Sequencing of rabies binding region on nicotinic acteylcholine receptor alpha subunits in four host species

• Rabies virus is known to bind to nicotinic acetylcholine receptors (nAchR) • The virus is known to bind to alpha 1 subunits nAchR • The virus binding region has been characterized in alpha 1 subunits of these receptors • Little research has been done on the other alpha subunits • Understanding binding region sequences can help understand virus adaptation to host species • Using primers based on dog sequences, the proposed binding region of alpha subunits were amplified and sequenced • Current Results: • Red fox and dog have nearly identical alpha 1, 2, 3, 5, and 6 sequences for the proposed binding region • Arctic fox has nearly identical sequences to dog and red fox in alpha 1, 2, and 6 • Raccoon’s alpha 1, 2, 3, 5, and 6 subunits are similar enough to allow for annealing of the dog-based primers in PCR • No clear PCR products were found for skunk DNA • Future goals: • Sequencing five individuals per species • Adding mongoose, bat, and opossu

Clinical utility of fixed combinations of sitagliptin–metformin in treatment of type 2 diabetes

Adequate glycemic control in type 2 diabetes remains a difficult but achievable goal. The development of new classes of glucose-lowering medications, including in particular the incretin-based therapies, provides an opportunity to utilize combinations of medications which target multiple physiologic abnormalities in type 2 diabetes. Complementary combination therapy with sitagliptin–metformin lowers glucose via enhancement of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Use of this combination in diabetes management will provide a greater degree of glycosylated hemoglobin-lowering than that seen with the use of either drug as monotherapy, is unlikely to cause significant hypoglycemia, and is generally associated with weight loss. The effectiveness, tolerability, and potential cost savings associated with the use of sitagliptin–metformin combination therapy make this an attractive option in diabetes management. The possible beneficial effects of this therapy on beta cell function, as well as its cardiovascular impact, remain inadequately explored but are of significant interest

Recognition of specific sialoglycan structures by oral streptococci impacts the severity of endocardial infection.

Streptococcus gordonii and Streptococcus sanguinis are primary colonizers of the tooth surface. Although generally non-pathogenic in the oral environment, they are a frequent cause of infective endocarditis. Both streptococcal species express a serine-rich repeat surface adhesin that mediates attachment to sialylated glycans on mucin-like glycoproteins, but the specific sialoglycan structures recognized can vary from strain to strain. Previous studies have shown that sialoglycan binding is clearly important for aortic valve infections caused by some S. gordonii, but this process did not contribute to the virulence of a strain of S. sanguinis. However, these streptococci can bind to different subsets of sialoglycan structures. Here we generated isogenic strains of S. gordonii that differ only in the type and range of sialoglycan structures to which they adhere and examined whether this rendered them more or less virulent in a rat model of endocarditis. The findings indicate that the recognition of specific sialoglycans can either enhance or diminish pathogenicity. Binding to sialyllactosamine reduces the initial colonization of mechanically-damaged aortic valves, whereas binding to the closely-related trisaccharide sialyl T-antigen promotes higher bacterial densities in valve tissue 72 hours later. A surprising finding was that the initial attachment of streptococci to aortic valves was inversely proportional to the affinity of each strain for platelets, suggesting that binding to platelets circulating in the blood may divert bacteria away from the endocardial surface. Importantly, we found that human and rat platelet GPIbα (the major receptor for S. gordonii and S. sanguinis on platelets) display similar O-glycan structures, comprised mainly of a di-sialylated core 2 hexasaccharide, although the rat GPIbα has a more heterogenous composition of modified sialic acids. The combined results suggest that streptococcal interaction with a minor O-glycan on GPIbα may be more important than the over-all affinity for GPIbα for pathogenic effects

Distribution of O-Acetylated Sialic Acids among Target Host Tissues for Influenza Virus.

Sialic acids (Sias) are important glycans displayed on the cells and tissues of many different animals and are frequent targets for binding and modification by pathogens, including influenza viruses. Influenza virus hemagglutinins bind Sias during the infection of their normal hosts, while the encoded neuraminidases and/or esterases remove or modify the Sia to allow virion release or to prevent rebinding. Sias naturally occur in a variety of modified forms, and modified Sias can alter influenza virus host tropisms through their altered interactions with the viral glycoproteins. However, the distribution of modified Sia forms and their effects on pathogen-host interactions are still poorly understood. Here we used probes developed from viral Sia-binding proteins to detect O-acetylated (4-O-acetyl, 9-O-acetyl, and 7,9-O-acetyl) Sias displayed on the tissues of some natural or experimental hosts for influenza viruses. These modified Sias showed highly variable displays between the hosts and tissues examined. The 9-O-acetyl (and 7,9-) modified Sia forms were found on cells and tissues of many hosts, including mice, humans, ferrets, guinea pigs, pigs, horses, dogs, as well as in those of ducks and embryonated chicken egg tissues and membranes, although in variable amounts. The 4-O-acetyl Sias were found in the respiratory tissues of fewer animals, being primarily displayed in the horse and guinea pig, but were not detected in humans or pigs. The results suggest that these Sia variants may influence virus tropisms by altering and selecting their cell interactions. IMPORTANCE Sialic acids (Sias) are key glycans that control or modulate many normal cell and tissue functions while also interacting with a variety of pathogens, including many different viruses. Sias are naturally displayed in a variety of different forms, with modifications at several positions that can alter their functional interactions with pathogens. In addition, Sias are often modified or removed by enzymes such as host or pathogen esterases or sialidases (neuraminidases), and Sia modifications can alter those enzymatic activities to impact pathogen infections. Sia chemical diversity in different hosts and tissues likely alters the pathogen-host interactions and influences the outcome of infection. Here we explored the display of 4-O-acetyl, 9-O-acetyl, and 7,9-O-acetyl modified Sia forms in some target tissues for influenza virus infection in mice, humans, birds, guinea pigs, ferrets, swine, horses, and dogs, which encompass many natural and laboratory hosts of those viruses

