Mitofusin-mediated contacts between mitochondria and peroxisomes regulate mitochondrial fusion.

Mitofusins are large GTPases that trigger fusion of mitochondrial outer membranes. Similarly to the human mitofusin Mfn2, which also tethers mitochondria to the endoplasmic reticulum (ER), the yeast mitofusin Fzo1 stimulates contacts between Peroxisomes and Mitochondria when overexpressed. Yet, the physiological significance and function of these "PerMit" contacts remain unknown. Here, we demonstrate that Fzo1 naturally localizes to peroxisomes and promotes PerMit contacts in physiological conditions. These contacts are regulated through co-modulation of Fzo1 levels by the ubiquitin-proteasome system (UPS) and by the desaturation status of fatty acids (FAs). Contacts decrease under low FA desaturation but reach a maximum during high FA desaturation. High-throughput genetic screening combined with high-resolution cellular imaging reveal that Fzo1-mediated PerMit contacts favor the transit of peroxisomal citrate into mitochondria. In turn, citrate enters the TCA cycle to stimulate the mitochondrial membrane potential and maintain efficient mitochondrial fusion upon high FA desaturation. These findings thus unravel a mechanism by which inter-organelle contacts safeguard mitochondrial fusion.

Discovery and Structure-Activity Relationship of Cadazolid: A First-In-Class Quinoxolidinone Antibiotic for the Treatment of Clostridioides difficile Infection.

Clostridioides difficile (C. difficile) is one of the leading causes of healthcare-associated infections worldwide. The increasing incidence of strains resistant to currently available therapies highlights the need for alternative treatment options with a novel mode of action. Oxazolidinones that are connected to a quinolone moiety with a pyrrolidine linker, such as compound 1, are reported to exhibit potent broadspectrum antibacterial activity. In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid (9), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile, including hypervirulent and epidemic strains.

Existe vantagem em utilizar o citrato de clomifene em pacientes ovuladoras? / Is there any advantage in using clomiphene citrate in patients with ovulatory cicles?

Retrospectiva: O citrato de clomifene tem sido utilizado em pacientes ovuladoras com a intençao de melhorar os índices de gravidez. Objetivo: O objetivo do presente trabalho foi comparar as variaços hormonais (LH e androstenediona), as respostas ovariana (número de folículos dominantes e índice de ovulaçao) e endometrial (espessura) e os índices de gravidez obtidos por diferentes doses de citrato de clomifene e em ciclos espontâneos, em pacientes com ciclos ovulatórios. Casuistica e Metodos: Foram estudadas 38 pacientes com esterilidade sem causa aparente, tratadas de 4 maneiras: citrato de clomifene 25 mg/dia (1O pacientes), citrato de clomifene 50 mg/dia (9 pacientes), citrato de clomifene 100 mg/dia (3 pacientes) e ciclo espontâneo (1O pacientes). Resultados: Houve somente diferença estatisticamente significativa em relaçao à espessura do endométrio (p