Exercise Blocks Ethanol-Induced Kappa Opioid Receptor Sensitization in Nucleus Accumbens and Ventral Tegmental Area

Exercise has been increasingly used as an adjunctive therapy in the treatment of alcohol use disorder (AUD). Despite this, the mechanism by which it influences the mesolimbic circuitry changes underlying alcohol addiction is not well understood. Previous studies have shown alcohol dependence to lead to upregulation of the Dynorphin-Kappa Opioid Receptor (KOR) system, making it a potential target for therapeutics. Thus, gaining a better understanding of these pathways will help develop evidence-based guidelines for integrating exercise into therapies for the treatment of AUD

Propanil Exposure Induces Delayed but Sustained Abrogation of Cell-Mediated Immunity through Direct Interference with Cytotoxic T-Lymphocyte Effectors

The postemergent herbicide propanil (PRN; also known as 3,4-dichloropropionanilide) is used on rice and wheat crops and has well-known immunotoxic effects on various compartments of the immune system, including T-helper lymphocytes, B lymphocytes, and macrophages. It is unclear, however, whether PRN also adversely affects cytotoxic T lymphocytes (CTLs), the primary (1°) effectors of cell-mediated immunity. In this study we examined both the direct and indirect effects of PRN exposure on CTL activation and effector cell function to gauge its likely impact on cell-mediated immunity. Initial experiments addressed whether PRN alters the class I major histocompatibility complex (MHC) pathway for antigen processing and presentation by antigen-presenting cells (APCs), thereby indirectly affecting effector function. These experiments demonstrated that PRN does not impair the activation of CTLs by PRN-treated APCs. Subsequent experiments addressed whether PRN treatment of CTLs directly inhibits their activation and revealed that 1° alloreactive CTLs exposed to PRN are unimpaired in their proliferative response and only marginally inhibited in their lytic activity. Surprisingly, secondary stimulation of these alloreactive CTL effectors, however, even in the absence of further PRN exposure, resulted in complete abrogation of CTL lytic function and a delayed but significant long-term effect on CTL responsiveness. These findings may have important implications for the diagnosis and clinical management of anomalies of cell-mediated immunity resulting from environmental exposure to various herbicides and other pesticides

Report of the 1st Workshop on Generative AI and Law

This report presents the takeaways of the inaugural Workshop on Generative AI and Law (GenLaw), held in July 2023. A cross-disciplinary group of practitioners and scholars from computer science and law convened to discuss the technical, doctrinal, and policy challenges presented by law for Generative AI, and by Generative AI for law, with an emphasis on U.S. law in particular. We begin the report with a high-level statement about why Generative AI is both immensely significant and immensely challenging for law. To meet these challenges, we conclude that there is an essential need for 1) a shared knowledge base that provides a common conceptual language for experts across disciplines; 2) clarification of the distinctive technical capabilities of generative-AI systems, as compared and contrasted to other computer and AI systems; 3) a logical taxonomy of the legal issues these systems raise; and, 4) a concrete research agenda to promote collaboration and knowledge-sharing on emerging issues at the intersection of Generative AI and law. In this report, we synthesize the key takeaways from the GenLaw workshop that begin to address these needs. All of the listed authors contributed to the workshop upon which this report is based, but they and their organizations do not necessarily endorse all of the specific claims in this report

Frequent capsule switching in 'ultra-virulent' meningococci - Are we ready for a serogroup B ST-11 complex outbreak?

The meningococcal ST-11 complex (cc11) causes large invasive disease outbreaks with high case fatality rates, such as serogroup C (MenC) epidemics in industrialised nations in the 1990s and the serogroup W epidemic currently expanding globally. Glycoconjugate vaccines are available for serogroups A, C, W and Y. Broad coverage protein-based vaccines have recently been licensed against serogroup B meningococci (MenB), however, these do not afford universal MenB protection. Capsular switching from MenC to MenB among cc11 organisms is concerning because a large MenB cc11 (B:cc11) outbreak has the potential to cause significant morbidity and mortality. This study aimed to assess the potential for licensed and developmental non-capsular meningococcal vaccines to protect against B:cc11. The population structure and vaccine antigen distribution was determined for a panel of >800 geo-temporally diverse, predominantly MenC cc11 and B:cc11 genomes. The two licensed vaccines potentially protect against many but not all B:cc11 meningococci. Furthermore, strain coverage by these vaccines is often due to a single vaccine antigen and both vaccines are highly susceptible to vaccine escape owing to the apparent dispensability of key proteins used as vaccine antigens. cc11 strains with MenB and MenC capsules warrant special consideration when formulating future non-capsular meningococcal vaccines

Conserved Genes Act as Modifiers of Invertebrate SMN Loss of Function Defects

Spinal Muscular Atrophy (SMA) is caused by diminished function of the Survival of Motor Neuron (SMN) protein, but the molecular pathways critical for SMA pathology remain elusive. We have used genetic approaches in invertebrate models to identify conserved SMN loss of function modifier genes. Drosophila melanogaster and Caenorhabditis elegans each have a single gene encoding a protein orthologous to human SMN; diminished function of these invertebrate genes causes lethality and neuromuscular defects. To find genes that modulate SMN function defects across species, two approaches were used. First, a genome-wide RNAi screen for C. elegans SMN modifier genes was undertaken, yielding four genes. Second, we tested the conservation of modifier gene function across species; genes identified in one invertebrate model were tested for function in the other invertebrate model. Drosophila orthologs of two genes, which were identified originally in C. elegans, modified Drosophila SMN loss of function defects. C. elegans orthologs of twelve genes, which were originally identified in a previous Drosophila screen, modified C. elegans SMN loss of function defects. Bioinformatic analysis of the conserved, cross-species, modifier genes suggests that conserved cellular pathways, specifically endocytosis and mRNA regulation, act as critical genetic modifiers of SMN loss of function defects across species

Preventing the diversion of Turkish opium

Turkey was once one of the world’s largest sources of illicit opium; the majority diverted from sparsely regulated licit production. Since 1972, however, it has contributed almost no opium to the global black market. As such, Turkey is one of a small number of states to have eradicated, or severally reduced, the national supply of illicit opium. This article reconsiders post-1974 Turkish controls from a situational crime prevention perspective. It is suggested that Turkish success was founded upon reducing opportunities for diversion from regulated production by hardening targets, increasing formal and informal surveillance, assisting compliance through fair procurement practices and increasing the risk of non-compliance

The Compoti of the Bursars of Whalley Abbey, Lancashire, 1508-1536

The purpose of this study is to investigate the condition of early sixteenth-oentury monasticism in England as it appears from the evidence in the financial accounts of the bursars of Whalley Abbey. The Whalley Abbey compoti provide a particularly fruitful field of study since a rather considerable body of documents from this Cistercian monastery have been preserved and a large number of these documents have already been published