Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues were also shown to be nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

List-level control in the flanker task

International audienceCurrent theories posit multiple levels of cognitive control for resolving conflict, including list-level control: the global or proactive biasing of attention across a list of trials. However, to date, evidence for pure list-level control has largely been confined to the Stroop task. Our goals were twofold: (a) test the generality of theoretical accounts by seeking evidence for list-level control in the letter flanker task, using an established method involving diagnostic items, and investigating the conditions under which list-level control may and may not be observed and (b) develop and test a potential solution to the challenge of isolating list-level control in tasks with a relatively limited set of stimuli and responses such as arrow flanker. Our key findings were that list-level control was observed for the first time in a letter flanker task on diagnostic items (Experiment 1), and it was not observed when the design was altered to encourage learning and use of simple stimulus–response associations (Experiment 2). These findings support the generalisability of current theoretical accounts positing dual-mechanisms or multiple levels of control, and the associations as antagonists to control account positing that list-level control may be a last resort, to conflict tasks besides Stroop. List-level control was also observed in the arrow flanker task using a modified design (Experiment 3), which could be extended to other conflict tasks with limited sets of stimuli (four or fewer), although this solution is not entirely free of confounds

On the automaticity of reactive item-specific control as evidenced by its efficiency under load

Traditionally cognitive control is described as slow-acting, effortful, and strategic. Against this backdrop, the notion of "automatic control" is an oxymoron. However, recent findings indicate control also operates quickly with adjustments occurring outside awareness, leaving open the possibility that control could be automatic under certain conditions. Harnessing one such finding, the item-specific proportion congruent (ISPC) effect (i.e., reduction in congruency effect for mostly incongruent compared with mostly congruent items), we systematically investigated the automaticity of reactive item-specific control by examining its efficiency under a concurrent load. In four experiments using a picture-word Stroop task, participants first performed a block of trials in which an ISPC manipulation was embedded to acquire the item-control associations. In later blocks, we manipulated working memory load within-subjects (verbal in Experiment 1, visuospatial in Experiment 2, and n-back updating in Experiments 3 and 4) and compared the ISPC effect between low- and high-load conditions. The results of all four experiments showed that the ISPC effect was robust regardless of working memory load. In Experiment 4, we additionally included diagnostic items to assess whether transfer of item-specific control settings was also automatic. The ISPC transfer effect was abolished under high working memory load. Collectively, the findings suggest that reactive item-specific control is triggered and executed in an automatic manner (regardless of the available attentional resources), but only for items that directly support learning of the item-control associations that underlie item-specific control. We propose several hypotheses to account for these findings and discuss theoretical implications for control.11Nsciessciscopu

The shaping of cognitive control based on the adaptive weighting of expectations and experience.

Existing approaches in the literature on cognitive control in conflict tasks almost exclusively target the outcome of control (by comparing mean congruency effects) and not the processes that shape control. These approaches are limited in addressing a current theoretical issue-what contribution does learning make to adjustments in cognitive control? In the present study, we evaluated an alternative approach by reanalyzing existing data sets using generalized linear mixed models that enabled us to examine trial-level changes in control within abbreviated lists that varied in theoretically significant ways (e.g., probability of conflict; presence vs. absence of a precue). For the first time, this allowed us to characterize (a) the trial-by-trial signature of experience-based processes that support control as a list unfolds under various conditions and (b) how explicit precues conveying the expected probability of conflict within a list influence control learning. This approach uncovered novel theoretical insights: First, slopes representing control learning varied depending on whether a cue was available or not suggesting that explicit expectations about conflict affected whether and the rate at which control learning occurred; and second, this pattern was modulated by task demands and incentives. Additionally, analyses revealed a cue-induced heightening of control in high conflict likelihood lists that mean level analyses had failed to capture. The present study showed how control is shaped by the adaptive weighting of experience and expectations on a trial-by-trial basis and demonstrated the utility of a novel method for revealing the contributions of learning to control, and modulation of learning via precues.11Nsciessciscopu