Allosteric Conversation in the Androgen Receptor Ligand-Binding Domain Surfaces

Androgen receptor (AR) is a major therapeutic target that plays pivotal roles in prostate cancer (PCa) and androgen insensitivity syndromes. Wepreviously proposed that compounds recruited to ligand-binding domain (LBD) surfaces could regulate AR activity in hormone-refractory PCa and discovered several surface modulators of AR function. Surprisingly, the most effective compounds bound preferentially to a surface of unknown function [binding function 3 (BF-3)] instead of the coactivator-binding site [activation function 2 (AF-2)]. Different BF-3 mutations have been identified in PCa or androgen insensitivity syndrome patients, and they can strongly affect AR activity. Further, comparison of AR x-ray structures with and without bound ligands at BF-3 and AF-2 showed structural coupling between both pockets. Here, we combine experimental evidence and molecular dynamic simulations to investigate whether BF-3 mutations affect AR LBD function and dynamics possibly via allosteric conversation between surface sites. Our data indicate that AF-2 conformation is indeed closely coupled to BF-3 and provide mechanistic proof of their structural interconnection. BF-3 mutations may function as allosteric elicitors, probably shifting the AR LBD conformational ensemble toward conformations that alter AF-2 propensity to reorganize into subpockets that accommodate N-terminal domain and coactivator peptides. The induced conformation may result in either increased or decreased AR activity. Activating BF-3 mutations also favor the formation of another pocket (BF-4) in the vicinity of AF-2 and BF-3, which we also previously identified as a hot spot for a small compound. We discuss the possibility that BF-3 may be a protein-docking site that binds to the N-terminal domain and corepressors. AR surface sites are attractive pharmacological targets to develop allosteric modulators that might be alternative lead compounds for drug design. © 2012 by The Endocrie Society

Influenza Vaccination Behaviour of Healthcare Workers in Switzerland: A Cross-Sectional Study

Objectives: As no data are available regarding the influenza vaccination status of Swiss healthcare workers (HCW) in the ambulatory setting, this study aims to investigate their influenza vaccination behaviours. Methods: We conducted an online survey using a four-item, semi-structured questionnaire to assess HCWs influenza vaccination coverage and behaviour. Associations between influenza vaccination status, age and language as well as recommendation behaviour and reasons for vaccination were assessed using descriptive statistics and logistic regression analyses. Results: Of the 1057 completed questionnaires, 425 (40.2%) HCW were vaccinated and 632 (59.8%) not. 78.1% of the physicians and 47.3% pharmacists were vaccinated, compared to only 29.1% of the nurses, 24.3% pharmacy technicians and 13.0% medical practice assistants (MPA). There was a significant association between influenza vaccination status and HCW profession, age, language and how often an influenza vaccination recommendation was made. Conclusion: Demographic factors seem to influence HCWs’ attitudes towards influenza vaccination, which in turn affects the prospect of them recommending the influenza vaccination. Diverse strategies might be necessary to encourage HCW to get vaccinated and hence, promote influenza vaccination

Selection of DNA nanoparticles with preferential binding to aggregated protein target.

High affinity and specificity are considered essential for affinity reagents and molecularly-targeted therapeutics, such as monoclonal antibodies. However, life's own molecular and cellular machinery consists of lower affinity, highly multivalent interactions that are metastable, but easily reversible or displaceable. With this inspiration, we have developed a DNA-based reagent platform that uses massive avidity to achieve stable, but reversible specific recognition of polyvalent targets. We have previously selected these DNA reagents, termed DeNAno, against various cells and now we demonstrate that DeNAno specific for protein targets can also be selected. DeNAno were selected against streptavidin-, rituximab- and bevacizumab-coated beads. Binding was stable for weeks and unaffected by the presence of soluble target proteins, yet readily competed by natural or synthetic ligands of the target proteins. Thus DeNAno particles are a novel biomolecular recognition agent whose orthogonal use of avidity over affinity results in uniquely stable yet reversible binding interactions

Three essays on corporate debt mix, maturity structure, and inside debt compensation

