A comprehensive welfare scoring system for graft versus host disease clinical assessment in humanised mouse models used for pharmaceutical research

Immuno-oncology drug discovery increasingly relies on humanised mouse models of cancer due to limitations of murine surrogate tools and differences between mouse and human immune systems. Graft-versus-Host Disease (GvHD) is a significant complication following xenogeneic transplantation of human immune cells into mice, limiting their lifespan and impacting the utility of these studies. Existing GvHD scoring systems inadequately capture the disease’s complexity, hampering optimal welfare management and clinical progression monitoring. We propose a comprehensive, practical scoring system for monitoring clinical signs of GvHD in humanised mice. It evaluates seven clinical signs reflecting disease complexity, sums the scores, and categorises overall GvHD severity into four stages, each with specific welfare actions. This refined tool reduces animal suffering through early detection and timely interventions, enabling mice to remain on studies where possible to maximise scientific impact. Our scoring system correlates with histological scores of GvHD-induced tissue damage across multiple organs, with liver and kidney histopathology ranking highly, unlike lung pathology. The system is reproducible among independent experimenters and versatile, effectively applied across multiple types of humanised mouse models and strains. It identifies common clinical signs including weight loss, swelling/reddening of extremities, fur condition, and posture changes, aiding users in distinguishing relevant signs. This system refines and standardises welfare decision-making, supporting the responsibility to minimise suffering when working with humanised mice

Humanity's Last Exam

Benchmarks are important tools for tracking the rapid advancements in large language model (LLM) capabilities. However, benchmarks are not keeping pace in difficulty: LLMs now achieve over 90\% accuracy on popular benchmarks like MMLU, limiting informed measurement of state-of-the-art LLM capabilities. In response, we introduce Humanity's Last Exam (HLE), a multi-modal benchmark at the frontier of human knowledge, designed to be the final closed-ended academic benchmark of its kind with broad subject coverage. HLE consists of 3,000 questions across dozens of subjects, including mathematics, humanities, and the natural sciences. HLE is developed globally by subject-matter experts and consists of multiple-choice and short-answer questions suitable for automated grading. Each question has a known solution that is unambiguous and easily verifiable, but cannot be quickly answered via internet retrieval. State-of-the-art LLMs demonstrate low accuracy and calibration on HLE, highlighting a significant gap between current LLM capabilities and the expert human frontier on closed-ended academic questions. To inform research and policymaking upon a clear understanding of model capabilities, we publicly release HLE at https://lastexam.ai

Humanity's Last Exam

Benchmarks are important tools for tracking the rapid advancements in large language model (LLM) capabilities. However, benchmarks are not keeping pace in difficulty: LLMs now achieve over 90\% accuracy on popular benchmarks like MMLU, limiting informed measurement of state-of-the-art LLM capabilities. In response, we introduce Humanity's Last Exam (HLE), a multi-modal benchmark at the frontier of human knowledge, designed to be the final closed-ended academic benchmark of its kind with broad subject coverage. HLE consists of 3,000 questions across dozens of subjects, including mathematics, humanities, and the natural sciences. HLE is developed globally by subject-matter experts and consists of multiple-choice and short-answer questions suitable for automated grading. Each question has a known solution that is unambiguous and easily verifiable, but cannot be quickly answered via internet retrieval. State-of-the-art LLMs demonstrate low accuracy and calibration on HLE, highlighting a significant gap between current LLM capabilities and the expert human frontier on closed-ended academic questions. To inform research and policymaking upon a clear understanding of model capabilities, we publicly release HLE at https://lastexam.ai

Preventing synaptic deficits in Alzheimer’s disease by inhibiting tumor necrosis factor alpha signaling

The characterization of preclinical stages of Alzheimer’s disease (AD) would provide a therapeutic window for prevention. One of the challenges of developing preventive therapy for AD is to identify early biomarkers for intervention studies. We have recently shown that in the TgCRND8 transgenic AD mouse model, increased hippocampal levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) and enhanced excitatory synaptic transmission were early-onset changes that occurred weeks before amyloid plaque formation. Inhibiting TNFα before plaque formation not only normalized excitatory synaptic function, but also prevented the impairment of synaptic function 4 months later. In this review paper, we will examine the potential contributions of TNFα to the alteration of brain function in preclinical AD. The prospective use of TNFα inhibitors for preventing AD will be discussed. Keywords: Amyloid precursor protein, Hippocampus, Neuroinflammation, Prevention, TgCRND8 mice, Tumor necrosis factor alpha, XPro159

“Dark” student volunteers: commitment, motivation, and leadership

Purpose Drawing from the cognitive evaluation theory, the purpose of this paper is to explore the relationship between student volunteers’ narcissism, Machiavellianism and psychopathy, and commitment to university volunteer programmes through the mediating mechanisms of self-orientation and pro-social motivation. Further, it investigates the roll of servant leadership in mitigating these personality types and encouraging student volunteers to become more pro-socially motivated. Design/methodology/approach The study uses data collected via questionnaire from 156 student volunteers across Australia. Hypothesis testing was conducted using ordinary least squares regression with the path-analytic conditional process modelling (PROCESS) macro for SPSS. Findings The study’s analysis indicated that self-orientated motivation mediated the relationship between narcissism and normative commitment, and pro-social motivation mediated the relationship between both Machiavellianism and psychopathy, and affective commitment. Further, servant leadership was found to moderate the relationship between both Machiavellianism and psychopathy, and pro-social motivation, such that the negative relationship became weaker under a servant leader. These findings suggest that servant leaders play a significant role in encouraging “dark” personalities to see the light. Originality/value This research is the first to examine the use of the Dark Triad in a student volunteering context. It extends the cognitive evaluation theory by revealing that extrinsic (in contrast to intrinsic) motivations are “crowded out” as intrinsic (in contrast to extrinsic) motivations develop within individuals. The study also refines the social learning theory, by examining the influences of “positive” leadership attributes (servant leadership) on “darker” (Dark Triad) personalities. </jats:sec

Increased incidence of spontaneous seizures in laboratory mice in an IVC environment

Over the past decade, there has been an enormous shift away from the use of open top rodent cages to the use of individually ventilated cages (IVCs). This has brought with it many benefits, including better control of health status and minimisation of contamination of immunocompromised animals. At King's College London (KCL), the transfer of mice from open top cages to IVCs has coincided with an apparent increased incidence of spontaneous seizures in mice. The majority of seizures were observed when the cage was opened in a change station and it has therefore been proposed that a significant change in environmental stimuli may contribute to the incidence of seizures. This study aimed to record the incidence of seizures in mice following their transfer to IVCs and investigate the environmental differences between the inside and outside of IVCs, in particular, noise levels. This study highlights the increase in spontaneous seizure incidence in mice in IVCs and the need to investigate the impact of environment on seizures amongst laboratory animals in order to ensure the highest level of animal welfare maintained.</p

Family Structure and Secondary Exposure to Violence in the Context of Varying Neighborhood Risks and Resources

Secondary exposure to violence in the community is a prevalent developmental risk with implications for youths’ short- and long-term socioemotional functioning. This study used longitudinal, multilevel data from the Project on Human Development in Chicago Neighborhoods to consider how family structure, including parental instability, is associated with youths’ secondary exposure to violence across diverse neighborhood contexts. Results showed that both living in a stable single-parent household and experiencing parental instability were associated with greater secondary exposure to violence compared with living in a stable two-parent household. The associations between having a single parent or experiencing parental instability and secondary exposure to violence were especially strong in neighborhoods with high levels of crime and strong neighborhood ties. </jats:p