Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase

In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes.     

Stabilizing ER Ca2+ Channel Function as an Early Preventative Strategy for Alzheimer’s Disease

Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca²⁺ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca²⁺ signaling, predominantly through the ER-localized inositol triphosphate (IP₃) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca²⁺ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca²⁺ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca²⁺ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca²⁺ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.     

Visualizing themselves: Tongan videography in Utah 1

This paper examines the process and product of video visualizations made by and for Tongan immigrants in Salt Lake City, Utah. Videographers and other members of the Tongan community collaborate on videos of events such as birthdays, weddings, funerals, and fund‐raising dances. Through video recording, editing, and viewing processes, they have many opportunities to create images of themselves within American society. The videos, prized among Utah Tongans and often sent to relatives in the islands, reflect their values and ideals. Here, I offer my examination of Tongan videography as a new approach to understanding others through their own visualizations.     

The nature of the β-adrenoceptor involved in the inhibition of antigen-induced histamine release

Antigen stimulated release of histamine from chopped sensitized guinea-pig lung is inhibited by the addition of β-adrenoceptor agonists in a manner indicating a β₂ response. Preaddition of β-adrenoceptor antagonists blocks this inhibition in a manner indicating a β₁ response. This apparent dichotomy probably results from a hybrid receptor, though the danger of the use of chemical analogues for classifying receptors is highlighted. Inhibition of histamine release by β-stimulation is shown to be species rather than organ specific.     

CULTURALLY INDUCED VARIATION IN FOUR MORPHOLOGICALLY DIVERSE BLUEGREEN ALGAE

Characters used in taxonomic placement at levels from family to species appeared, disappeared, or varied widely, while others remained constant, in cultures of four disparate species of blue-green algae (Cyanophyta) under varying conditions of culture. Species of Anabaena and Gloeocapsa displayed fairly stable characteristics. Species of Calothrix and Lyngbya exhibited much greater variability, especially in twisting of filaments, presence or absence of constrictions at the cross walls, abundance of heterocysts, pseudovacuoles, fragmentation of filaments, and change of color. Color change was associated with abrupt pH shift in Lyngbya and could be reversed by adding nitrate. In the putatively nitrogen-fixing Anabaena, similar change in color with age was not associated with sharp pH shift, nor could it be reversed with nitrate. In general, growth on agar in turbulent conditions and with decreased CO₂–O₂ exchange was less than that obtainable under other conditions, and media with acid pH were partially or totally inhibitory to growth.     

Acetamide Agar for Differentiation of Nonfermentative Bacteria

An acetamide agar medium is described for use in the differentiation of nonfermentative gram-negative bacteria. With few exceptions, indicator reactions were rapid, intense, and clear-cut.