An Interview with Mark Earley

...in America, unless each generation has a recommitment to fundamental principles of freedom and liberty, we can lose what we have in a generation. And so I decided I wanted to be a part in my generation of trying to rekindle a passion and a commitment to those first freedoms that laid the foundation for America to be a great nation. So I wanted to go to law school and change the world. ------------------------------------ In this oral history, dated April 5, 2024, William & Mary Law alum Mark Earley, Sr. gives us an overview of his lengthy legal and political career, including snippets of his time in the Virginia State Senate and his former position as Attorney General of Virginia. He shares stories from his childhood, undergraduate years at William & Mary, and time working at a ministry in the Philippines prior to law school. We learn about how the composition of the Virginia State Senate shifted from 1988 until he left in 2001 and what the process of appointing a judge looks like in Virginia. Mark explains why his philosophy on the death penalty and tough-on-crime initiatives shifted from full support during his years as AG to outspoken opposition today. We also hear a touching story about the lasting connection he made with a Richmond elementary schooler through a mentorship lunch program for at-risk youth.https://scholarship.law.wm.edu/oralhist_all/1012/thumbnail.jp

The neuropsychological effects of pituitary macroadenomas and their treatment

Pituitary adenomas account for roughly 12% of all intracranial tumours and are treated either surgically or medically. Due to the prevalence, there have been many articles focusing on their treatment. Recently, a few studies have been published suggesting a link between pituitary tumours, their treatment and cognitive dysfunction. These articles challenge the texts put forward to date, texts that demarcate adenoma treatment effects to the realm of the physicaL The mechanism(s) behind these supposed deficits have not yet been identified, largely because of problematic research designs and sampling. In the South African context, practitioners tend to encounter a greater proportion of macroadenomas than developed countries. Working on the assumption that the effects of adenomas are magnified in macroadenoma patients, the South African situation provides a base of extreme cases in which any potential dysfunction has the best chance to declare itself. This is particularly valuable given the controversy surrounding the presence of these cognitive deficits

Predicting adherence to antiretroviral therapy and retention to HIV care : effects of baseline biopsychosocial status and neuropsychological functioning

These drugs have demonstrated efficacy in improving immune function and reducing HIV-related morbidity and mortality, and while a cure is not available, patients on treatment may live longer, healthier lives. However, early optimism has been tempered by the growing recognition that meticulous adherence is a prerequisite for optimal clinical response and prevention of drug resistance

In Vitro Osteogenic Performance of Two Novel Strontium and Zinc-Containing Glass Polyalkenoate Cements

Glass polyalkenoate cements (GPCs) are under investigation as potential bone adhesives, as they may provide an alternative to polymethylmethacrylate-based cements. GPCs containing strontium (Sr) and zinc (Zn) in place of aluminum (Al) are of particular interest because these ions are known stimulators of osteoprogenitor differentiation. GPCs have been manufactured from a novel bioactive glass (SiO2:0.48, ZnO:0.36, CaO:0.12, SrO:0.04) in the past, but, while such materials have been assessed for their influence on viability, their influence on osteogenic function has not been investigated until now. For this study, two GPCs were formulated from the same glass precursor evaluated in previous studies. These GPCs were named GPC A and GPC B, and they differed in glass particle size, polyacrylic acid molecular weight, and their powder: liquid ratios. The effect of these two GPCs on osteogenic differentiation of primary rat osteoblasts were evaluated using three culture systems: culture with dissolution extracts, indirect contact with trans well-inserts and direct contact. Additionally, the degradation characteristics of GPCs were assessed, including their interfacial pH and surrounding pH. The experimental outcomes revealed that collagen deposition, alkaline phosphatase expression, and mineralization were largely dependent on GPC composition as well as the mode of interaction with cells. These markers were found to be significantly elevated in response to GPC A\u27s dissolution products. However, osteogenic differentiation was inhibited when osteoblasts were cultured indirectly and directly with GPCs, with, overall, GPC B significantly outperforming GPC A. These results suggest that GPC degradation products effect osteogenic differentiation in a dose-dependent manner

A Review of the Latest Insights into the Mechanism of Action of Strontium in Bone

Interest in strontium (Sr) has persisted over the last three decades due to its unique mechanism of action: it simultaneously promotes osteoblast function and inhibits osteoclast function. While this mechanism of action is strongly supported by in vitro studies and small animal trials, recent large-scale clinical trials have demonstrated that orally administered strontium ranelate (SrRan) may have no anabolic effect on bone formation in humans. Yet, there is a strong correlation between Sr accumulation in bone and reduced fracture risk in post-menopausal women, suggesting Sr acts via a purely physiochemical mechanism to enhance bone strength. Conversely, the local administration of Sr with the use of modified biomaterials has been shown to enhance bone growth, osseointegration and bone healing at the bone-implant interface, to a greater degree than Sr-free materials. This review summarizes current knowledge of the main cellular and physiochemical mechanisms that underly Sr\u27s effect in bone, which center around Sr\u27s similarity to calcium (Ca). We will also summarize the main controversies in Sr research which cast doubt on the \u27dual-acting mechanism\u27. Lastly, we will explore the effects of Sr-modified bone-implant materials both in vitro and in vivo, examining whether Sr may act via an alternate mechanism when administered locally

Comparative biochemical analysis of recombinant reverse transcriptase enzymes of HIV-1 subtype B and subtype C

<p>Abstract</p> <p>Background</p> <p>HIV-1 subtype C infections account for over half of global HIV infections, yet the vast focus of HIV-1 research has been on subtype B viruses which represent less than 12% of the global pandemic. Since HIV-1 reverse transcriptase (RT) is a major target of antiviral therapy, and since differential drug resistance pathways have been observed among different HIV subtypes, it is important to study and compare the enzymatic activities of HIV-1 RT derived from each of subtypes B and C as well as to determine the susceptibilities of these enzymes to various RT inhibitors in biochemical assays.</p> <p>Methods</p> <p>Recombinant subtype B and C HIV-1 RTs in heterodimeric form were purified from <it>Escherichia coli </it>and enzyme activities were compared in cell-free assays. The efficiency of (-) ssDNA synthesis was measured using gel-based assays with HIV-1 PBS RNA template and tRNA₃^Lysas primer. Processivity was assayed under single-cycle conditions using both homopolymeric and heteropolymeric RNA templates. Intrinsic RNase H activity was compared using 5'-end labeled RNA template annealed to 3'-end recessed DNA primer in a time course study in the presence and absence of a heparin trap. A mis-incorporation assay was used to assess the fidelity of the two RT enzymes. Drug susceptibility assays were performed both in cell-free assays using recombinant enzymes and in cell culture phenotyping assays.</p> <p>Results</p> <p>The comparative biochemical analyses of recombinant subtype B and subtype C HIV-1 reverse transcriptase indicate that the two enzymes are very similar biochemically in efficiency of tRNA-primed (-) ssDNA synthesis, processivity, fidelity and RNase H activity, and that both enzymes show similar susceptibilities to commonly used NRTIs and NNRTIs. Cell culture phenotyping assays confirmed these results.</p> <p>Conclusions</p> <p>Overall enzyme activity and drug susceptibility of HIV-1 subtype C RT are comparable to those of subtype B RT. The use of RT inhibitors (RTIs) against these two HIV-1 enzymes should have comparable effects.</p

Comparative Evaluation of Two Glass Polyalkenoate Cements: An in Vivo Pilot Study using a Sheep Model

Poly(methyl methacrylate) (PMMA) is used to manage bone loss in revision total knee arthroplasty (rTKA). However, the application of PMMA has been associated with complications such as volumetric shrinkage, necrosis, wear debris, and loosening. Glass polyalkenoate cements (GPCs) have potential bone cementation applications. Unlike PMMA, GPC does not undergo volumetric shrinkage, adheres chemically to bone, and does not undergo an exothermic setting reaction. In this study, two different compositions of GPCs (GPCA and GPCB), based on the patented glass system SiO2-CaO-SrO-P2O5-Ta2O5, were investigated. Working and setting times, pH, ion release, compressive strength, and cytotoxicity of each composition were assessed, and based on the results of these tests, three sets of samples from GPCA were implanted into the distal femur and proximal tibia of three sheep (alongside PMMA as control). Clinical CT scans and micro-CT images obtained at 0, 6, and 12 weeks revealed the varied radiological responses of sheep bone to GPCA. One GPCA sample (implanted in the sheep for 12 weeks) was characterized with no bone resorption. Furthermore, a continuous bone–cement interface was observed in the CT images of this sample. The other implanted GPCA showed a thin radiolucent border at six weeks, indicating some bone resorption occurred. The third sample showed extensive bone resorption at both six and 12 weeks. Possible speculative factors that might be involved in the varied response can be: excessive Zn2+ ion release, low pH, mixing variability, and difficulty in inserting the samples into different parts of the sheep bone

Enhancing dopamine tone modulates global and local cortical perfusion as a function of COMT Val158Met genotype

The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone

The Oceanus Moving Group: A New 500 Myr-Old Host for the Nearest Brown Dwarf

We report the discovery of the Oceanus moving group, a $\approx$ 500 Myr-old group with 50 members and candidate members at distances 2-50 pc from the Sun using an unsupervised clustering analysis of nearby stars with Gaia DR3 data. This new moving group includes the nearest brown dwarf WISE J104915.57-531906.1 AB (Luhman 16 AB) at a distance of 2 pc, which was previously suspected to be young (600-800 Myr) based on a comparison of its dynamical mass measurements with brown dwarf evolutionary models. We use empirical color-magnitude sequences, stellar activity and gyrochronology to determine that this new group is roughly coeval with the Coma Ber open cluster, with an isochronal age of 510 $\pm$ 95 Myr. This newly discovered group will be useful to refine the age and chemical composition of Luhman 16 AB, which is already one of the best substellar benchmarks known to date. Furthermore, the Oceanus moving group is one of the nearest young moving groups identified to date, making it a valuable laboratory for the study of exoplanets and substellar members, with 8 brown dwarf candidate members already identified here.Comment: Submitted to ApJ, first revision. 32 pages, 6 figures, 6 table

Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor κB (NF-κB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-κB–induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced α-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications