Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.

The NLRP3 inflammasome plays a pivotal role in host defense and drives inflammation against microbial threats, crystals, and danger-associated molecular patterns (DAMPs). Dysregulation of NLRP3 activity is associated with various human diseases, making it an attractive therapeutic target. Patients with NLRP3 mutations suffer from Cryopyrin-Associated Periodic Syndrome (CAPS) emphasizing the clinical significance of modulating NLRP3.

An open-source, battery-powered, low-cost, and dual-channel pneumatic pulse generator for microfluidic cell-stretch assays.

Cells in the body are regularly subjected to mechanical forces that influence their biological fate in terms of morphology, gene expression, and differentiation. The current gold standard method to replicate these effects in vitro is to culture cells on devices with elastic substrates and to impart mechanical stretch using mechanical or pneumatic pull-push methods. Microfluidic device designs offer several advantages in this context for general uniform and controlled stretching.

Impact of Polypharmacy on Symptoms and Health Outcomes in Older Adults With and Without Alzheimer's Disease and Related Dementias.

Background: There is a critical gap in understanding the symptom experience and health outcomes of older adults with and without Alzheimer's Disease and related dementias (ADRD) and polypharmacy (PPY). The primary aim of the study was to compare the number of symptoms experienced over time in older adults with and without ADRD by polypharmacy status. The secondary aim was to examine the trajectory of physical function and health outcomes over time in each group.

Differential relationships between physical activity and pain phenotypes in individuals with spinal cord injury.

Background: Chronic pain affects 70% of individuals with spinal cord injury (SCI) and leads to declines in health and quality of life. Neuropathic and nociceptive pain are phenotypes derived from different mechanisms that contribute to pain perception. The objective of this research was to investigate differential pain responses to moderate-to-vigorous physical activity (MVPA) in two chronic pain phenotypes: neuropathic and nociceptive pain.

Identification of highly selective SIK1/2 inhibitors that modulate innate immune activation and suppress intestinal inflammation.

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site.