Morphological arrangement of the coronary vasculature in a shark (Squalus sucklei) and a teleost (Oncorhynchus mykiss)

The coronary circulation is of great importance in maintaining cardiovascular function and consequently it has been extensively studied in many mammalian species. However, much less attention has been paid to the coronary circulation in other vertebrates. For example, while elasmobranch fishes are of special interest as they are the most ancient lineage of vertebrates to possess a coronary circulation, only qualitative studies exist on their coronary circulation and most concern the architecture of the large arteries. Our study tested the prediction that the coronary circulation of sharks is better developed than previously thought. However, to test this idea, a methodology was needed to quantify vascularity, vessel morphology and oxygen diffusion distances in a heart with predominantly spongy myocardium. Here, we describe this methodology using dogfish and rainbow trout and suggest that the dogfish spongy myocardium appears to rely predominantly on the coronary circulation for its oxygen supply, an arrangement that contrasts with the spongy myocardial tissue of rainbow trout. In support of this suggestion, the density of the microvasculature of the spongy myocardial tissue of dogfish exceeded that of their compact tissue. Although vascularity in the compact myocardium of dogfish was significantly lower than trout, intervascular distances were similar on account of a significantly larger vessel diameter in dogfish, which corresponds to a larger red blood cell size of the dogfish when compared to trout. J. Morphol. 277:896–905, 2016. © 2016 Wiley Periodicals, Inc.     

Heterogeneity of γ-Aminobutyric Acid/Benzodiazepine/β-Carboline Receptor Complex in Rat Spinal Cord

The properties of muscimol, beta-carboline (BC), and benzodiazepine (BZD) binding to crude synaptic membranes were studied in the spinal cord and cerebellum of rats. In cerebellar membranes, the density of high-affinity [3H]muscimol and [3H]6,7-dimethoxy-4-ethyl-beta-carboline ([3H]BCCM) binding sites is almost identical to that of [3H]flunitrazepam ([3H]FLU) or [3H]flumazenil (Ro 15-1788; ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a] [1-4]benzodiazepine-3-carboxylate). In contrast to the cerebellum, the number of muscimol and BC binding sites in rat spinal cord is approximately 20-25% of the number of FLU or flumazenil binding sites. Moreover, in spinal cord membranes, BC recognition site ligands displace [3H]-flumazenil bound to those sites, with low affinity and a Hill slope significantly less than 1; the potency of the different BCs in displacing [3H]flumazenil is 20-50-fold lower in the spinal cord than in the cerebellum. [3H]Flumazenil is not displaced from spinal cord membranes by the peripheral BZD ligand Ro 5-4864 (4'-chlorodiazepam), whereas it is displaced with low affinity and a Hill slope of less than 1 (nH = 0.4) by CL 218,872 (3-methyl-6-(3-trifluoromethylphenyl)-1,2,4-triazolol[4,3-b] pyridazine). These data suggest that a large number of BZD binding sites in spinal cord (approximately 80%) are of the central-type, BZD2 subclass, whereas the BZD binding sites in cerebellum are predominantly of the central-type, BZD1 subclass.(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantifying Human Health Risks Caused by Toxoplasmosis from Open System Production of Swine

Open livestock production systems, including free-range and organic livestock systems, seek to improve the welfare of animals by letting them roam in unconfined spaces. This increases their exposure to potentially harmful micro-organisms. For example, swine in open production systems have a much greater risk of Toxoplasma gondii infection. When transmitted through the food chain, T. gondii threatens human health, especially in unborn children of women infected during pregnancy, as well as the lives of patients with compromised immune systems. By contrast, conventional total confinement production systems can now keep this human health risk at or near zero. This article describes a probabilistic risk simulation model that quantified the tradeoff between greater use of open swine production systems and increased cases of toxoplasmosis in humans. The model predicts that every 1804 pigs shifted from conventional total confinement to open production (95% confidence interval 747–9520) would cause the loss of one additional human quality-adjusted life year (QALY), and that increasing the fraction of U.S. swine raised in open/free range operations by 0.1% (approx. 65,000 pigs) would cause a loss of approximately 36 human QALYs per year, including between 1 and 2 extra adult deaths per year.     

