Carlisle Memorial Volume

Table of Contents: The Carlisle Family Life Sketch of Dr. Carlisle - by Dr. Charles Forster Smith Dr. Carlisle as a Citizen - by Watson B. Duncan The Wofford Chapel Hour - by Dr. Henry Nelson Snyder Wofford College and its President Twenty Years Ago - by Dr. Robert A. Law Dr. Carlisle as a Teacher - by Dr. David Duncan Wallace Tributes to Dr. Carlislehttps://digitalcommons.wofford.edu/collegebooks/1005/thumbnail.jp

Investigation of a transgenic model of Alzheimer's disease, the TASTPM mouse, using magnetic resonance spectroscopy and matrix assisted laser desorption imaging

There is currently no definitive biomarker for Alzheimer's Disease (AD), confirmation of diagnosis is only possible post-mortem. Magnetic resonance spectroscopy (MRS) has potential in aiding diagnosis, an MRS scan can be performed during an MRI scan, only adding around 10 minutes to scan time. Use of data from the two scans may allow more accurate diagnosis of AD. This thesis investigates a transgenic mouse model of AD, the TASTPM mouse, using in vitro and in vivo MRS as well as matrix assisted laser desorption ionisation mass spectrometry imaging (MALDI MS Imaging). The first aim of the study was to search for a biomarker of AD that may allow better diagnosis or further our understanding of the pathology of the disease. The second aim was to evaluate the TASTPM mouse as a model of AD for use in preclinical testing of amyloid lowering agents. The third aim was to investigate a thalamic pathology in the TASTPM mice using MALDI MS Imaging. Metabolically, we found differences between the brains of TASTPM mice and their wild type base strain in both in vitro and in vivo scans. These differences may be exploited in the preclinical testing of novel amyloid lowering therapies. We also found similarities with human AD and other mouse models, lower N-acetylaspartate, lower glutamate and higher myo-inositol are all observed in human AD, as well as the TASTPM mice in vivo. We also found further evidence of impaired neuronal energy metabolism in TASTPM mice, such as lower succinate. Cerebral hypometabolism is a symptom of human AD. The TASTPM mouse seems to be a fairly good approximation of the human disease, sharing several traits. In our investigation of the thalamic pathology, we discovered a peptide which was strongly localised to the regions of the pathology and isolated it, but were unable to identify it, the work in this area will continue.EThOS - Electronic Theses Online ServiceGlaxoSmithKlineGBUnited Kingdo

Radiation-induced neuroinflammation:a potential protective role for poly(ADP-ribose) polymerase inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity

Development and validation of a risk score (Delay-7) to predict the occurrence of a treatment delay following cycle 1 chemotherapy

BACKGROUND: The risk of toxicity-related dose delays, with cancer treatment, should be included as part of pretreatment education and be considered by clinicians upon prescribing chemotherapy. An objective measure of individual risk could influence clinical decisions, such as escalation of standard supportive care and stratification of some patients, to receive proactive toxicity monitoring. PATIENTS AND METHODS: We developed a logistic regression prediction model (Delay-7) to assess the overall risk of a chemotherapy dose delay of 7 days for patients receiving first-line treatments for breast, colorectal and diffuse large B-cell lymphoma. Delay-7 included hospital treated, age at the start of chemotherapy, gender, ethnicity, body mass index, cancer diagnosis, chemotherapy regimen, colony stimulating factor use, first cycle dose modifications and baseline blood values. Baseline blood values included neutrophils, platelets, haemoglobin, creatinine and bilirubin. Shrinkage was used to adjust for overoptimism of predictor effects. For internal validation (of the full models in the development data) we computed the ability of the models to discriminate between those with and without poor outcomes (c-statistic), and the agreement between predicted and observed risk (calibration slope). Net benefit was used to understand the risk thresholds where the model would perform better than the ‘treat all’ or ‘treat none’ strategies. RESULTS: A total of 4604 patients were included in our study of whom 628 (13.6%) incurred a 7-day delay to the second cycle of chemotherapy. Delay-7 showed good discrimination and calibration, with c-statistic of 0.68 (95% confidence interval 0.66-0.7), following internal validation and calibration-in-the-large of −0.006. CONCLUSIONS: Delay-7 predicts a patient’s individualised risk of a treatment-related delay at cycle two of treatment. The score can be used to stratify interventions to reduce the occurrence of treatment-related toxicity

