Neurological examination of sheep (Ovis aries) with unilateral and bilateral quinolinic acid lesions of the striatum assessed by magnetic resonance imaging

Acute toxic models of Huntington’s disease (HD) and Parkinson’s disease (PD) have been used extensively to study neuropathology and behaviour in rodents and non-human primates, but not large animals. We have created an acute quinolinic acid (QA) model of HD in sheep (Ovis aries), first to investigate the clinical signs of ovine striatum pathology and second to assess the value of a veterinary neurological examination in the symptomology investigation. Sixteen sheep underwent two surgeries, four weeks apart, in which either QA or saline was infused into the left (unilateral) and then the right (bilateral) caudate nucleus. Neurological examinations were performed pre-surgically, two weeks after the unilateral surgery and eight weeks after the bilateral surgery. Examining veterinarians were blind to treatment group. Evidence of laterality and hind limb motor dysfunction was identified in the QA-lesioned sheep. The neurological examination identified clinical signs in two out of eight saline control sheep and four out of eight QA-lesioned sheep after the unilateral surgery and three out of eight saline control sheep and seven out of eight QA-lesioned sheep after the bilateral lesion surgery. There was no association between clinical profile and treatment group, or lesion size and location. While the neurological examination was moderately useful for identification of quinolinic acid-lesioned sheep, it was not informative about lesion characteristics

Response-inhibition during problem solving in sheep

Response inhibition is a behavioural skill that is important for flexible behaviour and appropriate decision making. It requires the suppression of a prepotent, but inappropriate action, in order to achieve a more advantageous outcome. Response inhibition has been tested in many animal species using the cylinder task. This task requires the self-driven inhibition of an impulse to obtain a visible food reward via a detour, rather than a direct but blocked route. We have shown previously using the stop-signal task that sheep can successfully interrupt an already-started response, if a reward is going to be restricted. However, it is not known if sheep can show self-driven response inhibition in a task that provides a reward independent of performance. Here we tested two groups of sheep on the cylinder task (11 Lleyn sheep: aged 8 months; 8 Welsh mountain sheep aged ~8 years old). Sheep were trained using an opaque cylinder and all sheep successfully learned the task. When response inhibition was tested using the transparent cylinder, all sheep performed significantly better than chance, but the older sheep showed a reduced number of correct responses compared to the young sheep (72.5±5.0% and 86.4±4.3% respectively). The results show that sheep have a mechanism for self-regulating their actions in order to retrieve food faster

Desperately seeking assurances: segmenting users by their information-seeking preferences: A Q methodology study of users’ ranking of privacy, security & trust cues

Users of technology services try to evaluate the risks of disclosing personal information in light of the benefits they believe they will receive. However, because of cognitive, time or other constraints, users concentrate on minimizing the uncertainties of disclosure – reducing their level of privacy concern – by using a limited set of information cues. We suggest an individual’s information-seeking behavior is focused on those cues which are important to them. Q methodology was used to determine if users of technology services can be segmented, based on the type of information cues they consider important – many of which are related to technology services’ privacy behavior. The study consisted of 58 participants split into two cohorts, who rank-ordered 40 statements describing the attributes of a technology service. In our study, 69% of participants loaded significantly into only one of five groups: 1) Information Controllers; 2) Security Concerned; 3) Benefits Seekers; 4) Crowd Followers; and 5) Organizational Assurance Seekers. Only 12% of participants did not load significantly into any of the five groups. Our findings assist practitioners in understanding how their privacy behavior (e.g. repurposing information) and privacy-sensitive technology design (e.g. providing feedback and control mechanisms) could encourage or discourage the adoption of technology services by different types of users. We argue the user segmentation identified by this study can inform the construction of more holistic privacy persona

Characteristic patterns of EEG oscillations in sheep (Ovis aries) induced by ketamine may explain the psychotropic effects seen in humans.

