Ethanol alters BK (slo1) channel function leading to perturbation of physiology and behavior. Site(s) and mechanism(s) of ethanol-BK channel interaction are unknown. We demonstrate that ethanol docks onto a water-accessible site that is strategically positioned between the slo1 calcium-sensors and gate. Ethanol only accesses this site in presence of calcium, the BK channel's physiological agonist. Within the site, ethanol hydrogen-bonds with K361. Moreover, substitutions that hamper hydrogen bond formation or prevent ethanol from accessing K361 abolish alcohol action without altering basal channel function. Alcohol interacting site dimensions are approximately 10.7 × 8.6 × 7.1 Å, accommodating effective (ethanol-heptanol) but not ineffective (octanol, nonanol) channel activators. This study presents: (i) to our knowledge, the first identification and characterization of an n-alkanol recognition site in a member of the voltage-gated TM6 channel superfamily; (ii) structural insights on ethanol allosteric interactions with ligand-gated ion channels; and (iii) a first step for designing agents that antagonize BK channel-mediated alcohol actions without perturbing basal channel function.is a psychoactive agent that has been overwhelmingly consumed by mankind across cultures and civilizations. Alcohol actions on central nervous system (CNS) physiology and behavior are largely independent of beverage type but due to ethanol itself (1). Ethanol alters cell excitability by modifying function of transmembrane (TM) ion channel proteins, including K + channels. These channels constitute the most heterogeneous and extensive group of ion channels, its members belonging to TM2, TM4, and TM6 protein superfamilies. Within this myriad of proteins, several K + channels have been shown to modify behavior in response to acute exposure to ethanol concentrations that reach the CNS and other excitable tissues during alcohol drinking (2-5). However, with the sole exception of the TM2, G protein-regulated inward rectifier K + (GIRK) channel (6), there is no structural information on ethanol-K + channel protein interacting sites currently available. Voltage/Ca 2+ -gated, large conductance K + channels (BK), which are members of the TM6 voltage-gated ion channel superfamily, constitute major mediators of alcohol actions in excitable tissues. Acute exposure to ethanol levels reached in CNS during alcohol intoxication alters BK-mediated currents and thus, elicits widespread and profound modifications in physiology and behavior. In rodent models, acute ethanol exposure leads to reduced vasopressin, oxytocin and growth hormone release with consequent perturbation in physiology and behavior (7), altered firing rates in nucleus accumbens (8) and dorsal root ganglia neurons (9), and alcohol-induced cerebral artery constriction (10, 11). Moreover, studies in both mammals and invertebrate models demonstrate that ethanol targeting of neuronal BK is involved in development of alcohol tolerance and dependence (12-16). Although the physiological and be...

Acinetobacter baumannii is increasingly recognized as an important multidrug-resistant nosocomial pathogen. Recent work has highlighted enhanced growth and heightened virulence in the presence of ethyl alcohols. As alcohol-based hand rubs (ABHRs) are extensively used in health care settings, the authors set out to determine whether the hand rubs could also influence the growth of prevalent multidrug-resistant strains circulating in UK hospitals. A significant increase in growth was observed when minimal media were supplemented with concentrations of 1 % and lower of four commercially available hand rubs. In addition, growth in ABHR-supplemented media resulted in secretion of proteins into the culture supernatant. One of these was identified as OmpA, which is recognized as having emulsifying activity, which could potentially confer enhanced pathogenicity to A. baumannii.

In winter 2007-2008, an outbreak of pediatric pneumonia caused by serotype 5 pneumococci was identified in a northeast London suburb. Variable number of tandem repeat analyses clustered these pneumococci from the other serotype 5 pneumococci in the United Kingdom, highlighting the importance of this discriminative typing method in supporting epidemiological investigations.

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cellular dynamics of the beating heart, as a critical step in understanding its development. To meet the challenges of obtaining sub-cellular resolution imaging of a dynamic 100-micron length scale 3D structure, which moves quasiperiodically at frequency of a few Hertz, over tens of microns amplitude, we have employed two-photon light sheet microscopy (2p-SPIM) and a novel independent optical phase stamping method to generate well-resolved 3D movies (4D) of the beating heart. Applying this 4D imaging modality to zebrafish embryos, we have found remarkable heterogeneity in cardiomyocyte morphology, gene expression, and behavior both during the cardiac cycle, and over the developmental time. The observed heterogeneity appears to play a key role in the maintenance of tissue geometry and cardiac output as the heart undergoes cycles of contraction and expansion. The variation in cellular morphology and behavior provide new insights into the tight link between cellular dynamics, mechanical environment exerted and felt by the beating heart, and the genetic program that governs not only the differentiation and construction but also the maintenance of this important organ.