The Study of Au(III) Compounds and their Interaction with Zinc Finger Proteins

Gold compounds have been used in medicine dating back as early as 2500 BC. Over the years gold(I) and gold(III) compounds have been used and designed to target rheumatoid arthritis, cancer, and viral diseases. New drug targets have been found for gold compounds that give insight into their mechanisms of action. Here we focus on the synthesis of Au(III) compounds designed to selectively target zinc finger (ZF) proteins. ZF proteins exhibit a variety of functions, including transcription, DNA repair, and apoptosis. Displacement of the central zinc ion, along with mutation of coordinated amino acids can result in a loss of biological function. Synthesis of complexes that selectively target zinc finger proteins, in turn inhibiting DNA/ZF interactions and therefore resulting in loss of protein function, is of great interest. Of particular interest here is the Cys3His (Cys = cysteine, His = histidine) HIV nucleocapsid zinc finger protein, NCp7. NCp7 is involved in multiple steps of the HIV life cycle, thus making it a desirable drug target. Previous studies from our group show platinated nucleobases such as [Pt(dien)(9-EtG)]2+ (dien = diethylenetriamine; 9-EtG = 9-ethylguanine) to stack effectively in a non-covalent manner with tryptophan of the C-terminal finger of HIV Nucleocapsid, NCp7(F2), a key residue involved in nucleic acid recognition. Due to the isoelectronic and isostructural relationship of Au(III) to Pt(II), we have expanded this system to Au(III)-(nucleobase/N-heterocycle) compounds. Novel Au(III)(dien)(N-heterocycle) compounds, including the first Au(III)N3(N-purine) examples, were synthesized. As previously reported for [AuCl(dien)]Cl2, these compounds exhibit pH dependency of the 1H NMR chemical shifts of the dien ligand. The acidity of the dien ligand is affected by the nature of the fourth ligand as a leaving group. The presence of an inert nitrogen donor, compared to that of the more labile Cl-, as the leaving group stabilizes the Au(III) metal center towards reduction, resulting in significant enhancement of π−π stacking interactions with tryptophan relative to platinum(II) and palladium(II) compounds. The presence of a more inert N-donor as the leaving group slows down the reaction with the sulfur-containing amino acid N-Acetylmethionine (N-AcMet); essentially no reaction was observed for the Au(III)-N-heterocycle compounds. All compounds react readily with N-Acetylcysteine (N-AcCys), however lack of N-heterocycle ligand dissociation indicates, to our knowledge, the first long-lived N-heterocycle-Au-S species in solution. Electrospray ionization mass spectrometry (ESI-MS) studies with NCp7(F2) indicate [Au(dien)(DMAP)]3+ (DMAP = 4-dimethylaminopyridine) to be the least reactive of the Au(III) compounds studied, showing the presence of intact NCp7(F2) zinc finger at initial reaction times. Reactivity of the Au-compounds was compared with that of Sp1(F3), a Cys2His2 ZF; in contrast, no intact ZF was observed for any of the compounds studied, suggesting the mode of action of these compounds is dependent on the nature of the zinc binding core. ESI-MS studies were expanded to that of the full HIV NCp7 zinc finger. [Au(dien)(9-EtG)]3+ reacts quickly with NCp7, resulting in immediate zinc ejection and replacement with up to three gold ions. Unlike with [Au(dien)(DMAP)]3+, no intact NCp7 was observed. Addition of [Au(dien)(9-EtG)]3+ to preformed NC-SL2 complex results in release of free RNA; based on EMSA (electrophoretic mobility shift assay) studies, [Au(dien)(9-EtG)]3+ disrupts the NCp7-RNA complex with an IC50 of ~450 µM. It is possible that this HIV nucleocapsid-nucleic acid antagonism may result in a loss of viral activity

