115 research outputs found

    Booze, Bets, and Brothels: The Moral Roots of the Modern American Polity

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    Reviewing: Kyle G. Volk, Moral Minorities and the Making of American Democracy (Oxford University Press 2014); John W. Compton, The Evangelical Origins of the Living Constitution (Harvard University Press 2014); Jessica R. Pliley, Policing Sexuality: The Mann Act and the Making of the FBI (Harvard University Press 2014)

    Evaluation of the Efficacy of Various Hydrophobic Degrons for PROTAC-Mediated Degradation of the Androgen Receptor

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    The androgen receptor (AR) pathway is a major contributor to prostate cancer (PC) & tumor growth. Because of this, many therapeutic strategies and drugs attempt to disrupt this pathway to slow or stop tumor growth. The typical solution has been to use an inhibitor, known as an AR antagonist, that binds to the AR to inhibit its function. However, PC cells can often develop resistance to this method of treatment, ignoring the AR antagonists or reversing their role, causing the inhibitor to activate their pathway. Targeted protein degradation is a rapidly growing area in drug design, & has been suggested as another treatment strategy for cancers that become resistant to traditional strategies. One method of targeted protein degradation is hydrophobic tagging: binding the protein to a hydrophobic molecule. This resembles a partially unfolded protein, leading to ubiquitination & activation of cellular protein degradation machinery. One novel method is to use heterobifunctional molecules known as proteolysis targeting chimeras (PROTACs). A PROTAC contains a ligand for the protein of interest (POI) on one side, connected by a linker to a group known to induce degradation, also known as a degron. These PROTACs are highly effective in theory, because they are highly selective, small molecules, & should be capable of eliminating POIs rather than attempting to alter their function. Our research aims to treat PC cells with PROTACs containing an AR antagonist that will selectively bind the AR, attached to various hydrophobic moieties to test their relative effectiveness as degrons. If these hydrophobic moieties are effective degrons, a chemical library of degrons can be established, making it possible to use them in future designs targeting other proteins

    The role of the Tennessee 4-H specialist as perceived by 4-H agents

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    The primary purpose of this study was to examine the perception of 4-H agents in terms of the role of the state level Extension 4-H specialist. The population included 225 county level 4-H agents employed by either University of Tennessee or Tennessee State University Extension. Data analyses for this study included an examination of demographic factors and 13 questions related to perception (quantitative) as well as three open ended questions (qualitative). Five research questions were examined to determine the perceived role of the 4-H specialists from the perspective of the current 4-H agents and identify what differences exist between role perceptions of the specialist and generational or demographic differences among the agents. The questions were: • Is there a difference between the perceptions of the role of the Extension 4-H specialist based on different ages of 4-H agents? • Is there a difference between the perceptions of the role of the Extension 4-H specialist based on different genders of 4-H agents? • Is there a difference between the perceptions of the role of the Extension 4-H specialist based on different years of experience of 4-H agents? • Is there a difference between the perceptions of the role of the Extension 4-H specialist based on different geographical locations of 4-H agents? • How do 4-H agents perceive that Extension 4-H Specialists are performing their duties? The quantitative results of this study, gleaned from research questions 1 – 4, concluded there was no significant difference in perception of the role of the 4-H specialist due to age, gender, years of experience, nor geographical location of the respondent. Additionally, the open-ended questions, which addressed research question five, provided mixed responses. Some respondents indicated that the Extension 4-H Specialists were performing their duties well. Other respondents provided feedback and methods for improvement

    Innovative practices for special warfare

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    Special Warfare forces are tasked with conducting operations in uncertain environments defined by rapidly changing environmental elements (instability) and the interaction of many diverse external factors (complexity). In order to succeed, organizations operating in uncertain environments should decentralize decision-making to the appropriate level and emphasize an organic approach that focuses on the importance of people, adaptation, and innovation. The current USASOC bureaucracy, mirroring the conventional Army, is built to maximize internal efficiency and specialize in previously predicted scenarios. Due to persistently high operational tempo, personnel downsizing, and fiscal constraints, redesigning USASOC is not feasible at this time. However, the improvement of processes and incremental enhancement to align better with the operational environment within the existing design is possible. This study explores best practices from innovative and adaptive organizations that ARSOF can draw upon to increase its capability to conduct special warfare. Through the examination of these best practices, the study identified four key factors that lead to innovation: collaboration, organizational structure, incentives, and acceptance. This study recommends that Special Warfare forces apply these factors by increasing career flexibility, internal and external linkages through broadening opportunities and liaisons, and the collective intelligence of the organization through the use of cross-functional teams and increased communication measures. Adopting these enhancements may promote innovation and adaptation and increase Special Warfare forces’ contributions to national defense.http://archive.org/details/innovativepracti1094547858Major, United States ArmyApproved for public release; distribution is unlimited

    HCV Broadly Neutralizing Antibodies Use a CDRH3 Disulfide Motif to Recognize an E2 Glycoprotein Site that Can Be Targeted for Vaccine Design

