Differential effects of inosine monophosphate dehydrogenase (IMPDH/GuaB) inhibition in and .

Inosine 5'-monophosphate dehydrogenase (IMPDH), known as GuaB in bacteria, catalyzes the rate-limiting step in guanine biosynthesis and is conserved from humans to bacteria. We developed a series of potent inhibitors that selectively target GuaB over its human homolog. Here, we show that these GuaB inhibitors are bactericidal, generate phenotypic signatures that are distinct from other antibiotics, and elicit different time-kill kinetics and regulatory responses in two important Gram-negative pathogens: and .

Cancer-associated DNA hypermethylation of Polycomb targets requires DNMT3A dual recognition of histone H2AK119 ubiquitination and the nucleosome acidic patch.

During tumor development, promoter CpG islands that are normally silenced by Polycomb repressive complexes (PRCs) become DNA-hypermethylated. The molecular mechanism by which de novo DNA methyltransferase(s) [DNMT(s)] catalyze CpG methylation at PRC-regulated regions remains unclear. Here, we report a cryo-electron microscopy structure of the DNMT3A long isoform (DNMT3A1) amino-terminal region in complex with a nucleosome carrying PRC1-mediated histone H2A lysine-119 monoubiquitination (H2AK119Ub).

Ubiquitinated histone H2B as gatekeeper of the nucleosome acidic patch.

Monoubiquitination of histones H2B-K120 (H2BK120ub) and H2A-K119 (H2AK119ub) play opposing roles in regulating transcription and chromatin compaction. H2BK120ub is a hallmark of actively transcribed euchromatin, while H2AK119ub is highly enriched in transcriptionally repressed heterochromatin. Whereas H2BK120ub is known to stimulate the binding or activity of various chromatin-modifying enzymes, this post-translational modification (PTM) also interferes with the binding of several proteins to the nucleosome H2A/H2B acidic patch via an unknown mechanism.

Exploration of Materials for Three-Dimensional NMR Microcoil Production via CNC Micromilling and Laser Etching.

The excellent versatility of 5-axis computer numerical control (CNC) micromilling has led to its application for prototyping NMR microcoils tailored to mass-limited samples (reducing development time and cost). However, vibrations during 5-axis milling can hinder the creation of complex 3D volume microcoils (i.e.

Antegrade balloon dilatation of the duodenal papilla during laparoscopic cholecystectomy versus endoscopic retrograde cholangiography in patients with acute choledocholithiasis: a case control matched study.

Introduction: In acute obstructive common bile duct (CBD) stones endoscopic retrograde cholangiography for CBD stone removal before cholecystectomy (ChE) ('ERC-first') is the gold standard of treatment. Intraoperative antegrade balloon dilatation of the duodenal papilla during ChE with flushing of CBD stones to the duodenum ('ABD-during-ChE') may be an alternative 'one-stop-shop' treatment option. However, a comparison of outcomes of the 'ABD-during-ChE' technique and the'ERC-first' approach has never been performed.