Symbiont-Produced Byrostatins: Investigation of their Biosynthesis and Effects on Host Target

The marine bryozoan Bugula neritina is the source of the bioactive polyketide compounds, the bryostatins. The biosynthesis of the bryostatins is putatively prescribed by the Type I modular polyketide synthase (PKS), bry, from the uncultured bacterial symbiont “Candidatus Endobugula sertula”. The bry gene cluster has a non-canonical, discrete acyltransferase (AT) enzymatic domain upstream of the PKS gene cluster. The AT is hypothesized to add the polyketide extender units onto an acyl carrier protein (ACP) in the bry PKS and, as such, is termed a trans-AT. In addition, some trans-ATs have been shown to have more extender unit substrate flexibility than cis-ATs, which are usually very substrate-specific. The ability of trans-ATs to discriminate between the modular ACPs and load them with the correct extender unit to form the desired polyketide product during biosynthesis is unclear. To examine how trans-AT’s discriminate between modules, protein-protein interactions between the BryP trans-AT and interdomain regions between ketosynthase (KS) and AT regions of PKS modules were assessed using surface plasmon resonance (SPR) to compare binding events via dissociation data. On average, BryPAT1 had a higher affinity for BryBM4 KS-AT interdomain region as compared to the EryAIII M5 KS-AT interdomain region. Bryostatins are versatile compounds that are ecologically relevant for the survival of Bugula larvae. The mechanism for this activity could be due to activation of protein kinase C (PKC) via high affinity for the PKC C1b domain. As the symbiont-produced bryostatins are potent activators of a eukaryotic cellular target, the question of how the bryozoan host has adapted to their presence arises. Interestingly, there is variation in symbiont and bryostatin status within the genus Bugula, with some species possessing a symbiont that produces bryostatins, some species possessing a closely-related symbiont that does not produce bryostatins, and some species with no symbiont. Using SPR, on average, bryostatin has a higher affinity for bryostatin-producing B. neritina C1b domain as compared to non-bryostatin containing Bugula pacifica and Rattus norvegicus C1b domains. Understanding aspects of bryostatin biosynthesis and symbiont effects on the host will provide deeper insight into the vital role that they play in the interaction between B. neritina and E. sertula

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Additional file 1 of Inferring metabolic pathway activity levels from RNA-Seq data

Supplementary table. The Supplementary table is supplied in PDF format. (PDF 16 kb

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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