Neuroinflammatory disease disrupts the blood-CNS barrier via crosstalk between proinflammatory and endothelial-to-mesenchymal-transition signaling.

Breakdown of the blood-central nervous system barrier (BCNSB) is a hallmark of many neuroinflammatory disorders, such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we show that endothelial-to-mesenchymal transition (EndoMT) occurs in the CNS before the onset of clinical symptoms and plays a major role in the breakdown of BCNSB function. EndoMT can be induced by an IL-1β-stimulated signaling pathway in which activation of the small GTPase ADP ribosylation factor 6 (ARF6) leads to crosstalk with the activin receptor-like kinase (ALK)-SMAD1/5 pathway.

Preserving Vascular Integrity Protects Mice against Multidrug-Resistant Gram-Negative Bacterial Infection.

The rise in multidrug-resistant (MDR) organisms portends a serious global threat to the health care system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB), including , , and carbapenemase-producing (CPKP), are among the World Health Organization's and National Institutes of Health's high-priority MDR pathogens for targeted development of new therapies. Here, we show that stabilizing the host's vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with , , and CPKP.

Pharmacokinetic and Chemical Synthesis Optimization of a Potent d-Peptide HIV Entry Inhibitor Suitable for Extended-Release Delivery.

Peptides often suffer from short in vivo half-lives due to proteolysis and renal clearance that limit their therapeutic potential in many indications, necessitating pharmacokinetic (PK) enhancement. d-Peptides, composed of mirror-image d-amino acids, overcome proteolytic degradation but are still vulnerable to renal filtration due to their small size. If renal filtration could be slowed, d-peptides would be promising therapeutic agents for infrequent dosing, such as in extended-release depots.

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy.

The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis.

Cross-species gene modules emerge from a systems biology approach to osteoarthritis.

Complexities in degenerative disorders, such as osteoarthritis, arise from multiscale biological, environmental, and temporal perturbations. Animal models serve to provide controlled representations of the natural history of degenerative disorders, but in themselves represent an additional layer of complexity. Comparing transcriptomic networks arising from gene co-expression data across species can facilitate an understanding of the preservation of functional gene modules and establish associations with disease phenotypes.

Systems approaches in osteoarthritis: Identifying routes to novel diagnostic and therapeutic strategies.

Systems orientated research offers the possibility of identifying novel therapeutic targets and relevant diagnostic markers for complex diseases such as osteoarthritis. This review demonstrates that the osteoarthritis research community has been slow to incorporate systems orientated approaches into research studies, although a number of key studies reveal novel insights into the regulatory mechanisms that contribute both to joint tissue homeostasis and its dysfunction. The review introduces both top-down and bottom-up approaches employed in the study of osteoarthritis.

ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma.

Activating mutations in Gαq proteins, which form the α subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and β-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively.

A luminescent oxygen channeling biosensor that measures small GTPase activation.

We established a homogeneous luminescent oxygen channeling sensor for measuring activation states of small GTPases. The assay quantifies activated GTPases in cell lysates, can be applied to different GTPases, and can be used for multiplex screening. The study will provide guidelines for determining activation states of diverse GTPases in various biological contexts.