To Transformers and Beyond: Large Language Models for the Genome

In the rapidly evolving landscape of genomics, deep learning has emerged as a useful tool for tackling complex computational challenges. This review focuses on the transformative role of Large Language Models (LLMs), which are mostly based on the transformer architecture, in genomics. Building on the foundation of traditional convolutional neural networks and recurrent neural networks, we explore both the strengths and limitations of transformers and other LLMs for genomics. Additionally, we contemplate the future of genomic modeling beyond the transformer architecture based on current trends in research. The paper aims to serve as a guide for computational biologists and computer scientists interested in LLMs for genomic data. We hope the paper can also serve as an educational introduction and discussion for biologists to a fundamental shift in how we will be analyzing genomic data in the future

Moderate threat causes longer lasting disruption to processing in anxious individuals

Anxiety is associated with increased attentional capture by threat. Previous studies have used simultaneous or briefly separated (<1 s) presentation of threat distractors and target stimuli. Here, we tested the hypothesis that high trait anxious participants would show a longer time window within which distractors cause disruption to subsequent task processing, and that this would particularly be observed for stimuli of moderate or ambiguous threat value. A novel temporally separated emotional distractor task was used. Face or house distractors were presented for 250 ms at short (∼1.6 s) or long (∼3 s) intervals prior to a letter string comprising Xs or Ns. Trait anxiety was associated with slowed identification of letter strings presented at long intervals after face distractors with part surprise/part fear expressions. In other words, these distractors had an impact on high anxious individuals' speed of target identification seconds after their offset. This was associated with increased activity in the fusiform gyrus and amygdala and reduced dorsal anterior cingulate recruitment. This pattern of activity may reflect impoverished recruitment of reactive control mechanisms to damp down stimulus-specific processing in subcortical and higher visual regions. These findings have implications for understanding how threat-related attentional biases in anxiety may lead to dysfunction in everyday settings where stimuli of moderate, potentially ambiguous, threat value such as those used here are fairly common, and where attentional disruption lasting several seconds may have a profound impact

Development and evaluation of tools and an intervention to improve patient- and carer-centred outcomes in Longer-Term Stroke care and exploration of adjustment post stroke: the LoTS care research programme

Background: Evidence-based care pathways are required to support stroke patients and their carers in the longer term. Aims: The twofold aim of this programme of four interlinking projects was to enhance the care of stroke survivors and their carers in the first year after stroke and gain insights into the process of adjustment. Methods and results: We updated and further refined a purposely developed system of care (project 1) predicated on a patient-centred structured assessment designed to address areas of importance to patients and carers. The structured assessment is linked to evidence-based treatment algorithms, which we updated using a structured protocol: reviewing available guidelines, Cochrane reviews and randomised trials. A pragmatic cluster randomised controlled trial evaluation of the clinical effectiveness and cost-effectiveness of this system of care was undertaken in 29 community-based UK stroke care co-ordinator services (project 2). In total, 15 services provided the system of care and 14 continued with usual practice. The primary objective was to determine whether the intervention improved patient psychological outcomes (General Health Questionnaire-12) at 6 months; secondary objectives included functional outcomes for patients, outcomes for carers and cost-effectiveness, as measured through self-completed postal questionnaires at 6 and 12 months. A total of 800 patients and 208 carers were recruited; numbers of participants and their baseline characteristics were well balanced between intervention and control services. There was no evidence of statistically significant differences in primary or secondary end points or adverse events between the two groups, nor evidence of cost-effectiveness. Intervention compliance was high, indicating that this is an appropriate approach to implement evidence into clinical practice. A 22-item Longer-term Unmet Needs after Stroke (LUNS) questionnaire was developed and robustly tested (project 3). A pack including the LUNS questionnaire and outcome assessments of mood and social activity was posted to participants 3 or 6 months after stroke to assess acceptability and validity. The LUNS questionnaire was re-sent 1 week after return of the first pack to assess test–retest reliability. In total, 850 patients were recruited and the acceptability, validity and test–retest reliability of the LUNS questionnaire as a screening tool for post-stroke unmet need were confirmed. This tool is now available for clinical use. An in-depth qualitative investigation was undertaken with 22 patients (and carers) at least 1 year after stroke (project 4) to gain further insights into the experience of adjustment. This included initial semistructured interviews, limited observations and solicited diaries with a follow-up interview 3–4 months after the initial interview and highlighted a range of different trajectories for post-stroke recovery. Conclusions: The programme has been completed as planned, including one of the largest ever stroke rehabilitation trials. This work highlights that successfully addressing the needs of a heterogeneous post-stroke population remains problematic. Future work could explore stratifying patients and targeting services towards patients (and carers) with specific needs, leading to a more specialised bespoke service. The newly developed LUNS questionnaire and the qualitative work will help inform such services