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    Hepatitis C virus (HCV) vaccine efforts are hampered by the extensive genetic diversity of HCV envelope glycoproteins E1 and E2. Structures of broadly neutralizing antibodies (bNAbs) (e.g., HEPC3, HEPC74) isolated from individuals who spontaneously cleared HCV infection facilitate immunogen design to elicit antibodies against multiple HCV variants. However, challenges in expressing HCV glycoproteins previously limited bNAb-HCV structures to complexes with truncated E2 cores. Here we describe crystal structures of full-length E2 ectodomain complexes with HEPC3 and HEPC74, revealing lock-and-key antibody-antigen interactions, E2 regions (including a target of immunogen design) that were truncated or disordered in E2 cores, and an antibody CDRH3 disulfide motif that exhibits common interactions with a conserved epitope despite different bNAb-E2 binding orientations. The structures display unusual features relevant to common genetic signatures of HCV bNAbs and demonstrate extraordinary plasticity in antibody-antigen interactions. In addition, E2 variants that bind HEPC3/HEPC74-like germline precursors may represent candidate vaccine immunogens

    A Content Analysis of Psychological Resilience Among First Responders and the General Population

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    The current study examined how first responders and the general population described the concept of resilience. Categories of resilience were coded a priori using Stemler’s content analysis. For the general population, positive coping was the most frequently occurring category followed by social support and adaptability. The next most frequently occurring terms were societal resources and personal competence. Consistent with the general population, first responders described resilience most frequently with positive coping. Social support was the next most frequently occurring category, followed by personal competence, perseverance, emotional regulation, and physical fitness. Although both the general population and first responder participants highlighted the importance of having a support network, first responders suggested that dealing with traumatic experiences was more of an individual process, and seeking professional help was not common practice. Implications for mental health professionals and future directions for research are offered.ECU Open Access Publishing Support Fun

    Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance

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    A vaccine for hepatitis C virus (HCV) is urgently needed. Development of broadly neutralizing plasma antibodies during acute infection is associated with HCV clearance, but the viral epitopes of these plasma antibodies are unknown. Identifying these epitopes could define the specificity and function of neutralizing antibodies (NAbs) that should be induced by a vaccine. Here, we present the development and application of a high-throughput method that deconvolutes polyclonal anti-HCV NAbs in plasma, delineating the epitope specificities of anti-HCV NAbs in acute-infection plasma of 44 humans with subsequent clearance or persistence of HCV. Remarkably, we identified multiple broadly neutralizing antibody combinations that were associated with greater plasma neutralizing breadth and with HCV clearance. These studies have the potential to inform new strategies for vaccine development by identifying broadly neutralizing antibody combinations in plasma associated with the natural clearance of HCV, while also providing a high-throughput assay that could identify these responses after vaccination trials

    Sites of vulnerability in HCV E1E2 identified by comprehensive functional screening

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    The E1 and E2 envelope proteins of hepatitis C virus (HCV) form a heterodimer that drives virus-host membrane fusion. Here, we analyze the role of each amino acid in E1E2 function, expressing 545 individual alanine mutants of E1E2 in human cells, incorporating them into infectious viral pseudoparticles, and testing them against 37 different monoclonal antibodies (MAbs) to ascertain full-length translation, folding, heterodimer assembly, CD81 binding, viral pseudoparticle incorporation, and infectivity. We propose a model describing the role of each critical residue in E1E2 functionality and use it to examine how MAbs neutralize infection by exploiting functionally critical sites of vulnerability on E1E2. Our results suggest that E1E2 is a surprisingly fragile protein complex where even a single alanine mutation at 92% of positions disrupts its function. The amino-acid-level targets identified are highly conserved and functionally critical and can be exploited for improved therapies and vaccines

    Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes

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    Lens epithelium-derived growth factor (LEDGF/p75) tethers lentiviral preintegration complexes (PICs) to chromatin and is essential for effective HIV-1 replication. LEDGF/p75 interactions with lentiviral integrases are well characterized, but the structural basis for how LEDGF/p75 engages chromatin is unknown. We demonstrate that cellular LEDGF/p75 is tightly bound to mononucleosomes (MNs). Our proteomic experiments indicate that this interaction is direct and not mediated by other cellular factors. We determined the solution structure of LEDGF PWWP and monitored binding to the histone H3 tail containing trimethylated Lys36 (H3K36me3) and DNA by NMR. Results reveal two distinct functional interfaces of LEDGF PWWP: a well-defined hydrophobic cavity, which selectively interacts with the H3K36me3 peptide and adjacent basic surface, which non-specifically binds DNA. LEDGF PWWP exhibits nanomolar binding affinity to purified native MNs, but displays markedly lower affinities for the isolated H3K36me3 peptide and DNA. Furthermore, we show that LEDGF PWWP preferentially and tightly binds to in vitro reconstituted MNs containing a tri-methyl-lysine analogue at position 36 of H3 and not to their unmodified counterparts. We conclude that cooperative binding of the hydrophobic cavity and basic surface to the cognate histone peptide and DNA wrapped in MNs is essential for high-affinity binding to chromatin
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