Parasite and host kinases as targets for antimalarials

Introduction: The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades. Unfortunately, this trend is now reversing, in part due to resistance against available treatments, calling for the development of new drugs against untapped targets to prevent cross-resistance. Areas covered: In view of their demonstrated druggability in noninfectious diseases, protein kinases represent attractive targets. Kinase-focussed antimalarial drug discovery is facilitated by the availability of kinase-targeting scaffolds and large libraries of inhibitors, as well as high-throughput phenotypic and biochemical assays. We present an overview of validated Plasmodium kinase targets and their inhibitors, and briefly discuss the potential of host cell kinases as targets for host-directed therapy. Expert opinion: We propose priority research areas, including (i) diversification of Plasmodium kinase targets (at present most efforts focus on a very small number of targets); (ii) polypharmacology as an avenue to limit resistance (kinase inhibitors are highly suitable in this respect); and (iii) preemptive limitation of resistance through host-directed therapy (targeting host cell kinases that are required for parasite survival) and transmission-blocking through targeting sexual stage-specific kinases as a strategy to protect curative drugs from the spread of resistance

MAPPINGS, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

Large datasets of phosphorylation interactions are constantly being generated, but deciphering the complex network structure hidden in these datasets remains challenging. Many phosphorylation interactions occurring in human cells have been identified and constitute the basis for the known phosphorylation interaction network. We overlayed onto this network phosphorylation datasets obtained from an antibody microarray approach aimed at determining changes in phospho-signalling of host erythrocytes, during infection with the malaria parasite Plasmodium falciparum. We designed a pathway analysis tool denoted MAPPINGS that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. MAPPINGS highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in each dataset. MAPPINGS confirmed several signalling interactions previously shown to be modulated by infection, and revealed additional interactions which could form the basis of numerous future studies. The MAPPINGS analysis strategy described here is widely applicable to comparative phosphorylation datasets in any context, such as response of cells to infection, treatment, or comparison between differentiation stages of any cellular population

Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention

Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention

CANNONBALL ET COLTRANE EN DIRECT / Julian "Cannonball" ADDERLEY et son Quintet [JC Adderley, sax. ; J. Coltrane, sax t ; W. Kelly, p ...et al.]

Comprend : LIMEHOUSE BLUES / FURBER et BRAHAM - STARS FELL ON ALABAMA / F. PERKINS et M. PARISH - WABASH / J.C. ADDERLEY - GRAND CENTRAL / J. COLTRANE - YOU'RE A WEAVER OF DREAMS / Victor YOUNG et J. ELLIOTT - THE SLEEPER / J. COLTRANEBnF-Partenariats, Collection sonore - BelieveContient une table des matière

THE SOUND OF BIG BAND JAZZ IN HI-FI

Titre uniforme : [Lester leaps in]Titre uniforme : [Tenderly]Titre uniforme : [Tenderly]Titre uniforme : [Georgia on my mind]Comprend : JIMMY'S THEME / Leith STEVENS ; Chet BAKER et Bud SHANK - WHAT AM I HERE FOR ? / Duke ELLINGTON ; Cy TOUFF et Riche KAMUCA - GEORGIA ON MY MIND / CARMICHAEL et GORRELL ; l'ORCHESTRE JOHNNY MANDEL, avec Art PEPPER - TENDERLY / GROSS et LAWRENCE ; Chet BAKER et son Orchestre, avec Art PEPPER - LESTER LEAPS IN / Lester YOUNG ; l'ORCHESTRE GIL EVANS, avec Cannonball ADDERLEY - DEARLY BELOVED / J. KERN et MERCER ; l'Orchestre de Johnny MANDEL, avec Frank ROSOLINO - HOORAY FOR LOVE / ARLEN et ROBIN ; l'Orchestre de Bill HOLMAN, avec Bud SHANK - DISC JOCKEY JUMP / Gerry MULLIGAN ; l'Orchestre de Gerry MULLIGAN - BUNNY / Shorty ROGERS ; l'Orchestre Art PEPPER - LET ME SEE / Count BASIE et Harry EDISON ; l'Orchestre de Bill PERKINSBnF-Partenariats, Collection sonore - BelieveContient une table des matière

Weaning from mechanical ventilation in intensive care units across 50 countries (WEAN SAFE): a multicentre, prospective, observational cohort study

Background Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0–4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2–6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. Interpretation In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates