244 research outputs found
Lipopeptides derived from HIV and SIV mimicking the prehairpin intermediate of gp41 on solid supported lipid bilayers
No full textWe present a universal mimetic approach of the prehairpin intermediate of gp41, which represents the active drug target for fusion inhibitors of HIV (human immunodeficiency virus) and SIV (simian immunodeficiency virus) based on membrane anchored lipopeptides. For this purpose, we have in situ coupled terminal cysteine-modified peptides originating from the NHR of SIV and HIV to a maleimide-functionalized DOPC bilayer and monitored the interactions with potential antagonists of the trimer-of-hairpin conformation C34 and T20 peptides by means of atomic force microscopy and ellipsometry. FT-IR analysis in conjugation with CD-spectroscopy of hydrated N36-lipopeptides, incorporated in multilamellar bilayer stacks was employed to investigate peptide conformation prior to antagonist binding. In contrast to solution studies substantial secondary structure formation of S-N36 after in situ coupling to the bilayer was found. We could show that S-N36-lipopeptide-aggregates in bilayers were selectively able to bind T20 or the corresponding C-peptides (C34) and similar results could be achieved by using H-N36 lipopeptides. It was found that T20 binding to coiled coil S-N36 lipopeptide assemblies was fully reversible at elevated temperatures, while T20 binds irreversibly to H-N36 bundles. (C) 2009 Elsevier Inc. All rights reserved
Coiled‐Coil Lipopeptides Mimicking the Prehairpin Intermediate of Glycoprotein gp41
No full textNCRR NIH HHS [S10 RR017948]; NIGMS NIH HHS [R01 GM065500
Preparation of unnatural N-to-N and C-to-C protein fusions
Get PDFStandard genetic approaches allow the production of protein composites by fusion of polypeptides in head-to-tail fashion. Some applications would benefit from constructions that are genetically impossible, such as the site-specific linkage of proteins via their N or C termini, when a remaining free terminus is required for biological activity. We developed a method for the production of N-to-N and C-to-C dimers, with full retention of the biological activity of both fusion partners and without inflicting chemical damage on the proteins to be joined. We use sortase A to install on the N or C terminus of proteins of interest the requisite modifications to execute a strain-promoted copper-free cycloaddition and show that the ensuing ligation proceeds efficiently. Applied here to protein–protein fusions, the method reported can be extended to connecting proteins with any entity of interest.Netherlands Organization for Scientific ResearchHuman Frontier Science Program (Strasbourg, France)National Institutes of Health (U.S.) (R01 Award AI033456)National Institutes of Health (U.S.) (R01 Award AI087879
Die neue Harmonie, oder, eine neue Sammlung von Kirchen-Musik = The new harmony, or, a new collection of church music.
No full textC.2 in Don Yoder Collection of American Hymnody.Mode of access: Internet
REENERGIZING THE U.S. AND PHILIPPINES RELATIONSHIP: THE “PHILIPPINES BELT AND ROAD” PROPOSAL
Get PDFThe purpose of this thesis is to examine why the United States should care about its future relationship with the Philippines through the overarching lens of Pankaj Ghemawat’s Cultural, Administrative, Geographic, and Economic (CAGE) Distance Framework. In addition, we will delve deeper to investigate a more direct approach using Michael E. Porter’s classic diamond model found in The Competitive Advantage of Nations. Using qualitative and exploratory research methods, we explore three questions. First, why should the United States care from a national security and alliance perspective about an economically stronger Philippines? Second, what does an economically stronger Philippines mean strategically for the United States’ influence in the Southeast Asian region? Finally, what can be done to strengthen the United States and the Philippines relationship? In conclusion, our recommendations provide tangible solutions to current gaps between the Philippines and the United States whether they be cultural, political, or military to facilitate a prosperous relationship while simultaneously thwarting the actions of the Chinese Communist Party (CCP) sweeping through Southeast Asia.Approved for public release. Distribution is unlimited.Lieutenant Commander, United States NavyLieutenant Commander, United States Nav
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Three Essays in Water and Climate Economics
