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    Definition of the estrogen negative feedback pathway controlling the GnRH pulse generator in female mice

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    The mechanisms underlying the homeostatic estrogen negative feedback pathway central to mammalian fertility have remained unresolved. Direct measurement of gonadotropin-releasing hormone (GnRH) pulse generator activity in freely behaving mice with GCaMP photometry demonstrated striking estradiol-dependent plasticity in the frequency, duration, amplitude, and profile of pulse generator synchronization events. Mice with Cre-dependent deletion of ESR1 from all kisspeptin neurons exhibited pulse generator activity identical to that of ovariectomized wild-type mice. An in vivo CRISPR-Cas9 approach was used to knockdown ESR1 expression selectively in arcuate nucleus (ARN) kisspeptin neurons. Mice with >80% deletion of ESR1 in ARN kisspeptin neurons exhibited the ovariectomized pattern of GnRH pulse generator activity and high frequency LH pulses but with very low amplitude due to reduced responsiveness of the pituitary. Together, these studies demonstrate that estrogen utilizes ESR1 in ARN kisspeptin neurons to achieve estrogen negative feedback of the GnRH pulse generator in mice.Peer reviewe

    Intellectual exchange and the reception of classical literature at early medieval Fulda

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    This thesis studies the inheritance of classical literature at the monastery of Fulda in the ninth century. An examination of two writers, Rudolf of Fulda and Brun Candidus, provides a kind of case study of the broader intellectual networks and transmission of classical literature at work in the Carolingian Empire. The study attempts to situate Carolingian literary aesthetics within the context of Late Antique poetry and material culture. It argues that the dominant thread in these writers was the inheriting and refashioning of past classical sources. Through slight emendations made to the classical sources, Rudolf and Candidus are able to incorporate and synthesize pagan writers into the Christian culture of the ninth century. The thesis uses the transmission history of Vitruvius’ De architectura as a case study of the broader intellectual networks. Further, it uncovers a previously unknown Carolingian reader of Vitruvius, Rudolf, and argues for the onetime existence of a manuscript copy of Vitruvius at the Fulda monastery. Additionally, the thesis contains the first English translations of Rudolf’s Miracula sanctorum in Fuldenses ecclesias translatorum, and Brun Candidus’ opus geminatum or ‘twinned-work’, the prose Vita Eigilis, and the metrical Vita Aeigili. In the study of the metrical Vita the thesis argues that, contrary to being simply derivative or unoriginal, through the use and manipulation of fragments of classical poets such as Vergil and Ovid, Candidus created a narrative subtext to his poem that offered a commentary on the recent crisis at the Fulda monastery, while also offering a vision of ideal and harmonious monastic life. An extensive commentary on the poem adds to this evidence by examining in detail every classical reference in the poem

    Accuracy of healthcare systems data for identifying cardiovascular outcomes after stroke due to intracerebral haemorrhage in the United Kingdom

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    Funding: This work was funded by a British Heart Foundation Special Project grant (SP/12/2/20422).Background Healthcare systems data (HCSD) could improve the efficiency of clinical trials, but their accuracy and validity are uncertain. Our objective was to assess the accuracy of HCSD as the sole method of outcome detection in the REstart or STop Antithrombotics Randomised Trial (RESTART; ISRCTN71907627) compared with adjudicated questionnaire follow-up and compare estimates of treatment effect. Methods RESTART was a prospective, open, assessor-blind, parallel-group randomised controlled trial (RCT) of antiplatelet therapy after intracerebral haemorrhage (ICH) in the UK. We included 496 (92%) of 537 RESTART participants, who were resident in England or Scotland at randomisation. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. RESTART used annual questionnaires to detect its primary outcome (recurrent ICH) and secondary outcome (a composite of haemorrhagic or ischemic major adverse cardiovascular events [MACE]) over a median of 2.0 years; an independent adjudication committee verified outcomes using medical records and brain imaging. We obtained ICD10-coded HCSD on hospital admissions and deaths in England and Scotland to identify primary and secondary outcomes. We compared HCSD with a reference standard of adjudicated outcomes. We estimated the effects of antiplatelet therapy using HCSD alone in a Cox proportional hazards model adjusted for minimisation variables. Results In the original RESTART trial, 31 people experienced a primary outcome event. HCSD had sensitivity of 84% (95% CI 66 to 95%) and positive predictive value of 68% (51 to 82%) for recurrent ICH. HCSD estimated an effect of antiplatelet therapy (adjusted hazard ratio [aHR] 0.51, 95% CI 0.27 to 0.98; p = 0.044) that was almost identical to adjudicated outcomes (aHR 0.51, 95% CI 0.25 to 1.03; p = 0.060). HCSD had sensitivity of 84% (76 to 91%) and positive predictive value of 78% (69 to 85%) for MACE, on which HCSD estimated an effect of antiplatelet therapy (aHR 0.81, 95% CI 0.56 to 1.16; p = 0.247) that was similar to adjudicated outcomes (aHR 0.65, 95% CI 0.44 to 0.95; p = 0.025). Conclusions In a RCT of antiplatelet therapy for people with ICH, HCSD was reasonably accurate and provided similar estimates of treatment effect compared with adjudicated outcomes.Peer reviewe

