The Relationship between Substrate Structure and Selectivity of Ketoreduction in Multimodular Polyketide Synthases: A Comparative Study of A-Type Ketoreductases from Late Modules Using Complex Precursor Analogues.

Ketoreductases (KRs) are domains in the reductive loops of type I polyketide synthases (PKSs) and are responsible for the majority of stereocenters in reduced polyketides. Although the highly stereoselective reduction of ACP-bound β-ketothioester intermediates by KRs is crucial for the overall functioning of PKSs, the substrate-dependent stereoselectivity of KRs is a factor that is not yet fully understood, especially for KR domains in late PKS modules that act on biosynthetic precursors with complex polyketidic moieties. We present studies on the three KR domains FosKR7, PlmKR6, and EryKR6 from the biosynthetic pathways of fostriecin, phoslactomycin, and erythromycin by in vitro assays using close surrogates of the octaketidic FosKR7 biosynthetic precursor, complex derivatives and a diketide in the form of their biomimetic -acetylcysteamine thioesters.

Diagnosis, treatment, and prevention of ankle sprains: Comparing free chatbot recommendations with clinical guidelines.

Background: Free chatbots powered by large language models offer lateral ankle sprains (LAS) treatment recommendations but lack scientific validation.

Methods: The chatbots-Claude, Perplexity, and ChatGPT-were evaluated by comparing their responses to a questionnaire and their treatment algorithms against current clinical guidelines. Responses were graded on accuracy, conclusiveness, supplementary information, and incompleteness, and evaluated individually and collectively, with a 60 % pass threshold.

Anorexia nervosa-specific home treatment in children and adolescents and their families (the HoT study): a study protocol of a randomized, controlled, multicenter, open-label, parallel group superiority trial.

Background: New treatment approaches are urgently needed to improve the prognosis of children and adolescents with anorexia nervosa (AN). Recently, the feasibility of multidisciplinary home treatment that strongly involves the patients' parents/caregivers has been investigated. However, no RCT has yet been performed to test the efficacy and safety of this approach compared to standard treatment approaches, such as inpatient treatment.

Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity.

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication. Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis.