Pragmatic Selective Waiver: Re-Aligning Corporate Executives\u27 Personal Interests with Those of the Corporation Amidst Government Investigations

In the corporate setting, government investigators increasingly ask corporations to waive the attorney-client privilege as part of the cooperation necessary to receive incentives. In practice, however, these cooperation incentives have led to what has become known as a culture of waiver, where waiver of the privilege in the face of investigation has become virtually essential. One way courts have sought to diminish the negative externalities of waiver is through the doctrine of selective waiver. Selective waiver allows the corporation to waive the attorney-client privilege, but only to the government agency during the course of the investigation, while still retaining the right to assert the privilege against third parties. Thus far, the debate over selective waiver has focused on whether selective waiver should be judicially recognized and how to solve the unsettled nature of the law in the courts. Both the culture of waiver and the uncertainty regarding the selective waiver doctrine\u27s validity have created tension between a corporate executive\u27s personal interests and fiduciary duties. As currently implemented, the selective waiver doctrine may promote a perverse incentive for corporate managers to waive the corporation\u27s attorney-client privilege in order to be deemed cooperative individually and thereby decrease their own personal criminal liability while potentially subjecting the company to extensive third-party liability

Divergence of cAMP Signalling Pathways Mediating Augmented Nucleotide Excision Repair and Pigment Induction in Melanocytes

Loss‐of‐function melanocortin 1 receptor (MC1R) polymorphisms are common in UV‐sensitive fair‐skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV‐blocking eumelanin pigment and by enhancing the repair of UV‐induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP‐activated protein kinase (protein kinase A)‐mediated phosphorylation of the ataxia telangiectasia‐mutated and Rad3‐related (ATR) protein on the S435 residue. We investigated the interdependence of cAMP‐mediated melanin upregulation and cAMP‐enhanced DNA repair in primary human melanocytes and a melanoma cell line. We observed that the ATR‐dependent molecular pathway linking cAMP signalling to the NER pathway is independent of MITF activation. Similarly, cAMP‐mediated upregulation of pigment synthesis is independent of ATR, suggesting that the key molecular events driving MC1R‐mediated enhancement of genome maintenance (eg PKA‐mediated phosphorylation of ATR) and MC1R‐induced pigment induction (eg MITF activation) are distinct

Enhancement of anti-DIII antibodies by the C3d derivative P28 results in lower viral titers and augments protection in mice

Antibodies generated against West Nile virus (WNV) during infection are essential for controlling dissemination. Recent studies have demonstrated that epitopes in all three domains of the flavivirus envelope protein (E) are targets for neutralizing antibodies, with determinants in domain III (DIII) eliciting antibodies with strong inhibitory properties. In order to increase the magnitude and quality of the antibody response against the WNV E protein, DNA vaccines with derivatives of the WNV E gene (full length E, truncated E, or DIII region, some in the context of the pre-membrane [prM] gene) were conjugated to the molecular adjuvant P28. The P28 region of the complement protein C3d is the minimum CR2-binding domain necessary for the adjuvant activity of C3d. Delivery of DNA-based vaccines by gene gun and intramuscular routes stimulated production of IgG antibodies against the WNV DIII region of the E protein. With the exception of the vaccine expressing prM/E given intramuscularly, only mice that received DNA vaccines by gene gun produced protective neutralizing antibody titers (FRNT80 titer >1/40). Correspondingly, mice vaccinated by the gene gun route were protected to a greater level from lethal WNV challenge. In general, mice vaccinated with P28-adjuvated vaccines produced higher IgG titers than mice vaccinated with non-adjuvanted vaccines

A Better Life: Factors that Help and Hinder Entry and Retention in MAT from the Perspective of People in Recovery

Introduction: Opioid addiction and opioid-related overdoses and deaths are serious public health problems nationally and in West Virginia, in particular. Medication-assisted treatment (MAT) is an effective yet underutilized treatment for opioid use disorder (OUD). Purpose: Research examining factors that help individuals succeed in MAT has been conducted from provider and program perspectives, but little research has been conducted from the perspective of those in recovery. Methods: This study, co-developed with individuals in recovery, took place in West Virginia-based MAT programs using an exploratory sequential mixed methods approach. The survey was open February through August 2021. Data were analyzed late 2021 through mid 2022. Results: Respondents experienced many barriers to MAT entry and retention, including community bias / stigma, lack of affordable programming, and lack of transportation. Respondents sought MAT primarily for personal reasons, such as being tired of being sick, and tired of having to look for drugs every day. As one respondent shared, “I wanted to better my life, to get it under control.” Implications: Programs and policies should make it easy for individuals to enter treatment when ready, through affordable and accessible treatment options, reduced barriers to medications, focused outreach and education, individualized care, and reduced stigmatization

Both unmedicated and medicated individuals with schizophrenia show impairments across a wide array of cognitive and reinforcement learning tasks

BACKGROUND: Schizophrenia is a disorder characterized by pervasive deficits in cognitive functioning. However, few well-powered studies have examined the degree to which cognitive performance is impaired even among individuals with schizophrenia not currently on antipsychotic medications using a wide range of cognitive and reinforcement learning measures derived from cognitive neuroscience. Such research is particularly needed in the domain of reinforcement learning, given the central role of dopamine in reinforcement learning, and the potential impact of antipsychotic medications on dopamine function. METHODS: The present study sought to fill this gap by examining healthy controls (N = 75), unmedicated (N = 48) and medicated (N = 148) individuals with schizophrenia. Participants were recruited across five sites as part of the CNTRaCS Consortium to complete tasks assessing processing speed, cognitive control, working memory, verbal learning, relational encoding and retrieval, visual integration and reinforcement learning. RESULTS: Individuals with schizophrenia who were not taking antipsychotic medications, as well as those taking antipsychotic medications, showed pervasive deficits across cognitive domains including reinforcement learning, processing speed, cognitive control, working memory, verbal learning and relational encoding and retrieval. Further, we found that chlorpromazine equivalency rates were significantly related to processing speed and working memory, while there were no significant relationships between anticholinergic load and performance on other tasks. CONCLUSIONS: These findings add to a body of literature suggesting that cognitive deficits are an enduring aspect of schizophrenia, present in those off antipsychotic medications as well as those taking antipsychotic medications

Repurposing dichloroacetate for the treatment of women with endometriosis

Endometriosis is a chronic pain condition affecting ∼176 million women worldwide. It is defined by the presence of endometrium-like tissue (lesions) outside the uterus, most commonly on the pelvic peritoneum. There is no cure for endometriosis. All endometriosis drug approvals to date have been contraceptive, limiting their use in women of child-bearing age. We have shown that human peritoneal mesothelial cells (HPMCs) recovered from the pelvic peritoneum of women with endometriosis exhibit significantly higher glycolysis, lower mitochondrial respiration, decreased enzymatic activity of pyruvate dehydrogenase (PDH), and increased production of lactate compared to HPMCs from women without disease. Transforming growth factor-β1 (TGF-β1) is elevated in the peritoneal fluid from women with endometriosis, and exposure of HPMCs to TGF-β1 exacerbates this abnormal phenotype. Treatment of endometriosis HPMCs with the pyruvate dehydrogenase kinase (PDK) inhibitor/PDH activator dichloroacetate (DCA) normalizes HPMC metabolism, reduces lactate secretion, and abrogates endometrial stromal cell proliferation in a coculture model. Oral DCA reduced peritoneal fluid lactate concentrations and endometriosis lesion size in a mouse model. These findings provide the rationale for targeting metabolic processes as a noncontraceptive treatment for women with endometriosis either as a primary nonhormonal treatment or to prevent recurrence after surgery

word~river literary review (2009)

wordriver is a literary journal dedicated to the poetry, short fiction and creative nonfiction of adjuncts and part-time instructors teaching in our universities, colleges, and community colleges. Our premier issue was published in Spring 2009. We are always looking for work that demonstrates the creativity and craft of adjunct/part-time instructors in English and other disciplines. We reserve first publication rights and onetime anthology publication rights for all work published. We define adjunct instructors as anyone teaching part-time or full-time under a semester or yearly contract, nationwide and in any discipline. Graduate students teaching under part-time contracts during the summer or who have used up their teaching assistant time and are teaching with adjunct contracts for the remainder of their graduate program also are eligible.https://digitalscholarship.unlv.edu/word_river/1002/thumbnail.jp

A novel systems biology approach to evaluate mouse models of late-onset Alzheimer\u27s disease.

BACKGROUND: Late-onset Alzheimer\u27s disease (LOAD) is the most common form of dementia worldwide. To date, animal models of Alzheimer\u27s have focused on rare familial mutations, due to a lack of frank neuropathology from models based on common disease genes. Recent multi-cohort studies of postmortem human brain transcriptomes have identified a set of 30 gene co-expression modules associated with LOAD, providing a molecular catalog of relevant endophenotypes. RESULTS: This resource enables precise gene-based alignment between new animal models and human molecular signatures of disease. Here, we describe a new resource to efficiently screen mouse models for LOAD relevance. A new NanoString nCounter® Mouse AD panel was designed to correlate key human disease processes and pathways with mRNA from mouse brains. Analysis of the 5xFAD mouse, a widely used amyloid pathology model, and three mouse models based on LOAD genetics carrying APOE4 and TREM2*R47H alleles demonstrated overlaps with distinct human AD modules that, in turn, were functionally enriched in key disease-associated pathways. Comprehensive comparison with full transcriptome data from same-sample RNA-Seq showed strong correlation between gene expression changes independent of experimental platform. CONCLUSIONS: Taken together, we show that the nCounter Mouse AD panel offers a rapid, cost-effective and highly reproducible approach to assess disease relevance of potential LOAD mouse models

Neuropathologic assessment of participants in two multi-center longitudinal observational studies: the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN)

It has been hypothesized that the relatively rare autosomal dominant Alzheimer disease (ADAD) may be a useful model of the more frequent, sporadic, late-onset AD (LOAD). Individuals with ADAD have a predictable age at onset and the biomarker profile of ADAD participants in the preclinical stage may be used to predict disease progression and clinical onset. However, the extent to which the pathogenesis and neuropathology of ADAD overlaps with that of LOAD is equivocal. To address this uncertainty, two multicenter longitudinal observational studies, the Alzheimer Disease Neuroimaging Initiative (ADNI) and the Dominantly Inherited Alzheimer Network (DIAN), leveraged the expertise and resources of the existing Knight Alzheimer Disease Research Center (ADRC) at Washington University School of Medicine, St. Louis, Missouri, USA, to establish a Neuropathology Core (NPC). The ADNI/DIAN-NPC is systematically examining the brains of all participants who come to autopsy at the 59 ADNI sites in the USA and Canada and the 14 DIAN sites in the USA (8), Australia (3), UK (1), and Germany (2). By 2014, 41 ADNI and 24 DIAN autopsies (involving 9 participants and 15 family members) had been performed. The autopsy rate in the ADNI cohort in the most recent year was 93% (total since NPC inception: 70%). In summary, the ADNI/DIAN NPC has implemented a standard protocol for all sites to solicit permission for brain autopsy and to send brain tissue to the NPC for a standardized, uniform, and state-of-the-art neuropathologic assessment. The benefit to ADNI and DIAN of the implementation of the NPC is very clear. The NPC provides final ‘gold standard’ neuropathological diagnoses and data against which the antecedent observations and measurements of ADNI and DIAN can be compared