Get PDFThis dissertation includes three chapters on the economics of climate, water resources, agricultural production, and conflict. Chapter one is an introduction. In chapter two I provide an analysis of the impact of exposure to temperature on returns to irrigated and nonirrigated cropland. Chapter three is a theoretical approach to understand the economic implications of the forfeiture of water rights for nonuse. Chapter four looks at the relationship between drought, conflict, and governance using a disaggregated spatial analysis.Chapter two is on temperature effects on snowpack-dependent surfacewater irrigated production systems in the western US. Irrigated production in that region is characterized by a diverse mix of high value crops, so producers may have more of an ability to adapt to hotter temperatures. I focus on county rental prices for irrigated and nonirrigated cropland and find that economic returns to cropland begin to decrease starting at about 25C for irrigated acres and 20C for nonirrigated acres.Chapter three covers the economic history that led to the creation of forfeiture policies for the nonuse of surface water rights in the western US. I develop a theory of water rights under prior appropriations with forfeiture and use it to examine why forfeiture policies were adopted in all western states that allocate water via prior appropriation. Forfeiture reduced risk to junior water rights holders and limited speculative water claims, but did so at the cost of increased transaction costs when trading water rights. While these were small when remaining water resources were available to be claimed, they are significantly more costly when all water in a basin has been allocated.In chapter four I combine a spatiotemporal grid of drought and geolocated conflict with several measures of governance characteristics to examine how governance mediates the relationship between drought and conflict. I find little evidence of a relationship between drought and conflict in Africa and Latin and South America. In countries that are more democratic or in which doing business is easier, an increase in drought reduces the likelihood of riot incidence. Other governance measures have no discernible effect
Abstract 75: Comparison of site-specific and lysine-linked indolino-benzodiazepine antibody-drug conjugates (ADCs)
No full textAbstract
ADCs are a promising modality for cancer therapy enabled by chemical conjugation of potent cytotoxic compounds to monoclonal antibodies. While many ADCs in clinical evaluation employ heterogeneous conjugation chemistries where the payload is linked through lysine or endogenous cysteine residues, there has recently been considerable interest in site-specific conjugation. ADCs prepared using site-specific methods are believed to have a wider therapeutic index compared to heterogeneous ADCs. We have previously shown that site-specific ADCs incorporating the maytansinoid-based tubulin inhibitor DM1 were less efficacious in vivo when compared to analogous lysine-linked conjugates (Yoder et al AACR 2015 Abstract #545). More recently, we presented results from the evaluation of 2.5-3.0 drug-to-antibody ratio (DAR) heterogeneous lysine-linked and 2 DAR site-specific ADCs using antibodies with engineered cysteines at position 442 in the heavy chains (known as CYSMABTM). These ADCs used the peptide-linked indolino-benzodiazepine DNA alkylator DGN549 (also known as IGN-P1) as the effector. Unlike the DM1 case, site-specific DGN549 ADCs were at least as active in vivo when compared to lysine-linked ADCs (Yoder et al AACR 2016 Abstract #2960). We have made further pharmacological comparisons between CYSMAB and lysine-linked DGN549 ADCs at matched payload doses using two different antibodies targeting distinct cell surface receptors. In the case of mAb1, CYSMAB and lysine-linked ADCs were comparably active. For mAb2, the CYSMAB ADC was more active than the lysine-linked ADC in some models and similarly active in others. The mAb1 CYSMAB ADC exhibited a significantly higher maximum tolerated dose (MTD) compared to the lysine-linked ADC. In contrast, the MTDs of the mAb2 ADCs were similar. However, the mAb2 CYSMAB conjugate was better tolerated in terms of median lethal dose. The mechanism for the improved tolerability of the mAb1 CYSMAB conjugate is not apparent. In an effort to understand whether it is a consequence of conjugation chemistry or DAR, we compared the tolerability of the mAb1 CYSMAB conjugate to that of a ~4 DAR site-specific analog and found that both factors contribute. To determine if our observations can be rationalized in terms of in vivo disposition, we compared the pharmacokinetics of mAb1 CYSMAB and lysine-linked ADCs at matched antibody doses. Intriguingly, the CYSMAB ADC showed slightly greater exposure. These results, along with our previous work on site-specific DM1 ADCs, indicate that in some cases site-specific conjugation can lead to improved efficacy and tolerability. However, generalizations cannot be made across different combinations of antibody, linker, and payload. We conclude that the advantages and disadvantages of site-specific conjugation should be carefully considered for every candidate ADC.