High Affinity “Click” RGD Peptidomimetics as Radiolabeled Probes for Imaging αvβ3 Integrin

We thank The Development Trust, University of Aberdeen, for financial support and a fellowship to M.P. The work was also supported by the CRUK-EPSRC Cancer Imaging Centre in Cambridge and Manchester (KJW Co-I; reference 16465). We thank Dr Massimiliano Baldassarre (University of Aberdeen) for helpful discussions.Peer reviewedPostprin

Processes of Participation in the Development of Urban Food Strategies: A Comparative Assessment of Exeter and Eindhoven

Urban food strategies are increasingly being used as means to address a multitude of challenges presented by food system failings. The use of participatory approaches has become common practice in the field of urban food systems planning. These approaches are believed to democratize, legitimize and increase effectiveness of addressing challenges. Despite these “promises”, they have also been viewed as problematic for being unbalanced and lacking accountability. This paper sets out to compare the creation and use of new participatory spaces in two initiatives in two European cities in their on-going attempts to formulate urban food strategies through multi-actor processes. This is explored through operationalisation of two key concepts essential to participatory approaches: participation and accountability. As such, the paper addresses how participatory processes for urban food strategies can be conceptualised when policy making involves the interplay of actors, knowledges and spaces. We conclude that within the two cases, ample attention is given to get a cross-section of the types of participants involved, while accountability is an aspect still under-represented. Based on the two cases, we argue that incorporation of accountability in particular will be instrumental in the development and implementation of more mature urban food strategies. However, it is essential for participatory processes to not completely break from more “traditional” policy processes, at risk of limiting progress in strategy development and deploymen

A global blended tropopause based on ERA data, Part I: Climatology

A new tropopause definition, based on a flow-dependent blending of the traditional thermal tropopause with one based on potential vorticity, has been developed. The benefits of such a blending algorithm are most apparent in regions with synoptic scale fluctuations between tropical and extratropical airmasses. The properties of the local airmass determine the relative contributions to the location of the blended tropopause, rather than this being determined by a specified function of latitude. Global climatologies of tropopause height, temperature, potential temperature and zonal wind, based on European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis (ERA) ERA-Interim data, are presented for the period 1989-2007. Features of the seasonal-mean tropopause are discussed on a global scale, alongside a focus on selected monthly climatologies for the two high latitude regions and the tropical belt. The height differences between climatologies based on ERA-Interim and ERA-40 data are also presented. Key spatial and temporal features seen in earlier climatologies, based mainly on the World Meteorological Organization thermal tropopause definition, are reproduced with the new definition. Tropopause temperatures are consistent with those from earlier climatologies, despite some differences in height in the extratropics