Duplexed CeTEAM drug biosensors reveal determinants of PARP inhibitor selectivity in cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) targeting PARP1 and PARP2 have revolutionized cancer therapy by selectively killing cancer cells with defective DNA repair. However, achieving PARP1 or PARP2-selective inhibitors is difficult due to structural homology. Selectivity profiling is typically done with purified proteins, but these lack the complexity of intracellular environments and could therefore be inaccurate.

Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM.

Cellular target engagement technologies enable quantification of intracellular drug binding; however, simultaneous assessment of drug-associated phenotypes has proven challenging. Here, we present cellular target engagement by accumulation of mutant as a platform that can concomitantly evaluate drug-target interactions and phenotypic responses using conditionally stabilized drug biosensors. We observe that drug-responsive proteotypes are prevalent among reported mutants of known drug targets.

Single-cell sequencing deconvolutes cellular responses to exercise in human skeletal muscle.

Skeletal muscle adaptations to exercise have been associated with a range of health-related benefits, but cell type-specific adaptations within the muscle are incompletely understood. Here we use single-cell sequencing to determine the effects of exercise on cellular composition and cell type-specific processes in human skeletal muscle before and after intense exercise. Fifteen clusters originating from six different cell populations were identified.

Evidence for Vitamin D Receptor Expression and Direct Effects of 1α,25(OH)2D3 in Human Skeletal Muscle Precursor Cells.

Presence of the vitamin D receptor and direct effects of vitamin D on the proliferation and differentiation of muscle precursor cells have been demonstrated in animal models. However, the effects and mechanisms of vitamin D actions in human skeletal muscle, and the presence of the vitamin D receptor in human adult skeletal muscle, remain to be established. Here, we investigated the role of vitamin D in human muscle cells at various stages of differentiation.

Intracellular Ca(2+)-handling differs markedly between intact human muscle fibers and myotubes.

Background: In skeletal muscle, intracellular Ca(2+) is an important regulator of contraction as well as gene expression and metabolic processes. Because of the difficulties to obtain intact human muscle fibers, human myotubes have been extensively employed for studies of Ca(2+)-dependent processes in human adult muscle. Despite this, it is unknown whether the Ca(2+)-handling properties of myotubes adequately represent those of adult muscle fibers.