Comparing Intimacies: Race Relations and Racial Inequality in Hookup Culture

Racial inequality extends beyond socioeconomic measures: it shapes social interactions. With the shift in sexual scripts (i.e., the normative means to obtain sex) for young Americans from steady dating toward hooking up, recent scholarship has identified how hookups reveal gender and class inequality. However, research has not yet sufficiently investigated racial inequality. Because hookups are by their nature non-committal, they have arguably fewer barriers (e.g., disapproval by family) than more committed relationships. While this indicates that hooking up is a personal choice, broader research suggests that race/ethnicity and gender intersect in ways shaping participation in hookup culture and the interactions across racial lines. This three article dissertation explores how race/ethnicity and gender structure the opportunities to hook up and social distance between racial groups. Using data from the Online College Social Life Survey (n = 18,347), this dissertation identifies racial/ethnic differences within gender in participation in hookup culture. While Asian men and non-White women are less likely to participate, they are more likely to desire opportunities to hook up suggesting that they are excluded from hookup culture rather than opting-out. Rates of interracial hookups additionally suggest that non-White students are less likely to hook up with a partner of another race/ethnicity than are White students so they have fewer potential partners. Social distance is further revealed by two measures of interaction. Women who report interracial hookups are less likely than those who report same-race hookups to be familiar with their partner before the hookup, and men in interracial hookups are less likely to communicate after the hookup. Survey findings are supplemented with self-collected interview and focus group data (n = 69), which reveal how minority students feel vulnerable to negative social consequences because of their small group size. Additionally, they are more likely to feel ignored or sexualized by other racial/ethnic groups than are White students. Overall, minority students have fewer opportunities to hook up, especially outside their race. This dissertation builds on extant research detailing how racial inequality shapes the college experience by revealing the opportunity structure of hookup culture and that interracial hookups reflect and reinforce social distance

Marriage as a Mechanism: Women’s Education and Wealth in Malawi

Research has found that in the United States women have greater economic returns to a college degree than men, because of more stable marriages and other family income. Using cross-sectional data of women aged 19-40 years in Malawi from the Malawi Longitudinal Study of Families and Health (n = 898), we test whether higher education is associated with these same benefits in a context with lower educational attainment levels, fewer job opportunities, and different marriage patterns. We find that better educated women are more likely to have better educated spouses and higher household wealth. Though divorce is negatively associated with wealth, we do not find an association between education and divorce. This analysis provides motivation for further research on the how education is associated with outcomes for women in developing countries

Spatially heterogeneous argon-isotope systematics and apparent ⁴⁰Ar/³⁹Ar ages in perlitised obsidian

In situ laser ablation Ar-isotope analyses of variably hydrated and devitrified obsidian from the ~ 27 Ma Cochetopa Dome, San Juan, USA, reveal complex interplay between degassing of initial Ar and absorption of atmospheric Ar. These processes have locally modified the Ar-isotope composition of the obsidian and led to spurious, spatially-heterogeneous Ar-isotope and 40Ar/39Ar age data. Small perlite beads exhibit older apparent Ar-ages at the rims than the cores. This is interpreted as an apparent excess of 40Ar at the rims, produced either by a) diffusion of excess 40Ar into the bead during flushing of the lava with excess 40Ar-bearing volcanic gas, or by b) isotopic fractionation during degassing of initial Ar, causing preferential loss of 36Ar over 40Ar at the bead rims. The second interpretation is favoured by a relative enrichment of 36Ar in the core of a perlite bead along a microlite-free (poorly degassed) flow band, and by a lack of age variation in a larger, fresh, well-degassed perlite bead. These isotopic gradients were later overprinted during glass hydration by absorption of Ar with near-atmospheric composition, resulting in elevated 36Ar and reduced radiogenic 40Ar* yields at the rims of perlite beads. These complex interactions essentially represent the mixing of three distinct Ar reservoirs: initial trapped Ar that may or may not be fractionated, an isotopically atmospheric Ar component introduced during hydration, and radiogenic 40Ar*. Such reservoir mixing is the underlying reason for poor correlations on isotope correlation diagrams and the difficulties in validating the composition of the non-radiogenic Ar component. We thus suggest that high 36Ar yields are a combination of the incomplete degassing of initial (possibly magmatic) Ar and the gain of Ar during interaction between the obsidian and meteoric/atmospheric fluids. Our analyses emphasise the challenging nature of 40Ar/39Ar dating obsidian samples, but also point to possible solutions by careful sample characterisation and selection of highly degassed samples