Ketamine is a valuable anaesthetic and analgesic that in recent years has gained notoriety as a recreational drug. Recently, ketamine has also been proposed as a novel treatment for depression and post-traumatic stress disorder. Beyond its anaesthetic actions, however, the effects of ketamine on brain activity have rarely been probed. Here we examined the cortical electroencephalography (EEG) response to ketamine of 12 sheep. Following ketamine administration, EEG changes were immediate and widespread, affecting the full extent of the EEG frequency spectrum measured (0-125 Hz). After recovery from sedation during which low frequency activity dominated, the EEG was characterised by short periods (2-3 s) of alternating low (35 Hz) frequency oscillation. This alternating EEG rhythm phase is likely to underlie the dissociative actions of ketamine, since it is during this phase that ketamine users report hallucinations. At the highest intravenous dose used (24 mg/kg), in 5/6 sheep we observed a novel effect of ketamine, namely the complete cessation of cortical EEG activity. This persisted for up to several minutes, after which cortical activity resumed. This phenomenon is likely to explain the 'k-hole', a state of oblivion likened to a near death experience that is keenly sought by ketamine abusers

Prolonged day length exposure improves circadian deficits and survival in a transgenic mouse model of Huntington's disease

The circadian disruption seen in patients of Huntington's disease (HD) is recapitulated in the R6/2 mouse model. As the disease progresses, the activity of R6/2 mice increases dramatically during the rest (light) period and decreases during the active (dark) period, eventually leading to a complete disintegration of rest-activity rhythms by the age of ~16 weeks. The suprachiasmatic nucleus controls circadian rhythms by entraining the rest-activity rhythms to the environmental light-dark cycle. Since R6/2 mice can shift their rest-activity rhythms in response to a jet-lag paradigm and also respond positively to bright light therapy (1000 lx), we investigated whether or not a prolonged day length exposure could reduce their daytime activity and improve their behavioural circadian rhythms. We found that a long-day photoperiod (16 h light/8 h dark cycle; 100 lx) significantly improved the survival of R6/2 female mice by 2.4 weeks, compared to mice kept under standard conditions (12 h light/12 h dark cycle). Furthermore, a long-day photoperiod improved the nocturnality of R6/2 female mice. Mice kept under long-day photoperiod also maintained acrophase in activity rhythms (a parameter of rhythmicity strength) in phase with that of WT mice, even if they were symptomatic. By contrast, a short-day photoperiod (8 h light/16 h dark cycle) was deleterious to R6/2 female mice and further reduced the survival by ~1 week. Together, our results support the idea that light therapy may be beneficial for improving circadian dysfunction in HD patients.This research was supported by a grant from CHDIInc

Mutant HTT seeding activity: a marker of disease progression and neurotoxicity in models of Huntington’s disease

Self-propagating, amyloidogenic mutant huntingtin (HTT) aggregates may drive progression of Huntington’s disease (HD). Here, we report the development of a FRET-based HTT aggregate seeding (FRASE) biosensor assay that enables the quantification of mutant HTT seeding activity (HSA) in complex biosamples from HD patients and disease models. Application of the FRASE assay revealed HSA in brain homogenates of presymptomatic HD transgenic and knock-in mice and its progressive increase with phenotypic changes, suggesting that HSA quantitatively tracks disease progression. Biochemical investigations of mouse brain homogenates demonstrated that HSA is high in fractions that contain small HTT fibrils but is low in fractions with large, insoluble HTT aggregates, indicating that small rather than large mutant HTT structures possess HSA. Finally, we assessed the neurotoxicity of mutant HTT seeds in an inducible Drosophila model transgenic for HTT. We found a strong correlation between HSA measured in adult neurons and the increased mortality of transgenic HD flies, indicating that FRASE assays detect disease-relevant, neurotoxic, mutant HTT structures with severe phenotypic consequences in vivo

The Shared Experience of Caring: A Study of Care-workers’ Motivations and Identifications at Work

AcceptedThis article presents an analysis of long-term care workers’ work motivation that examines the way this is shaped by the social contexts in which they operate. We conducted a thematic analysis of 19 in-depth interviews with care-workers. Three core themes were identified as underpinning their motivation: those of ‘fulfilment’, ‘belonging’ and ‘valuing’, and together these contributed to a central theme of ‘pride’. We also found an overarching theme of ‘shared experience’ to be integral to the way in which care workers made sense of their motivation and work experience. We draw on the social identity approach to provide a conceptual framework through which to understand how this shared experience shapes careworkers’ motivation and the quality of care they deliver. In particular, we note the importance that care-workers’ attach to their relationships with clients/patients and highlight the way in which this relational identification shapes their collective identification with their occupation and organisation and, through this, their motivation.European Social Research CouncilSomerset Care Ltd

Early neurodegeneration in R6/2 mice carrying the Huntington’s disease mutation with a super-expanded CAG repeat, despite normal lifespan

The threshold of CAG repeat expansion in the HTT gene that causes HD is 36 CAG repeats, although ‘superlong’ expansions are found in individual neurons in post mortem brains. Previously, we showed that, compared to mice with 440) CAG repeat expansions was delayed, and disease progression was slower. Inclusion pathology also differed from 250 CAG repeat mice, being dominated by a novel kind of extranuclear neuronal inclusion (nENNI) that resembles a class of aggregate seen in patients with the adult onset form of HD. Here, we characterised neuropathology in R6/2 mice with >400 CAG repeats using light and electron microscopy. nENNIs were found with increased frequency and wider distribution with age. Some nENNIs appear to ‘mature’ as the disease develops, developing a multi-layered cored structure. Mice with superlong CAG repeats do not develop clinical signs until they are around 30-40 weeks of age, and they attain a normal life span (>2 years). Nevertheless, they show brain atrophy and unequivocal neuron loss from the striatum and cortex by 22 weeks of age, an age at which similar pathology is seen in 250 CAG repeat mice. Since this time-point is ‘end stage’ for a 250 CAG mouse, but very far (at least 18 months) from end stage for a >440 CAG repeat mouse, our data confirm that the appearance of clinical signs, the formation of inclusions, and neurodegeneration are processes that progress independently. A better understanding of the relationship between CAG repeat length, neurodegenerative pathways, and clinical behavioural signs is essential, if we are to find strategies to delay or reverse the course of this disease

Video Question Answering with Iterative Video-Text Co-Tokenization

Video question answering is a challenging task that requires understanding jointly the language input, the visual information in individual video frames, as well as the temporal information about the events occurring in the video. In this paper, we propose a novel multi-stream video encoder for video question answering that uses multiple video inputs and a new video-text iterative co-tokenization approach to answer a variety of questions related to videos. We experimentally evaluate the model on several datasets, such as MSRVTT-QA, MSVD-QA, IVQA, outperforming the previous state-of-the-art by large margins. Simultaneously, our model reduces the required GFLOPs from 150-360 to only 67, producing a highly efficient video question answering model.Comment: ECCV 202

Engaging stakeholders and target groups in prioritising a public health intervention: the Creating Active School Environments (CASE) online Delphi study

$\textbf{Objectives}$ Stakeholder engagement and public involvement are considered as integral to developing effective public health interventions and is encouraged across all phases of the research cycle. However, limited guidelines and appropriate tools exist to facilitate stakeholder engagement—especially during the intervention prioritisation phase. We present the findings of an online ‘Delphi’ study that engaged stakeholders (including young people) in the process of prioritising secondary school environment-focused interventions that aim to increase physical activity. $\textbf{Setting }$ Web-based data collection using an online Delphi tool enabling participation of geographically diverse stakeholders. $\textbf{Participants }$ 37 stakeholders participated, including young people (age 13–16 years), parents, teachers, public health practitioners, academics and commissioners; 33 participants completed both rounds. $\textbf{Primary and secondary outcome measures}$ Participants were asked to prioritise a (short-listed) selection of school environment-focused interventions (eg, standing desks, outdoor design changes) based on the criteria of ‘reach’, ‘equality’, ‘acceptability’, ‘feasibility’, ‘effectiveness’ and ‘cost’. Participants were also asked to rank the criteria and the effectiveness outcomes (eg, physical activity, academic achievement, school enjoyment) from most to least important. Following feedback along with any new information provided, participants completed round 2 4 weeks later. $\textbf{Results }$ The intervention prioritisation process was feasible to conduct and comments from participants indicated satisfaction with the process. Consensus regarding intervention strategies was achieved among the varied groups of stakeholders, with ‘active lessons’ being the favoured approach. Participants ranked ‘mental health and well-being’ as the most important outcome followed by ‘enjoyment of school’. The most important criteria was ‘effectiveness’, followed by ‘feasibility’. $\textbf{Conclusions }$ This novel approach to engaging a wide variety of stakeholders in the research process was feasible to conduct and acceptable to participants. It also provided insightful information relating to how stakeholders prioritise interventions. The approach could be extended beyond the specific project to be a useful tool for researchers and practitioners.This report is independent research commissioned and funded by the Department of Health Policy Research Programme (opportunities within the school environment to shift the distribution of activity intensity in adolescents, PR-R5-0213-25001). This work was also supported by the Medical Research Council (unit programme number: MC_UU_12015/7). The work was undertaken under the auspices of the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence which is funded by the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research, and the Wellcome Trust (MR/K023187/1)