Bordetella Adenylate Cyclase Toxin Mobilizes Its β2 Integrin Receptor into Lipid Rafts to Accomplish Translocation across Target Cell Membrane in Two Steps

Bordetella adenylate cyclase toxin (CyaA) binds the αMβ2 integrin (CD11b/CD18, Mac-1, or CR3) of myeloid phagocytes and delivers into their cytosol an adenylate cyclase (AC) enzyme that converts ATP into the key signaling molecule cAMP. We show that penetration of the AC domain across cell membrane proceeds in two steps. It starts by membrane insertion of a toxin ‘translocation intermediate’, which can be ‘locked’ in the membrane by the 3D1 antibody blocking AC domain translocation. Insertion of the ‘intermediate’ permeabilizes cells for influx of extracellular calcium ions and thus activates calpain-mediated cleavage of the talin tether. Recruitment of the integrin-CyaA complex into lipid rafts follows and the cholesterol-rich lipid environment promotes translocation of the AC domain across cell membrane. AC translocation into cells was inhibited upon raft disruption by cholesterol depletion, or when CyaA mobilization into rafts was blocked by inhibition of talin processing. Furthermore, CyaA mutants unable to mobilize calcium into cells failed to relocate into lipid rafts, and failed to translocate the AC domain across cell membrane, unless rescued by Ca2+ influx promoted in trans by ionomycin or another CyaA protein. Hence, by mobilizing calcium ions into phagocytes, the ‘translocation intermediate’ promotes toxin piggybacking on integrin into lipid rafts and enables AC enzyme delivery into host cytosol

Improved Spatial Filter for high power Lasers

A new pinhole architecture incorporates features intended to reduce the rate of plasma generation in a spatial filter for high-energy laser pulse beams. An elongated pinhole aperture is provided in an apertured body for rejecting off-axis rays of the laser pulse beam. The internal surface of the elongated aperture has a diameter which progressively tapers from a larger entrance cross-sectional area at an inlet to a smaller output cross-sectional area at an outlet. The tapered internal surface causes off-axis rays to be refracted in a low density plasma layer that forms on the internal surface or specularly reflected at grazing incidence from the internal surface. Off-axis rays of the high-energy pulse beam are rejected by this design. The external surface of the apertured body adjacent to the larger entrance cross-sectional area at the inlet to the elongated aperture is angled obliquely with respect to the to direction of the path of the high-energy laser pulse beam to backscatter off-axis rays away from the high-energy pulse beam. The aperture is formed as a truncated cone or alternatively with a tapered square cross-section. The internal surface of the aperture is coated with an ablative material, preferably high-density material which can be deposited with an exploding wire

A report on older-age bipolar disorder from the International Society for Bipolar Disorders Task Force

In the coming generation, older adults with bipolar disorder (BD) will increase in absolute numbers as well as proportion of the general population. This is the first report of the International Society for Bipolar Disorder (ISBD) Task Force on Older-Age Bipolar Disorder (OABD).This task force report addresses the unique aspects of OABD including epidemiology and clinical features, neuropathology and biomarkers, physical health, cognition, and care approaches.The report describes an expert consensus summary on OABD that is intended to advance the care of patients, and shed light on issues of relevance to BD research across the lifespan. Although there is still a dearth of research and health efforts focused on older adults with BD, emerging data have brought some answers, innovative questions, and novel perspectives related to the notion of late onset, medical comorbidity, and the vexing issue of cognitive impairment and decline.Improving our understanding of the biological, clinical, and social underpinnings relevant to OABD is an indispensable step in building a complete map of BD across the lifespan.16 page(s