Dose-Dependent Pulmonary Injury Following Nitrogen Dioxide Inhalation From Kinepak™ Detonation.

BACKGROUND: Nitrogen dioxide (NO2) is a pulmonary irritant produced as a byproduct of bacterial anaerobic metabolism of organic materials, and is also produced as a byproduct of explosive detonations. Significant NO2 exposure results in free-radical-induced pulmonary injury that may be delayed up to 3-30 h after exposure and can progress to acute respiratory distress syndrome (ARDS) and death. Here we present a case series of 3 patients with dose-dependent pulmonary injury consistent with NO2 inhalation following exposure to fumes from detonation of an ammonium nitrate/nitromethane (ANNM) explosive device. CASE REPORTS: Three individuals presented to the emergency department over the course of 16 h, beginning approximately 16 h after exposure to fumes from an ANNM explosive device. Patient 1, with the most significant exposure, developed ARDS necessitating intubation and mechanical ventilation. Patient 2 exhibited hypoxia and findings concerning for diffuse airway inflammation, but ultimately required only supplemental oxygen. Patient 3, with the least exposure, had imaging abnormalities but required no intervention. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Respiratory distress is a common presenting complaint to the emergency department. Because of the delayed presentation and the potential for progressive worsening of symptoms associated with NO2 exposure, it is important that emergency physicians be aware of the multiple potential means of exposure and consider this diagnosis in the proper clinical context. Patients with suspicion of NO2-related lung injury should undergo more extended observation than their initial clinical presentation may suggest.

Chromosome Missegregation Associated with RUVBL1 Deficiency.

RUVBL1 (RuvB-like1) and RUVBL2 (RuvB-like 2) are integral components of multisubunit protein complexes involved in processes ranging from cellular metabolism, transcription and chromatin remodeling to DNA repair. Here, we show that although RUVBL1 and RUVBL2 are known to form heterodimeric complexes in which they stabilize each other, the subunits separate during cytokinesis. In anaphase-to-telophase transition, RUVBL1 localizes to structures of the mitotic spindle apparatus, where it partially co-localizes with polo-like kinase 1 (PLK1). The ability of PLK1 to phosphorylate RUVBL1-but not RUVBL2-in vitro and their physical association in vivo suggest that this kinase differentially regulates the function of the RuvB-like proteins during mitosis. We further show that siRNA-mediated knock-down of RuvB-like proteins causes severe defects in chromosome alignment and segregation. In addition, we show that the ATPase activity of RUVBL1 is indispensable for cell proliferation. Our data thus demonstrate that RUVBL1 is essential for efficient mitosis and proliferation.

Niche-associated activation of rac promotes the asymmetric division of Drosophila female germline stem cells.

BACKGROUND: Drosophila female germline stem cells (GSCs) reside adjacent to a cellular niche that secretes Bone Morphogenetic Protein (BMP) ligands and anchors the GSCs through adherens junctions. The GSCs divide asymmetrically such that one daughter remains in the niche as a GSC, while the other is born away from the niche and differentiates. However, given that the BMP signal can be diffusible, it remains unclear how a local extracellular asymmetry is sufficient to result in a robust pattern of asymmetric division. METHODS AND FINDINGS: Here we show that GSCs are polarized with respect to the cellular niche. We first use a modified biosensor to demonstrate that the small GTPase Rac is asymmetrically activated within the GSC at the niche-GSC interface. Experiments using loss-of-function and gain-of-function mutations in Rac indicate that asymmetric Rac activity both localizes the microtubule binding protein Apc2 to orient one GSC centrosome at the niche-GSC interface during interphase and activates the Jun N-terminal kinase pathway to increase the ability of the GSC to respond to BMP ligands. Other processes act in concert with each function of Rac. Specifically, we demonstrate that the GSC cell cycle arrests at prometaphase if centrosomes are misoriented. CONCLUSIONS: Thus, the GSCs, an adult stem cell present in a cellular niche, have a niche-associated polarity that couples control of the division plane with increased response to an extracellular maintenance signal. Other processes work in parallel with the Rac-mediated polarity to ensure a robust pattern of asymmetric division. We suggest that all adult stem cells likely employ multiple, independently acting mechanisms to ensure asymmetric division to maintain tissue homeostasis.