Parental experiences of supporting children with clinically significant post-traumatic distress: a qualitative study of families accessing psychological services

The aim of this study was to investigate the experiences of parents in providing support to their child following trauma exposure in cases where children are experiencing clinically significant levels of post-traumatic distress. Qualitative interviews were conducted with parents whose child was exposed to a trauma and referred for psychological treatment. Parents reported considerable anxiety in coping with their child’s post-traumatic distress. Avoidance of trauma-related discussions was encouraged due to concerns that non-avoidant approaches may worsen children’s post-trauma difficulties. Nonetheless, parents were often sensitive to their child’s distress and offered reassurance and other forms of support. Many barriers existed to accessing psychological treatment, and perceptions of inadequate guidance from therapists on supporting child adjustment contributed to parental distress. The results illustrate the strategies used by parents in supporting their child post-trauma and may assist mental health professionals in providing acceptable guidance to parents following child trauma

[Au(dien)(N-heterocycle)]³⁺: Reactivity with Biomolecules and Zinc Finger Peptides

The reaction of [Au­(dien)­(N-heterocycle)]³⁺ (AuN₄) coordination compounds with simple amino acids and zinc finger proteins is reported. Compared to [AuCl­(dien)]²⁺, NMR studies show that the presence of a more substitution-inert N-donor as the putative leaving group slows the reaction with the sulfur-containing amino acids <i>N</i>-acetylmethionine (NAcMet) and <i>N</i>-acetylcysteine (NAcCys). Lack of ligand dissociation upon reaction with NAcCys indicates, to our knowledge, the first long-lived N-heterocycle–Au–S species in solution. Reactions with zinc finger proteins show a higher reactivity with the Cys₃His zinc finger than with Cys₂His₂, likely due to the presence of fewer aurophilic cysteines in the latter. Of the Au­(III) compounds studied, [Au­(dien)­(DMAP)]³⁺ (DMAP = 4-dimethylaminopyridine) appears to be the least reactive, with ESI-MS studies showing the presence of intact zinc fingers at initial reaction times. These results, in combination with previously reported characterization and pH dependency studies, will further aid in optimizing the structure of these AuN₄ species to obtain a substitution-reactive yet selective compound for targeting zinc finger proteins

Broadband technologies : a primer on access and solutions

"Access to high-speed internet, or broadband, encourages equitable distance-learning, remote-work, quality-of-life and entrepreneurial opportunities. Te COVID-19 pandemic not only reinforced but also elevated the importance of household access to high-speed internet. Tis primer provides background information about current issues related to broadband access -- both availability and adoption. It defnes often-used broadband terminology, discusses the pros and cons of diferent broadband technologies and illustrates broadband availability and adoption levels across Missouri and the U.S. It concludes by outlining next steps communities can take to enhance broadband availability and adoption in their regions."--First page.Written by: Sarah A. Low (Exceed Director and Associate Professor); Catherine Isley (Exceed Graduate Research Assistant); Alan Spell (Exceed Assistant Extension Professor); Matt Kures (Community Development Specialist, University of Wisconsin); Tessa Conroy (Assistant Professor, University of Wisconsin); Steve Deller (Professor, University of Wisconsin)New 6/2021Includes bibliographical reference

Dinner and a Conversation: Transgender Integration at West Point and Beyond

In 2016, the United States military lifted the ban on transgender members serving and are expected to begin accessions of transgender service members in 2017. A paucity of research exists on transgender matters in the military, especially on attitudes towards cisgender service members. This study deploys a qualitative methodology, comprised of 21 focus groups of undergraduate cadets and advanced schooled Army officers (N = 110), at the United States Military Academy at West Point, New York, using a semi-structured interview protocol. Overall, a diversity of experiences and familiarity with transgender people surfaced among cadets and officers. We distinguish between experiences and familiarity on a spectrum by introducing notions of transgender tourism and cosmopolitanism. Major concerns associated with (un)comfortableness emerged from the focus groups including privacy, physical standards, well-being, and costs. Interventions are offered by the participants based on their major concerns. We recommend education, increased cosmopolitism, privacy considerations, narrowing the civil-military propinquity gap, and more studies of diversity and inclusion issues in the military