Antiretroviral Therapy: New Mechanistic and Therapeutic Insights for HIV Single-Entity and Combination Drug Products.

With approximately 39 million people having died from AIDS-related causes so far, HIV is the world’s leading infectious killer. The large majority of the 35 million people currently living with the virus reside in low-/middle- income countries, but only 36% of the population eligible for therapy is receiving antiretroviral therapy in these regions. In order to promote the development of antiretroviral therapy, we have conducted research that pertains to both early- and late-stage aspects of antiretroviral products: investigating the mechanisms underlying HIV-1 infectivity in order to identify molecular targets to impede HIV infection and providing a biopharmaceutical rationale to accelerate and simplify the regulatory pathway for co-formulated, fixed-dose combination antiretroviral drug products. Data from the first half of this research demonstrate that HIV-1 infectivity is limited by the virus’ ability to efficiently engage target cells. The results show that the extent of non-specific interactions between HIV-1 and target cells is directly influenced by the amount of envelope spike glycoproteins on virus particles. Non-specific, receptor-independent interactions, which are more prevalent when there is a high virus-to-cell ratio, significantly impair the efficiency of HIV-1 infection and promote the degradation of virus particles in the lysosome. Therefore, our data identify molecular mechanisms that can be exploited as targets for alternative HIV treatment strategies. In the second half of this work, approved and investigational antiretroviral drug products were provisionally classified and evaluated relative to global bioequivalence standards. According to this provisional BCS classification, 36% of antiretroviral drug combination products were composed of high solubility compounds and potentially eligible for biowaivers under the current regulatory framework. By providing this evidence to justify simpler, yet science-based, regulatory routes to approval, and emphasizing that dissolution methodologies with in vivo relevancy can theoretically also be utilized in place of in vivo bioequivalence studies for products comprised of low solubility compounds, we are promoting development pathways that can lead to increased availability of effective combination drug products to address the health care disparities and significant unmet medical need in developing countries. Both aspects of this research present novel insights to aid the advancement of therapeutic approaches to combat HIV/AIDS.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113609/1/jamielen_1.pd

Thermal and Photochemical Reduction and Functionalization Chemistry of the Uranyl Dication, [U VI O2] 2+

The uranyl ion, [UVIO2]2+, possesses rigorously trans, strongly covalent, and chemically robust U-oxo groups. However, through the use of anaerobic reaction techniques, both one- and two-electron reductive functionalization of the uranyl oxo groups has been discovered and developed. Prior to 2010, this unusual reactivity centered around the reductive silylation of the uranyl ion which entailed conversion of the oxo ligands into siloxy ligands and reductive metalation of the uranyl oxo with Group 1 and f-block metals. This review surveys the large number of new examples of reductive functionalization of the uranyl ion that have been reported since 2010, including reductive borylation and alumination, metalation with d- or f-block metals, and new examples of reductive silylation. Other examples of oxo-group functionalization of [UVIO2]2+ that do not involve reduction, mainly with Group 1 cations, are also covered, along with new advances in the photochemistry of the uranyl(VI) ion that involve the transient formation of formally uranyl(V) [UVO2]+ ion

Optimal spatiotemporal scales to aggregate satellite ocean color data for nearshore reefs and tropical coastal waters: two case studies

Remotely sensed ocean color data are useful for monitoring water quality in coastal environments. However, moderate resolution (hundreds of meters to a few kilometers) satellite data are underutilized in these environments because of frequent data gaps from cloud cover and algorithm complexities in shallow waters. Aggregating satellite data over larger space and time scales is a common method to reduce data gaps and generate a more complete time series, but potentially smooths out the small-scale, episodic changes in water quality that can have ecological influences. By comparing aggregated satellite estimates of Kd(490) with related in-water measurements, we can understand the extent to which aggregation methods are viable for filling gaps while being able to characterize ecologically relevant water quality conditions. In this study, we tested a combination of six spatial and seven temporal scales for aggregating data from the VIIRS instrument at several coral reef locations in Maui, Hawai‘i and Puerto Rico and compared these with in situ measurements of Kd(490) and turbidity. In Maui, we found that the median value of a 5-pixels, 7-days spatiotemporal cube of satellite data yielded a robust result capable of differentiating observations across small space and time domains and had the best correlation among spatiotemporal cubes when compared with in situ Kd(490) across 11 nearshore sites (R2 = 0.84). We also found long-term averages (i.e., chronic condition) of VIIRS data using this aggregation method follow a similar spatial pattern to onshore turbidity measurements along the Maui coast over a three-year period. In Puerto Rico, we found that the median of a 13-pixels, 13-days spatiotemporal cube of satellite data yielded the best overall result with an R2 = 0.54 when compared with in situ Kd(490) measurements for one nearshore site with measurement dates spanning 2016–2019. As spatiotemporal cubes of different dimensions yielded optimum results in the two locations, we recommend local analysis of spatial and temporal optima when applying this technique elsewhere. The use of satellite data and in situ water quality measurements provide complementary information, each enhancing understanding of the issues affecting coastal ecosystems, including coral reefs, and the success of management efforts

Volume 06

Introduction from Dean Dr. Charles Ross Caught Between Folklore and the Cold War: The Americanization of Russian Children\u27s Literature by Kristen Gains Graphic Design by Amanda Willis Graphic Design by Holly Backer Prejudices in Swiss German Accents by Monika Gutierrez Photography by Cara O\u27Neal Photography by Sara Nelson Edmund Tyrone\u27s Long Journey through Night by Sasha Silberman Photography by Jessica Beardsley Photography by Jamie Gardner and Edward Peeples The Republican Razor: The Guillotine as a Symbol of Equality by Jamie Clift Graphic Design by Matthew Sakach Genocide: The Lasting Effects of Gender Stratification in Rwanda By Tess Lione and Emily Wilkins Photography by Kelsey Holt and Jessica Page Morocco and the 20 February Movement by Charles Vancampen, Gilbert Hall, Jenny Nehrt, Kasey Dye, Amanda Tharp, Jamie Leeawrik, & Ashley McGee Photography by Emily Poulin Photography by Michael Kropf Improving Performance of Arbitrary Precision Arithmetic Using SIMD Assembly Code Instructions by Nick Pastore Art by Austin Polasky and Morgan Glasco Art by Laura L. Kahler The Effects of the Neutral Response Option on the Extremeness of Participant Responses by Melinda L. Edwards and Brandon C. Smith Graphic Design by Mariah Asbell Graphic Design by Cabell Edmunds College Bullying: An Exploratory Analysis by Amelia D. Perry Photography by Alyssa Hayes Death-Related Crime: Applying Bryant\u27s Conceptual Paradigm of Thanatological Crime to Military Settings by Irina Boothe Graphic Design by Perry Bason Graphic Design by James Earl

Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induces Post-Translational Modifications of AKAP121, DRP1 and OPA1 That Promote Mitochondrial Fission

Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood. Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo. Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing long-chain acyl-CoA synthetase 1 in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate- treated neonatal rat ventricular cardiomyocytes (NRVCs). Palmitate exposure to NRVCs initially activates mitochondrial respiration, coupled with increased mitochondrial membrane potential and adenosine triphosphate (ATP) synthesis. However, long-term exposure to palmitate (\u3e8h) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of A-kinase anchor protein (AKAP121) leading to reduced phosphorylation of DRP1 at Ser637 and altered proteolytic processing of OPA1. Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro. Conclusions: Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy. 38 pp; includes supplemental materials

Buffy coat specimens remain viable as a DNA source for highly multiplexed genome-wide genetic tests after long term storage

<p>Abstract</p> <p>Background</p> <p>Blood specimen collection at an early study visit is often included in observational studies or clinical trials for analysis of secondary outcome biomarkers. A common protocol is to store buffy coat specimens for future DNA isolation and these may remain in frozen storage for many years. It is uncertain if the DNA remains suitable for modern genome wide association (GWA) genotyping.</p> <p>Methods</p> <p>We isolated DNA from 120 Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial buffy coats sampling a range of storage times up to 9 years and other factors that could influence DNA yield. We performed TaqMan SNP and GWA genotyping to test whether the DNA retained integrity for high quality genetic analysis.</p> <p>Results</p> <p>We tested two QIAGEN automated protocols for DNA isolation, preferring the Compromised Blood Protocol despite similar yields. We isolated DNA from all 120 specimens (yield range 1.1-312 ug per 8.5 ml ACD tube of whole blood) with only 3/120 samples yielding < 10 ug DNA. Age of participant at blood draw was negatively associated with yield (mean change -2.1 ug/year). DNA quality was very good based on gel electrophoresis QC, TaqMan genotyping of 6 SNPs (genotyping no-call rate 1.1% in 702 genotypes), and excellent quality GWA genotyping data (maximum per sample genotype missing rate 0.64%).</p> <p>Conclusions</p> <p>When collected as a long term clinical trial or biobank specimen for DNA, buffy coats can be stored for up to 9 years in a -80degC frozen state and still produce high yields of DNA suitable for GWA analysis and other genetic testing.</p> <p>Trial Registration</p> <p>The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is registered with ClinicalTrials.gov, number <a href="http://www.clinicaltrials.gov/ct2/show/NCT00000620">NCT00000620</a>.</p

Global evidence of gender equity in academic health research: a scoping review

Objectives: To chart the global literature on gender equity in academic health research. Design: Scoping review. Participants: Quantitative studies were eligible if they examined gender equity within academic institutions including health researchers. Primary and secondary outcome measures: Outcomes related to equity across gender and other social identities in academia: (1) faculty workforce: representation of all genders in university/faculty departments, academic rank or position and salary; (2) service: teaching obligations and administrative/non-teaching activities; (3) recruitment and hiring data: number of applicants by gender, interviews and new hires for various rank; (4) promotion: opportunities for promotion and time to progress through academic ranks; (5) academic leadership: type of leadership positions, opportunities for leadership promotion or training, opportunities to supervise/mentor and support for leadership bids; (6) scholarly output or productivity: number/type of publications and presentations, position of authorship, number/value of grants or awards and intellectual property ownership; (7) contextual factors of universities; (8) infrastructure; (9) knowledge and technology translation activities; (10) availability of maternity/paternity/parental/family leave; (11) collaboration activities/opportunities for collaboration; (12) qualitative considerations: perceptions around promotion, finances and support. Results: Literature search yielded 94 798 citations; 4753 full-text articles were screened, and 562 studies were included. Most studies originated from North America (462/562, 82.2%). Few studies (27/562, 4.8%) reported race and fewer reported sex/gender (which were used interchangeably in most studies) other than male/female (11/562, 2.0%). Only one study provided data on religion. No other PROGRESS-PLUS variables were reported. A total of 2996 outcomes were reported, with most studies examining academic output (371/562, 66.0%). Conclusions: Reviewed literature suggest a lack in analytic approaches that consider genders beyond the binary categories of man and woman, additional social identities (race, religion, social capital and disability) and an intersectionality lens examining the interconnection of multiple social identities in understanding discrimination and disadvantage. All of these are necessary to tailor strategies that promote gender equity. Trial registration number: Open Science Framework: https://osf.io/8wk7e/

Giving an Account of One’s Pain in the Anthropological Interview

In this paper, I analyze the illness stories narrated by a mother and her 13-year-old son as part of an ethnographic study of child chronic pain sufferers and their families. In examining some of the moral, relational and communicative challenges of giving an account of one’s pain, I focus on what is left out of some accounts of illness and suffering and explore some possible reasons for these elisions. Drawing on recent work by Judith Butler (Giving an Account of Oneself, 2005), I investigate how the pragmatic context of interviews can introduce a form of symbolic violence to narrative accounts. Specifically, I use the term “genre of complaint” to highlight how anthropological research interviews in biomedical settings invoke certain typified forms of suffering that call for the rectification of perceived injustices. Interview narratives articulated in the genre of complaint privilege specific types of pain and suffering and cast others into the background. Giving an account of one’s pain is thus a strategic and selective process, creating interruptions and silences as much as moments of clarity. Therefore, I argue that medical anthropologists ought to attend more closely to the institutional structures and relations that shape the production of illness narratives in interview encounters