Mycobacterial Dihydrofolate Reductase Inhibitors Identified Using Chemogenomic Methods and In Vitro Validation

The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s) and mechanism of action of the hits. This target identification, or deorphanization step, is often essential in further optimization and validation studies. Direct experimental identification of the molecular target of a screening hit is often complex, precisely because the properties and specificity of the hit are not yet optimized against that target, and so many false positives are often obtained. An alternative is to use computational, predictive, approaches to hypothesize a mechanism of action, which can then be validated in a more directed and efficient manner. Specifically here we present experimental validation of an in silico prediction from a large-scale screen performed against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. The two potent anti-tubercular compounds studied in this case, belonging to the tetrahydro-1,3,5-triazin-2-amine (THT) family, were predicted and confirmed to be an inhibitor of dihydrofolate reductase (DHFR), a known essential Mtb gene, and already clinically validated as a drug target. Given the large number of similar screening data sets shared amongst the community, this in vitro validation of these target predictions gives weight to computational approaches to establish the mechanism of action (MoA) of novel screening hit.     

Mass Drug Administration for Trachoma: How Long Is Not Long Enough?

BackgroundBlinding trachoma is targeted for elimination by 2020 using the SAFE strategy (Surgery, Antibiotics, Facial cleanliness, and Environmental improvements). Annual mass drug administration (MDA) with azithromycin is a cornerstone of this strategy. If baseline prevalence of clinical signs of trachomatous inflammation – follicular among 1-9 year-olds (TF1-9) is ≥10% but <30%, the World Health Organization guidelines are for at least 3 annual MDAs; if ≥30%, 5. We assessed the likelihood of achieving the global elimination target of TF1-9 <5% at 3 and 5 year evaluations using program reports.ConclusionsNumber of annual MDAs alone appears insufficient to predict program progress; more information on the effects of baseline prevalence, coverage, and underlying environmental and hygienic conditions is needed. Programs should not skip MDAs, and at prevalences >30%, 7 or more annual MDAs may be required to achieve the target. There are five years left before the 2020 deadline to eliminate blinding trachoma. Low endemic settings are poised to succeed in their elimination goals. However, newly-identified high prevalence districts warrant immediate inclusion in the global program. Intensified application of the SAFE strategy is needed in order to guarantee blinding trachoma elimination by 2020.     

Essential Role of Nr2f Nuclear Receptors in Patterning the Vertebrate Upper Jaw

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Tobacco genes encoding acidic and basic isoforms of pathogenesis-related proteins display different expression patterns

The induction by cytokinin stress and ethylene of nine different tobacco mosaic virus-inducible mRNA classes (termed A-I) encoding pathogenesis-related (PR) proteins was studied. The induced mRNA levels were compared to basal levels in healthy tobacco plants grown in tissue culture and in a greenhouse. Cytokinin stress and ethylene were found to induce different subsets of the mRNAs, indicating that ethylene is not the primary inducing signal in cytokinin-stressed shoots. mRNAs F, H and G encoding the basic hydrolytic enzymes chitinase, -1,3-glucanase and a basic equivalent of PR-1, respectively, were found to be expressed at high levels in roots of healthy plants. mRNAs D, I and B encoding the acidic equivalents of the proteins proved to be present at low levels in healthy plants. These results indicate that genes encoding basic and acidic isoforms of pathogenesis-related proteins are differentially regulated.     

Techniques for Imaging Vascular Supply of Peripheral Nerves

Few studies have been developed to map the vascular structures feeding peripheral nerves, with the majority using cadaveric models and inadequate sample sizes. Preliminary evidence, while limited, indicates that the mapping of these vessels may allow or preclude certain procedures in nerve reconstruction due to the location of essential arterial inflow to the vasa nervorum. This review evaluates the evidence regarding historical, current, and emerging techniques for visualizing these vascular structures in vivo and considers their potential application in peripheral nerve vasculature.