    Exploring mental time travel experiences and their influence on behavioral intentions and learning

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    Drawing on cognitive science research, this study presents mental time travel experiences to the marketing literature and explores their value to brands. Specifically, we examine how marketing stimuli can be used to elicit mental time travel experiences and the impact these experiences have on important brand outcomes including purchase intentions, word of mouth, loyalty intentions, and learning. We do so with two studies using branded experiences from two marketing campaigns across four different conditions: augmented reality, a 360° website, a video, and a static image. Results identify positive episodic memories as an important primer of mental time travel experiences and that mental time travel to the past is a key factor to influencing purchase intentions, word of mouth, loyalty intentions, and learning. We also show that cognitive load can have an inhibiting effect on mental time travel's ability to influence purchase intentions, word of mouth, and loyalty intentions. Finally, we demonstrate that a state of immersion can enhance mental time travel's ability to influence learning.Peer reviewe

    The genome sequence of the whiskered bat, Myotis mystacinus (Kuhl, 1817)

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    Funding: SCV was supported by a UKRI Future Leaders Fellowship, (MR/T021985/1), an ERC Consolidator Grant (101001702; BATSPEAK), and a Max Planck Research Group awarded by the Max Planck Society. This work was supported by Wellcome through core funding to the Wellcome Sanger Institute [206194, https://doi.org/10.35802/206194] and the Darwin Tree of Life Discretionary Award [218328, https://doi.org/10.35802/218328 ].We present a genome assembly from an individual male Myotis mystacinus (whiskered bat; Chordata; Mammalia; Chiroptera; Vespertilionidae). The genome sequence has a total length of 2,081.20 megabases. Most of the assembly (97.52%) is scaffolded into 23 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 16.93 kilobases in length.Peer reviewe

    Whale song shows language-like statistical structure

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    Funding: Surveys of humpback whales in New Caledonia were made possible by contributions from Fondation d’Entreprise Total and Total Pacifique; the Provinces Sud, North, and Isles; and the Ministère de la Transition Ecologique et Solidaire. This work was funded by the following grants to E.C.G: Royal Society University Research Fellowship (UF160081 and URF\R\221020), Royal Society Research Fellows Enhancement Award (RGF\EA\180213), Royal Society Research Grants for Research Fellows 2018 (RGF\R1\181014), National Geographic Grant (NGS-50654R-18), Carnegie Trust Research Incentive Grant (RIG007772), British Ecological Society Small Research Grant(SR18/1288), and School of Biology Research Committee funding. E.L.C. was supported by a Rutherford Discovery Fellowship from the Royal Society of New Zealand Te Aparangi. J.A.A. was supported by a National Science Foundation Office of Polar Programs Postdoctoral Fellowship (2218949) and a grant from the Winifred Violet Scott Trust. I.A. was supported by an Israeli Science Foundation Grant (ISF 445/20). I.A. and S.K. were supported by a fellowship from the Israel Institute for Advanced Studies.Humpback whale song is a culturally transmitted behavior. Human language, which is also culturally transmitted, has statistically coherent parts whose frequency distribution follows a power law. These properties facilitate learning, and may therefore arise because of their contribution to the faithful transmission of language over multiple cultural generations. If so, we would expect to find them in other culturally transmitted systems. Here, we apply methods based on infant speech segmentation to eight years of humpback recordings, uncovering the same statistical structure that is a hallmark of human language in whale song. This commonality, in two evolutionarily distant species, points to the role of learning and cultural transmission in the emergence of properties thought to be unique to human language.Peer reviewe

