A Role for Cross-linking Proteins in Actin Filament Network Organization and Force Generation.

The high turgor pressure across the plasma membrane of yeasts creates a requirement for substantial force production by actin polymerization and myosin motor activity for clathrin-mediated endocytosis (CME). Endocytic internalization is severely impeded in the absence of fimbrin, an actin filament crosslinking protein called Sac6 in budding yeast. Here, we combine live-cell imaging and mathematical modeling to gain new insights into the role of actin filament crosslinking proteins in force generation. Genetic manipulation showed that CME sites with more crosslinking proteins are more effective at internalization under high load. Simulations of an experimentally constrained, agent-based mathematical model recapitulate the result that endocytic networks with more double-bound fimbrin molecules internalize the plasma membrane against elevated turgor pressure more effectively. Networks with large numbers of crosslinks also have more growing actin filament barbed ends at the plasma membrane, where the addition of new actin monomers contributes to force generation and vesicle internalization. Our results provide a richer understanding of the crucial role played by actin filament crosslinking proteins during actin network force generation, highlighting the contribution of these proteins to the self-organization of the actin filament network and force generation under increased load.

Managing violence and aggression in the emergency department.

Half of all reported violent incidents in healthcare settings occur in the emergency department (ED), so ED nurses are disproportionately affected by violence and aggression. Violence and aggression can cause physical injury, psychological harm, delays to patient care, eroded staff morale, increased sick leave and low staff retention. This article explores potential causes and risk factors for violent or aggressive behaviour from patients and visitors in the ED. It discusses risk assessment tools, management approaches and risk reduction strategies that can be used in the ED to tackle violence and aggression. The article also features a case study describing a successful small-scale trial of body-worn cameras at an East London ED.

Toxicological Characterization of Exon Skipping Phosphorodiamidate Morpholino Oligomers (PMOs) in Non-human Primates.

BACKGROUND: Phosphorodiamidate morpholino oligomers (PMOs) are a class of exon skipping drugs including eteplirsen, which has shown considerable promise for treatment of the degenerative neuromuscular disease, Duchenne musculardystrophy (DMD). OBJECTIVE: Toxicity studies in non-human primates (NHPs) of 12 weeks duration with two new PMOs for DMD, SRP-4045 and SRP-4053, along with results from a chronic study in NHPs of 39 weeks duration for eteplirsen, are described here. METHODS: PMOs were administered once-weekly by bolus intravenous (IV) injections to male NHPs. Endpoints evaluated included plasma exposures, clinical observations, body weight/food consumption, eye exams, electrocardiograms, male reproductive hormones/endpoints, complement alternative pathway, clinical pathology, urinalysis, and macroscopic/light microscopic pathology. RESULTS: Findings in these studies were limited to the kidneys, with a common presentation of tubular basophilia, vacuolation, and/or minimal degeneration that was considered non-adverse. No necrosis, glomerular lesions, or effects on renal function tests such as serum creatinine or urea nitrogen were observed, suggesting that PMO-related kidney findings are not likely to develop into frank nephrotoxicity. There were no adverse effects on other potential target organs after repeated IV injections at the highest dose levels tested, 320 mg/kg. CONCLUSIONS: Nonclinical results in NHPs for these three PMOs, together with the excellent clinical safety established for eteplirsen to date, suggest that once-weekly IV administration of PMOs for lifetime durations at therapeutic doses will be well tolerated by patients with DMD.

Toxicogenomics: a new revolution in drug safety.

New drugs are screened for adverse reactions using a laborious, costly process and still some promising therapeutics are withdrawn from the marketplace because of unforeseen human toxicity. Novel higher throughput methods in toxicology need to be developed. These new approaches should provide more insight into potential human toxicity than current methods. Toxicogenomics, the examination of changes in gene expression following exposure to a toxicant, offers the potential to identify a human toxicant earlier in drug development and to detect human-specific toxicants that cause no adverse reaction in rats.