Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein-Protein Interaction.

The DNA excision repair protein ERCC1 and the DNA damage sensor protein, XPA are highly overexpressed in patient samples of cisplatin-resistant solid tumors including lung, bladder, ovarian, and testicular cancer. The repair of cisplatin-DNA crosslinks is dependent upon nucleotide excision repair (NER) that is modulated by protein-protein binding interactions of ERCC1, the endonuclease, XPF, and XPA. Thus, inhibition of their function is a potential therapeutic strategy for the selective sensitization of tumors to DNA-damaging platinum-based cancer therapy.

Evaluating Scalable Supervised Learning for Synthesize-on-Demand Chemical Libraries.

Traditional small-molecule drug discovery is a time-consuming and costly endeavor. High-throughput chemical screening can only assess a tiny fraction of drug-like chemical space. The strong predictive power of modern machine-learning methods for virtual chemical screening enables training models on known active and inactive compounds and extrapolating to much larger chemical libraries.

Inflammatory mediators act at renal pericytes to elicit contraction of vasa recta and reduce pericyte density along the kidney medullary vascular network.

Regardless of initiating cause, renal injury promotes a potent pro-inflammatory environment in the outer medulla and a concomitant sustained decrease in medullary blood flow (MBF). This decline in MBF is believed to be one of the critical events in the pathogenesis of acute kidney injury (AKI), yet the precise cellular mechanism underlying this are still to be fully elucidated. MBF is regulated by contractile pericyte cells that reside on the descending vasa recta (DVR) capillaries, which are the primary source of blood flow to the medulla.

A novel functional role for the classic CNS neurotransmitters, GABA, glycine, and glutamate, in the kidney: potent and opposing regulators of the renal vasculature.

The presence of a renal GABA/glutamate system has previously been described; however, its functional significance in the kidney remains undefined. We hypothesized, given its extensive presence in the kidney, that activation of this GABA/glutamate system would elicit a vasoactive response from the renal microvessels. The functional data here demonstrate, for the first time, that activation of endogenous GABA and glutamate receptors in the kidney significantly alters microvessel diameter with important implications for influencing renal blood flow.

A proposed framework for point of care musculoskeletal ultrasound and ultrasound image-guided interventions by physiotherapists: scope of practice, education and governance.

Background: The use of point of care ultrasound (PoCUS) in the management of musculoskeletal (MSK) disorders is a diverse area of PoCUS practice. Its use by clinicians, such as physiotherapists, can occur across a wide range of roles and care pathway configurations; however, professional, educational and regulatory uncertainties can leave clinicians, managers and patients at risk.

Main Body: A PoCUS framework approach (previously applied to support PoCUS consolidation and expansion) is used to frame these proposals.