    Quality assurance and validity of AI-generated single best answer questions

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    Background Recent advancements in generative artificial intelligence (AI) have opened new avenues in educational methodologies, particularly in medical education. This study seeks to assess whether generative AI might be useful in addressing the depletion of assessment question banks, a challenge intensified during the Covid-era due to the prevalence of open-book examinations, and to augment the pool of formative assessment opportunities available to students. While many recent publications have sought to ascertain whether AI can achieve a passing standard in existing examinations, this study investigates the potential for AI to generate the exam itself. Summary of work This research utilized a commercially available AI large language model (LLM), OpenAI GPT-4, to generate 220 single best answer (SBA) questions, adhering to Medical Schools Council Assessment Alliance guidelines the and a selection of Learning Outcomes (LOs) of the Scottish Graduate-Entry Medicine (ScotGEM) program. All questions were assessed by an expert panel for accuracy and quality. A total of 50 AI-generated and 50 human-authored questions were used to create two 50-item formative SBA examinations for Year 1 and Year 2 ScotGEM students. Each exam, delivered via the Speedwell eSystem, comprised 25 AI-generated and 25 human-authored questions presented in random order. Students completed the online, closed-book exams on personal devices under exam conditions that reflected summative examinations. The performance of both AI-generated and human-authored questions was evaluated, focusing on facility and discrimination index as key metrics. Summary of results   The screening process revealed that 69% of AI-generated SBAs were fit for inclusion in the examinations with little or no modifications required. Modifications, when necessary, were predominantly due to reasons such as the inclusion of "all of the above" options, usage of American English spellings, and non-alphabetized answer choices. 31% of questions were rejected for inclusion in the examinations, due to factual inaccuracies and non-alignment with students’ learning. When included in an examination, post hoc statistical analysis indicated no significant difference in performance between the AI- and human- authored questions in terms of facility and discrimination index. Discussion and conclusion   The outcomes of this study suggest that AI LLMs can generate SBA questions that are in line with best-practice guidelines and specific LOs. However, a robust quality assurance process is necessary to ensure that erroneous questions are identified and rejected. The insights gained from this research provide a foundation for further investigation into refining AI prompts, aiming for a more reliable generation of curriculum-aligned questions. LLMs show significant potential in supplementing traditional methods of question generation in medical education. This approach offers a viable solution to rapidly replenish and diversify assessment resources in medical curricula, marking a step forward in the intersection of AI and education.Peer reviewe

    Semi-pagans? : Some mutations of non-Christian thought in late antiquity

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    Ambiguities of religious practice and belief are a crucial feature of the religious transformation of the late Roman world. Recent scholarship on the limits of Christianization has focused, above all, on the tension between the lifestyles of ordinary Christians and bishops’ normative standards. This article turns attention to a different set. As Charles Guignebert suggested in a seminal article (1923), some traditionalists may have embraced Christian ideas without joining Christian churches. This article teases out Christian elements in the thinking of two traditionalist Latin intellectuals. Often identified as a lax Christian, Augustine’s correspondent Nectarius was in fact a Ciceronian pluralist who rejected traditional cults, yet he had not followed his father in embracing Christian practice. A loose parallel can be found in the Platonist commentator Calcidius (most likely active in the early fourth century). Definitely not an adherent of Christianity, Calcidius nonetheless endorsed key Christian ideas, including the Incarnation, the notion of a singular “true god,” and association between primordial floods and the invention of idolatrous cult. To add new terms (such as Guignebert’s semi-pagans) to an already problematic division among pagans, Jews, and various sorts of Christian would only complicate an imperfect model. However, as these examples illustrate, it is necessary to reckon, when analyzing the complex reality of late antique religion, not just with pervasive deviation from Christian norms but also with potential influence of Christian thought on people, otherwise traditionalist in their thinking, who did not belong to Christian churches.Peer reviewe