Citation Format: Chen Bai, Nicholas C. Yoder, Alan Wilhelm, Sharlene Adams, Kathleen Whiteman, Jenny Lee, Katie O'Callaghan, Erin Maloney, Manami Shizuka, Yelena Kovtun, Thomas A. Keating. Comparison of site-specific and lysine-linked indolino-benzodiazepine antibody-drug conjugates (ADCs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 75. doi:10.1158/1538-7445.AM2017-75</jats:p
CAN YOU HEAR ME NOW? INTERNATIONAL WIRELESS SOLUTIONS FOR THE DOD
Get PDFThis topic has been directly requested for research by Naval Supply Systems Command (NAVSUP) Fleet Logistics Center (FLC) San Diego. The Navy and other Department of Defense (DOD) entities use a contracting vehicle called the Spiral 3 Multiple Award Contract (MAC) that provides cellular and other handheld wireless services to Navy commands within all 50 states. Broadly, the Spiral 3 contract is set up with three participating vendors: AT&T, Verizon, and T-Mobile. For any given Navy command, they each submit to their local NAVSUP FLC contracting officer a list of their cellular and wireless requirements. These requirements are then solicited to the Spiral 3 vendors. A task order against the Spiral 3 contract is then awarded to the vendor that came in with the lowest-priced, technically acceptable offer. This contract model has consistently been able to keep domestic cellular costs down from older contract vehicles. However, costs have remained high for international services, with frequent cost overruns occurring due to overages in international service by various Navy commands. Our research found that high international costs were due to a combination of suboptimal contract language and not fully utilizing vendor competition. Better defined contractual language and better utilizing existing vendor competition should lower international wireless costs.Approved for public release. distribution is unlimitedLieutenant Commander, United States NavyLieutenant Commander, United States NavyNAVSU
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Marginal Coexistence: Anabaptists between Persecution and Toleration in Reformed Zurich, 1585-1650
No full textFor more than a century after the genesis of an Anabaptist movement in Zurich in 1525, participants in this prohibited religious culture continued to live in rural lands under the city- republic’s control. This dissertation examines the character of the coexistence of members of the Anabaptist minority and representatives of the Reformed majority in this territory between 1585, when the city council promulgated a new set of anti-Anabaptist mandates, and c. 1650, when official coercion eliminated the presence of nonconformist communities from the area. Drawing on a diverse body of archival evidence, the author concludes that Anabaptist-Reformed coexistence during this period occurred under conditions of repression. This phrase describes relations between a subordinate but active minority and a dominant majority when the latter both desired and took concrete steps to eliminate religious diversity as a notable feature of public life. Under such conditions, manifestations of Anabaptist religious culture—illicit mobility, recounting of conversion experiences, selective withdrawal from parish life, and courtship and marriage practices—often triggered a repressive response. These actions, by rendering nonconformity visible, violated cultural norms and boundaries that representatives of the Reformed majority considered worthy of defense. While levels of Anabaptist activity remained relatively stable, the severity of conflict between these groups vacillated markedly, influenced by varying configurations of governmental power, understandings of communal space, solidarities of kinship and neighborliness, and practices of record-production and record-keeping. Although repression pushed Anabaptists into marginal spaces, it did not provoke widespread dissimulation. Rather, dissidents generally remained willing, if not eager, to incur costs for the articulation of religious difference. The fact and nature of long-term Anabaptist-Reformed coexistence in Zurich’s lands expands appreciation of the breadth of possibilities for religious diversity in early modern Europe. At the same time, it shows how tenuous and cruel coexistence could be when stamped by conflict, domination, and human suffering.Dissertation not available (per author's request
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