Rapid Communication Chronic Ingestion of Ethanol Up-Regulates NMDAR1 Receptor Subunit Immunoreactivity in Rat Hippocampus

We examined the effects of chronic ethanol exposure on the levels of N -methyl-D-aspartate receptor subunit 1 (NMDAR1) protein, an essential component of N -methyl-D-aspar- tate glutamate receptors, in rat brain. By immunoblotting procedures using a specific antibody for the NMDAR1 subunit, we found that ethanol dramatically up-regulated (by 65%) NMDAR1 immunoreactivity in the hippocampus but not in the nucleus accumbens, cerebral cortex, or striatum. In contrast, ethanol did not alter the levels of glutamate receptor subunit (GLUR) 1 or GLUR2 protein, subunits that make up the α-amino-3-hydroxy-5-methy4-isoxazole propionic acid glutamate receptor, in the hippocampus. Because ethanol can potentially influence many different neurotransmitter systems, we examined whether chronic treatment with several psychotropic drugs with different pharmacological profiles (cocaine, haloperidol, SCH 23390, imipramine, and morphine) could mimic the effect of ethanol. None of these agents increased hippocampal NMDAR1 subunit immunoreactivity after chronic administration. Increased NMDAR1 subunit levels in the hippocampus after chronic ethanol exposure may represent an important neurochemical substrate for some of the features associated with ethanol dependence and withdrawal.     

Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects

Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H⁺-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals.     

Epitopia: a web-server for predicting B-cell epitopes

Background  

Detecting candidate B-cell epitopes in a protein is a basic and fundamental step in many immunological applications. Due to the impracticality of experimental approaches to systematically scan the entire protein, a computational tool that predicts the most probable epitope regions is desirable.     

The Influence of 150-Cavity Binders on the Dynamics of Influenza A Neuraminidases as Revealed by Molecular Dynamics Simulations and Combined Clustering

Neuraminidase inhibitors are the main pharmaceutical agents employed for treatments of influenza infections. The neuraminidase structures typically exhibit a 150-cavity, an exposed pocket that is adjacent to the catalytic site. This site offers promising additional contact points for improving potency of existing pharmaceuticals, as well as generating entirely new candidate inhibitors. Several inhibitors based on known compounds and designed to interact with 150-cavity residues have been reported. However, the dynamics of any of these inhibitors remains unstudied and their viability remains unknown. This work reports the outcome of long-term, all-atom molecular dynamics simulations of four such inhibitors, along with three standard inhibitors for comparison. Each is studied in complex with four representative neuraminidase structures, which are also simulated in the absence of ligands for comparison, resulting in a total simulation time of 9.6µs. Our results demonstrate that standard inhibitors characteristically reduce the mobility of these dynamic proteins, while the 150-binders do not, instead giving rise to many unique conformations. We further describe an improved RMSD-based clustering technique that isolates these conformations – the structures of which are provided to facilitate future molecular docking studies – and reveals their interdependence. We find that this approach confers many advantages over previously described techniques, and the implications for rational drug design are discussed.     

Functional characteristics of dystrophic skeletal muscle: insights from animal models.

Muscular dystrophies are a clinically and genetically heterogeneous group of disorders that show myofiber degeneration and regeneration. Identification of animal models of muscular dystrophy has been instrumental in research on the pathogenesis, pathophysiology, and treatment of these disorders. We review our understanding of the functional status of dystrophic skeletal muscle from selected animal models with a focus on 1) the mdx mouse model of Duchenne muscular dystrophy, 2) the Bio 14.6 delta-sarcoglycan-deficient hamster model of limb-girdle muscular dystrophy, and 3) transgenic null mutant murine lines of sarcoglycan (alpha, beta, delta, and gamma) deficiencies. Although biochemical data from these models suggest that the dystrophin-sarcoglycan-dystroglycan-laminin network is critical for structural integrity of the myofiber plasma membrane, emerging studies of muscle physiology suggest a more complex picture, with specific functional deficits varying considerably from muscle to muscle and model to model. It is likely that changes in muscle structure and function, downstream of the specific, primary biochemical deficiency, may alter muscle contractile properties.     

Comparing models and observations of shelf plankton

In a previous paper (Solow and Steele, J. Plankton Res., 17,1995), the differences between variability in zooplankton biomassand in copepod stage structure were demonstrated using datafrom the northern North Sea. Here, a model is used to describethe underlying demographic processes and the effects of interannualphysical variability. Comparison of output with observationscan test the theory and so help to reconcile the apparent contradictionbetween great variability and persistence in these populations.     

An improved survey method for monitoring population trends of Golden‐winged Warblers and other patchily distributed birds

Conventional surveys designed to monitor common and widespread species may fail to adequately track population changes of rare or patchily distributed species that are often of high conservation concern. We evaluated the performance of a new monitoring approach that employs both a spatially balanced sampling design and a targeted survey protocol designed to estimate population trends of one such patchily distributed species, the Golden‐winged Warbler (Vermivora chrysoptera), in the Appalachian Mountains Bird Conservation Region (BCR 28), USA. Our spatially balanced survey consisted of 105 sample quads (one‐quarter Delorme Atlas pages) across the current range of Golden‐winged Warblers within BCR 28, each with five sample points located in early successional habitat. From 2009 to 2013, collaborators visited each sample point once per year during the peak breeding season and conducted a 17‐min survey consisting of passive observation and playback of conspecific songs and mobbing vocalizations. We used multi‐season, single‐species occupancy models to estimate probability of quad occupancy, detection probability, and occupancy dynamics for Golden‐winged Warblers and closely related Blue‐winged Warblers (Vermivora cyanoptera). Our survey protocol resulted in high estimates of detection probability for Golden‐winged (92%) and Blue‐winged (79%) warblers, with 47% and 56% of quads estimated to be initially occupied, respectively. Derived population trend estimates (λ) indicated an average decline in population of 6% for Golden‐winged Warblers and 7% for Blue‐winged Warblers, resulting in estimated 21% and 22% declines, respectively, in quad occupancy after 5 yr. Our results demonstrate that coupling a spatially balanced survey design in appropriate habitat with a playback protocol to increase detection rates is a viable strategy for tracking populations of Golden‐winged Warblers in the Appalachian Mountains BCR. Similar survey methods should be considered for other rare, declining, or patchily distributed bird species that require targeted monitoring.