Crosslinking intermodular condensation in non-ribosomal peptide biosynthesis.

Non-ribosomal peptide synthetases are assembly line biosynthetic pathways that are used to produce critical therapeutic drugs and are typically arranged as large multi-domain proteins called megasynthetases. They synthesize polypeptides using peptidyl carrier proteins that shuttle each amino acid through modular loading, modification and elongation steps, and remain challenging to structurally characterize, owing in part to the inherent dynamics of their multi-domain and multi-modular architectures. Here we have developed site-selective crosslinking probes to conformationally constrain and resolve the interactions between carrier proteins and their partner enzymatic domains.

Differentiating carrier protein interactions in biosynthetic pathways using dapoxyl solvatochromism.

Carrier protein-dependent synthases are ubiquitous enzymes involved both in primary and secondary metabolism. Biocatalysis within these synthases is governed by key interactions between the carrier protein, substrate, and partner enzymes. The weak and transient nature of these interactions has rendered them difficult to study.

Repositioning Brusatol as a Transmission Blocker of Malaria Parasites.

Currently, primaquine is the only malaria transmission-blocking drug recommended by the WHO. Recent efforts have highlighted the importance of discovering new agents that regulate malarial transmission, with particular interest in agents that can be administered in a single low dose, ideally with a discrete and -selective mechanism of action. Here, our team demonstrates an approach to identify malaria transmission-blocking agents through a combination of screening and analyses.

Longitudinal cardiac magnetic resonance imaging following clinical response to rilonacept and prior to recurrence upon treatment suspension: a RHAPSODY subgroup analysis.

Aims: In the phase 3 trial, RHAPSODY, rilonacept effectively resolved active pericarditis recurrences, and long-term treatment led to sustained pericarditis recurrence risk reduction. Prior analysis suggested association between higher late gadolinium enhancement (LGE) at baseline and more rapid recurrence upon rilonacept suspension after 12 weeks of treatment. This subgroup analysis assessed the utility of longitudinal serial cardiac magnetic resonance (CMR) imaging for tracking clinical improvement and predicting post-treatment-cessation outcomes to help guide clinical decision making.

Elevated neutrophil extracellular traps in systemic sclerosis-associated vasculopathy and suppression by a synthetic prostacyclin analog.

Objectives: Neutrophils and neutrophil extracellular traps (NETs) contribute to the vascular complications of multiple diseases, but their role in systemic sclerosis (SSc) is understudied. We sought to test the hypothesis that NETs are implicated in SSc vasculopathy and that treatment with prostacyclin analogs may ameliorate SSc vasculopathy not only through vasodilation but also by inhibiting NET release.

Methods: Blood from 125 patients with SSc (87 diffuse cutaneous SSc and 38 limited cutaneous SSc) was collected at a single academic medical center.