Possible joint pathways of early pre-eclampsia and congenital heart defects via angiogenic imbalance and potential evidence for cardio-placental syndrome Downloaded from

This editorial refers to 'Maternal and foetal angiogenic imbalance in congenital heart defects' † , by E. Llurba et al., on page 701 Foetal vasculogenesis and angiogenesis and maternal angiogenesis are essential requirements for a pregnancy. Decidua-associated vascular changes arise in the inner junctional zone myometrium in early pregnancy, followed by trophoblast invasion with associated remodelling. 1 Decidual natural killer and dendritic cells regulate key developmental processes at the human foetal -maternal interface via human leucocyte antigen (HLA)-C, HLA-E, and HLA-G. 3 In the past decade, extensive research has investigated the abnormalities that can occur in the first trimester of pregnancy that could lead to chorionic regression or small placenta, contributing to intrauterine growth restriction and early-onset pre-eclampsia. 5 This excessive systemic inflammatory response results in endothelial dysfunction and an associated increase in vascular reactivity, preceding onset of the clinical condition pre-eclampsia, which affects 2-8 % of all pregnancies. Flt-1 is expressed on endothelial cells and macrophages, and binds to VEGF and a platelet-derived protein called placental growth factor (PlGF), with a wide range of functions which are not completely understood. 6 A potential endogenous opponent of PlGF in the plasma is soluble fms-like tyrosine kinase (sFlt-1), which represents a type of Flt-1, without the transmembrane and intracellular tyrosine kinase domain. sFlt-1 and PlGF have comprehensive involvement not only in the development of atherosclerotic processes and myocardial infarction, but also in a wider range of other inflammatory processes such as sepsis, acute lung injury, and neoplasm, as recently reviewed by Hochholzer et al. 6 However, most work on this interesting biomarker has been performed in pre-eclampsia. sFlt-1 can be measured in the placenta and serum of pregnant women. In normotensive pregnancy, the sFlt-1 levels are stable up to the middle stages of gestation, followed by a steady increase from 33 weeks onwards. This increase corresponds to a late-gestational decrease in free PlGF levels. It is postulated that this serves to slow placental vascular growth by increasing antiangiogenic factors such as sFlt-1, and decreasing levels of proangiogenic factors such as VEGF and PlGF

Toward a sustainable culture of peer partnership

This project is a two phase design working in partnership with five universities to develop, implement and systematically embed a distributive leadership model that aims to embed peer partnership (review, development) within the culture of teaching and learning excellence. This presentation will posit a ‘prototype’ peer review leadership model based on ongoing research that brings together both the fundamentals of peer review with the broader importance of context and persons. It will be argued that essential to teaching development is a need to address not only the implementation of peer partnership programs but also strategies to influence and change both the contexts of teaching and the advantages for colleagues. Peer review as a strategy to develop excellence in teaching needs to be considered from a holistic perspective encompassing all elements of the teaching environment. The emphasis is on working to foster the type of conditions needed for leadership and change to begin and be sustained. The work has implications for policy, research, leadership development and student outcomes and has potential application world-wide. Phase 1 has collected focus interview and questionnaire data to inform the research and is being analysed using a thematic qualitative approach and statistical analysis. Evidence is emerging currently as the project is ongoing

A survey of the effectiveness of existing marsh toe protection structures in Virginia

Using tidal marshes and other vegetated treatments for upland erosion control has been an accepted practice for years, yet the scientific understanding and established guidelines for this approach are limited. This survey was conducted to evaluate the efficacy of existing marsh toe protection structures, a particular type of erosion control treatment associated with tidal marshes on Chesapeake Bay shorelines. Field evaluations were conducted at 36 sites in 6 localities on the Middle Peninsula and Northern Neck of Virginia. General dimensions of each structure were recorded and observations made of erosion evidence, structural integrity, construction access impacts, and adjacent landscape settings. Most of the projects provide effective erosion protection for the tidal marsh and adjacent upland bank. Twenty projects (55%) were also determined to be effective as living shoreline treatments based on tidal marsh condition and because the riparian and wetland vegetation cover was interconnected. Common design standards from these projects have been incorporated into advisory guidelines

"Women's rights, the European Court and Supranational Constitutionalism"

This analysis examines supranational constitutionalism in the European Union. In particular, the study focuses on the role of the European Court of Justice in the creation of women’s rights. I examine the interaction between the Court and member state governments in legal integration, and also the integral role that women’s advocates – both individual activists and groups – have played in the development of EU social provisions. The findings suggest that this litigation dynamic can have the effect of fueling the integration process by creating new rights that may empower social actors and EU organizations, with the ultimate effect of diminishing member state government control over the scope and direction of EU law. This study focuses specifically on gender equality law, yet provides a general framework for examining the case law in subsequent legal domains, with the purpose of providing a more nuanced understanding of supranational governance and constitutionalism