    Examining the influence of virtual reality tourism on consumers' subjective wellbeing

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    Funding: This work was supported by the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research, King Faisal University [Grant No. 2823].Tourism consumption has been outlined as having a positive effect on individuals' subjective wellbeing, however, we had limited empirical or conceptual understanding on the propensity of VR tourism in fostering positive subjective wellbeing and the subsequent effects this has for tourism providers and policymakers. A vacation transports one's self to an alternative world, physically. In parallel, VR transports one's self to an alternative world, virtually. Accordingly, through a multiple quantitative study research-design and drawing on the theoretical lens of Presence-Theory and Effort-Recovery-Theory, this research uncovers the positive effect of VR tourism on individuals' subjective wellbeing, the nuance of the sense of presence in VR tourism in enabling psychological-detachment and enhancing consumer wellbeing along with the subsequent attitude and behaviour intentions stimulated by consumer wellbeing. Our results pertain that not only can VR tourism provide important societal and health benefits in recovery and enhancing individuals' wellbeing, but also benefits from an economic perspective.Peer reviewe

    Investigating the effects of environmental change on lipids of tropical reef building corals and the roles of skeletal lipids on coral biomineralization

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    Understanding the effects of climate change on coral biology and biomineralization is critical for projecting the future of coral reefs. Essential to this understanding are lipid biomolecules which occur both within the tissues and skeletons of corals and fulfil a variety of biological functions. Here we conducted fieldwork and culturing experiments to determine how environmental parameters influence scleractinian coral tissue and skeleton lipid compositions. Our results revealed variations in tissue lipid compositions in cultured Porites spp. due to temperature, genotype, and/or species differences, with no significant effect observed from seawater pCO2. We also observe that elevated temperatures significantly increased total fatty acid and decreased total wax ester contributions to total skeletal lipids within cultured Seriatopora spp. We find a significantly higher contribution of unsaturated fatty acids to the total fatty acid pool at 5 m water depth compared to 25 m in the tissues of Acropora retusa and Pocillopora meandrina collected from a reef site in Moorea. This work together highlights how lipids compositions within reef-building corals change according to their surrounding environment. Skeletal fatty acids in these scleractinian corals were dominated by saturated fatty acids C16:O (palmitic acid) and C18:O (stearic acid), these being the main building blocks of various lipid molecules. We also find a predominance of saturated wax esters C16:0-C14:0, C16:0-C16:0, and C16:0-C18:0 in the skeletons of Seriatopora spp. and Stylophora sp. coral colonies. To explore the role of lipids in coral biomineralization we precipitated aragonite in-vitro under various pH and dissolved inorganic carbon conditions inferred to occur at the coral calcification site, in conjunction with the absence and presence of lipids identified within coral skeletons. Lecithin (a mixture of phospholipids, the primary constituents of biological membranes) significantly inhibited aragonite precipitation and altered the morphology of the aragonite crystals produced. Stearic acid and cholesterol had no significant effects on precipitation rates, nor on aragonite structure and morphology. This research demonstrates that coral lipids are influenced by the environment and that skeletal lipids may be involved in controlling the formation of coral skeletons. Given that future climate change scenarios are likely to increase seawater temperatures and pCO2, potential variations in coral tissue and skeletal lipid compositions as observed in this research could affect the ability of reef-building corals' CaCO3 skeletons to withstand future climate scenarios."This research was financially supported by a University of St. Andrews’ St. Leonard’s PhD Scholarship. Financial support for the fieldwork and collection of samples in Chapter 3 was provided by MASTS’ (Marine Alliance for Science and Technology for Scotland) Aquatic Stressors Travel Grant. Additional financial support for Chapter 5 was provided by the UK Natural Environment Research Council."--Fundin

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