Citations

To identify high-affinity interactions between long-chain α-neurotoxins and nicotinic receptors, we determined the crystal structure of the complex between α-btx (α-bungarotoxin) and a pentameric ligand-binding domain constructed from the human α7 AChR (acetylcholine receptor) and AChBP (acetylcholine-binding protein). The complex buries ~2000 Å2 (1 Å=0.1 nm) of surface area, within which Arg36 and Phe32 from finger II of α-btx form a π-cation stack that aligns edge-to-face with the conserved Tyr184 from loop-C of α7, while Asp30 of α-btx forms a hydrogen bond with the hydroxy group of Tyr184. These inter-residue interactions diverge from those in a 4.2 Å structure of α-ctx (α-cobratoxin) bound to AChBP, but are similar to those in a 1.94 Å structure of α-btx bound to the monomeric α1 extracellular domain, although compared with the monomer-bound complex, the α-btx backbone exhibits a large shift relative to the protein surface. Mutational analyses show that replacing Tyr184 with a threonine residue abolishes high-affinity α-btx binding, whereas replacing with a phenylalanine residue maintains high affinity. Comparison of the α-btx complex with that coupled to the agonist epibatidine reveals structural rearrangements within the binding pocket and throughout each subunit. The overall findings highlight structural principles by which α-neurotoxins interact with nicotinic receptors.

Depletion of interstitial cells of Cajal (ICC) networks is known to occur in several gastrointestinal motility disorders. Although confocal microscopy can effectively image and visualize the spatial distribution of ICC networks, current descriptors of ICC depletion are limited to cell numbers and volume computations. Spatial changes in ICC network structural properties have not been quantified. Given that ICC generate electrical signals, the organization of a network may also affect physiology. In this study, six numerical metrics were formulated to automatically determine complex ICC network structural properties from confocal images: density , thickness , hole size , contact ratio , connectivity and anisotropy . These metrics were validated and applied in proof-of-concept studies to quantitatively determine jejunal ICC network changes in mouse models with decreased ( 5-HT 2 B receptor knockout (KO)) and normal ( Ano1 KO) ICC numbers, and during post-natal network maturation. Results revealed a novel remodelling phenomenon occurring during ICC depletion, namely a spatial rearrangement of ICC and the preferential longitudinal alignment. In the post-natal networks, an apparent pruning of the ICC network was demonstrated. The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development.

AbstractTraumatic brain injury (TBI) and post‐traumatic stress disorder (PTSD) are signature injuries of the wars in Iraq and Afghanistan and have been linked to an increased risk of Alzheimer's disease (AD) and other dementias. A meeting hosted by the Alzheimer's Association and the Veterans' Health Research Institute (NCIRE) in May 2012 brought together experts from the U.S. military and academic medical centers around the world to discuss current evidence and hypotheses regarding the pathophysiological mechanisms linking TBI, PTSD, and AD. Studies underway in civilian and military populations were highlighted, along with new research initiatives such as a study to extend the Alzheimer's Disease Neuroimaging Initiative (ADNI) to a population of veterans exposed to TBI and PTSD. Greater collaboration and data sharing among diverse research groups is needed to advance an understanding and appropriate interventions in this continuum of military injuries and neurodegenerative disease in the aging veteran.

Objectives: To determine the prevalence and relationship of frailty and health-related quality of life (HRQOL) among residents of long-term care [nursing homes (NH) and assisted living (AL)] facilities. Methods: Residents of NH and AL facilities in La Crosse County, Wisconsin, were recruited 1/2009-6/2010 and assessed for frailty (gait speed, unintended weight loss, grip strength), comorbidity (Charlson index), and HRQOL [Short Form (SF)-36]. Results: Among 137 participants, 85% were frail. Frail residents were older, had more comorbidities (2.0 vs. 0, p < .001) and lower mean SF-36 Physical Component Score (PCS, 32 vs. 48, p < .001). Following adjustments for age, sex, and comorbidities, compared to nonfrail residents, frail residents had lower SF-36 PCS (mean difference −14.7, 95% CI. −19.3,−10.1, p < .001). Frailty, comorbidity, and HRQOL did not differ between NH and AL facilities. Discussion: Frail residents had lower HRQOL, suggesting that preventing frailty may lead to better HRQOL among residents of long-term care facilities.

SummaryAssuming a coin is fair is common place in introductory statistical education. This article offers three approaches to test if a coin is fair. The approaches lend themselves to straightforward simulation studies that can enrich student understanding of joint probability and sample size requirements. Simulation studies comparing the relative merits of the three, or potential other, approaches are an example of problem‐based learning.

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SAGE-Journals-Accessible-Video-Player 10.1089/vid.2013.0018.M1 sj-vid-1-vid-10.1089_vid.2013.0018