In Chapter 1, we use a large sample of new debt to examine the determinants of corporate debt mix and to test the substitute/complement effects among debt sources. We find that both firm-level factors and macroeconomic variables are important determinants of debt mix. In addition, the set of determinants varies across time and economic conditions. In general, we find evidence for a substitution effect between public debt and private debt, both at rating downgrades and new issuance events. In Chapter 2, we examine the impacts of product market competition and corporate governance on debt maturity. We find that firms in less competitive industries use more short-term maturity than firms in more competitive industries, while firms with weak corporate governance use less short-term maturity. However, there is mixed evidence on the impact of the interaction between product market competition and corporate governance on maturity. In Chapter 3, we study the relations between inside debt compensation and corporate policies. We find a positive relationship between inside debt and leverage, indicating that CEOs with higher inside debt holdings tend to use higher leverage. We also find strong (weak) evidence on the negative relationship between inside debt and R&D activities (capital expenditures). We provide the first evidence about the relationship between inside debt and debt maturity. In one direction, short-term maturity increases in inside debt. However, in other direction, inside debt decreases in short-term maturity. Additionally, we document new evidence about the determinants of inside debt

Twisting of graded quantum groups and solutions to the quantum Yang-Baxter equation

Let $H$ be a Hopf algebra that is $\mathbb Z$-graded as an algebra. We provide sufficient conditions for a 2-cocycle twist of $H$ to be a Zhang twist of $H$. In particular, we introduce the notion of a twisting pair for $H$ such that the Zhang twist of $H$ by such a pair is a 2-cocycle twist. We use twisting pairs to describe twists of Manin's universal quantum groups associated to quadratic algebras and provide twisting of solutions to the quantum Yang-Baxter equation via the Faddeev-Reshetikhin-Takhtajan construction.Comment: In this version, our title is new and Section 3 is updated with applications of twisting pairs to obtain new solutions to the quantum Yang-Baxter equatio

Spatiotemporal Impact Analysis of Hurricanes and Storm Surges on Power Systems

This paper develops a spatiotemporal probabilistic impact assessment framework to analyze and quantify the compounding effect of hurricanes and storm surges on the bulk power grid. The probabilistic synthetic hurricane tracks are generated using historical hurricane data, and storm surge scenarios are generated based on observed hurricane parameters. The system losses are modeled using a loss metric that quantifies the total load loss. The overall simulation is performed on the synthetic Texas 2000-bus system mapped on the geographical footprint of Texas. The results show that power substation inundation due to storm surge creates additional load losses as the hurricane traverses inland.Comment: 5 pages, 9 figures, submitted to 2023 IEEE Power and Energy Society General Meeting for revie

Cardiovascular Disease Risk Among the Poor and Homeless – What We Know So Far

Homelessness [and poverty] is rapidly escalating across North America and is associated with dire implications for public health and our health care systems. Both are compelling states of existence affecting all ages, ethnicities and both genders. Homelessness frequently evolves through a complex interaction of factors that are both internal and external to the individual themselves. Once homeless, equitable access to both preventative and remedial health care is lacking and is associated with a higher than average burden of cardiovascular disease [CVD] risk factors, morbidity and mortality and is accompanied by disproportionately high health care costs. The emergence of limited, small scale programs aimed at addressing the unique health and social needs of the homeless is encouraging. However, there has been inadequate commitment at the National, State or Provincial and local levels to implement policies and dedicate funding and resources to the expansion of such “individual level” interventions into comprehensive programs that deliver sustainable, integrated prevention and services, especially with regard to CVD. The long-term solutions that address the links between homelessness and CVD lie in preventing homelessness and reversing the trends in our health care system that create disparities for lower socioeconomic status [SES] and homeless individuals

Late Window Imaging Selection for Endovascular Therapy of Large Vessel Occlusion Stroke: An International Survey

Background - Current stroke guidelines recommend advanced imaging (computed tomography [CT] perfusion or magnetic resonance imaging) prior to endovascular therapy (EVT) in patients with late presentation of large vessel occlusion. Adherence to guidelines may be constrained by resources or timely access to imaging. We sought to understand the factors which influence late window imaging selection for EVT candidates with large vessel occlusion. Methods - We conducted an international survey from January to May 2022. The questions aimed to identify advanced imaging and treatment decisions based on access to imaging, time delays, and simulated patient scenarios. Results - There were 3000 invited participants and 1506 respondents, the majority (89.6%) from comprehensive stroke centers in high‐income countries. Neurointerventionalists comprised 31.8% and noninterventionalists 68.2% of respondents. Overall, 70.7% reported routine use of advanced imaging for late EVT selection, and 63.6% reported its usage in every case. There was greater availability of advanced imaging in comprehensive stroke centers versus primary stroke centers (67.0% versus 33.7%; P Conclusion - Current guidelines for imaging late window EVT candidates are inconsistent with imaging decisions by physicians. Most respondents consider an imaging delay of greater than 20 minutes unacceptable. Access to advanced imaging was greater in comprehensive stroke centers and high‐income countries. In the case of limited access most respondents would consider EVT based on CT only