damage.

Understanding how antibiotics impact bacterial metabolism may provide insight into their mechanisms of action and could lead to enhanced therapeutic methodologies. Here, we profiled the metabolome of Escherichia coli after treatment with three different classes of bactericidal antibiotics (?-lactams, aminoglycosides, quinolones). These treatments induced a similar set of metabolic changes after 30 min that then diverged into more distinct profiles at later time points.

The transcriptional programs of iNKT cells.

Invariant natural killer T (iNKT) cells are innate T cells that express a semi-invariant T cell receptor (TCR) and recognize lipid antigens presented by CD1d molecules. As part of innate immunity, iNKT cells rapidly produce large amounts of cytokines after activation and regulate the function of innate and adaptive immune cells in antimicrobial immunity, tumor rejection and inflammatory diseases. Global transcriptional profiling has advanced our understanding of all aspects of iNKT cell biology.

Microbial persistence and the road to drug resistance.

Microbial drug persistence is a widespread phenomenon in which a subpopulation of microorganisms is able to survive antimicrobial treatment without acquiring resistance-conferring genetic changes. Microbial persisters can cause recurrent or intractable infections, and, like resistant mutants, they carry an increasing clinical burden. In contrast to heritable drug resistance, however, the biology of persistence is only beginning to be unraveled.

The transcriptional landscape of αβ T cell differentiation.

The differentiation of αβT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes.

Identification of transcriptional regulators in the mouse immune system.

The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages.

Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells.

Invariant natural killer T cells (iNKT cells) are innate-like T lymphocytes that act as critical regulators of the immune response. To better characterize this population, we profiled gene expression in iNKT cells during ontogeny and in peripheral subsets as part of the Immunological Genome Project. High-resolution comparative transcriptional analyses defined developmental and subset-specific programs of gene expression by iNKT cells.

Intrathymic programming of effector fates in three molecularly distinct γδ T cell subtypes.

Innate γδ T cells function in the early phase of immune responses. Although innate γδ T cells have often been studied as one homogenous population, they can be functionally classified into effector subsets on the basis of the production of signature cytokines, analogous to adaptive helper T cell subsets. However, unlike the function of adaptive T cells, γδ effector T cell function correlates with genomically encoded T cell antigen receptor (TCR) chains, which suggests that clonal TCR selection is not the main determinant of the differentiation of γδ effector cells.

Innate recognition of cell wall β-glucans drives invariant natural killer T cell responses against fungi.

iNKT cells are innate T lymphocytes recognizing endogenous and foreign lipid antigens presented in the MHC-like molecule CD1d. The semi-invariant iNKT cell TCR can detect certain bacterial and parasitic lipids and drive iNKT cell responses. How iNKT cells respond to fungi, however, is unknown.

Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection.

Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection.

Rapid and reliable generation of invariant natural killer T-cell lines in vitro.

Several tools have proved useful in the study of invariant natural killer T (iNKT) cells, including CD1d-deficient mice, J alpha281-deficient mice, synthetic lipid antigens and antigen-loaded CD1d tetramers. However, the generation and examination of long-term primary murine iNKT cell lines in vitro has been challenging. Here, we show the rapid generation of iNKT cell lines from splenic iNKT cells of V alpha14 T-cell receptor (TCR) transgenic (Tg) mice.

Antigen Presentation by CD1 Lipids, T Cells, and NKT Cells in Microbial Immunity.

The discovery of molecules capable of presenting lipid antigens, the CD1 family, and of the T cells that recognize them, has opened a new dimensionin our understanding of cell-mediated immunity against infection. Like MHC Class I molecules, CD1 isoforms (CD1a, b, c and d) are assembled in the ER and sent to the cell surface. However, in contrast to MHC molecules, CD1 complexes are then re-internalized into specific endocytic compartments where they can bind lipid antigens.

Evasion of peptide, but not lipid antigen presentation, through pathogen-induced dendritic cell maturation.

Dendritic cells (DC) present lipid and peptide antigens to T cells on CD1 and MHC Class II (MHCII), respectively. The relative contribution of these systems during the initiation of adaptive immunity after microbial infection is not characterized. MHCII molecules normally acquire antigen and rapidly traffic from phagolysosomes to the plasma membrane as part of DC maturation, whereas CD1 molecules instead continually recycle between these sites before, during, and after DC maturation.

NK T cells provide lipid antigen-specific cognate help for B cells.

The mechanisms of T cell help for production of antilipid antibodies are largely unknown. This study shows that invariant NK T cells (iNK T cells) and B cells cooperate in a model of antilipid antigen-specific antibody responses. We use a model haptenated lipid molecule, 4-hydroxy-3-nitrophenyl-alphaGalactosylCeramide (NP-alphaGalCer), to demonstrate that iNK T cells provide cognate help to lipid-antigen-presenting B cells.

Impact of hip fracture, heart failure and weight loss on the risk of institutionalization of community-dwelling patients with dementia.

Objectives: This study sought to identify the influence of medical symptoms and diseases on the risk of nursing home placement in a prospective cohort of newly diagnosed community-dwelling patients with dementia.

Study Design And Setting: This study included 348 patients with dementia, consecutively diagnosed, recruited and followed at a geriatric outpatient center (mean age: 81 years, 65.5% with Alzheimer's disease, mean baseline MMSE score: 20.

Increased surveillance of cells in mitosis by human NK cells suggests a novel strategy for limiting tumor growth and viral replication.

The threat from cancer cells is inherently linked to cell-cycle progression, and viral genomes commonly replicate, for example, within episomes or proviruses, during mitosis. We report here that human natural killer (NK) cells bound cells in mitosis and attacked pathogenic cells in mitosis more effectively than the same cells in other stages of the cell cycle. Thus, cells in mitosis warrant and undergo heightened surveillance, a novel strategy for immunologic assessment of danger.