Similar Progression of Morphological and Metabolic Phenotype in R6/2 Mice with Different CAG Repeats Revealed by In Vivo Magnetic Resonance Imaging and Spectroscopy.

BACKGROUND: Huntington's disease (HD) is caused by an unstable polyglutamine (CAG) repeat in the HD gene, whereby a CAG repeat length greater than ∼36 leads to the disease. In HD patients, longer repeats correlate with more severe disease and earlier death. This is also seen in R6/2 mice carrying repeat lengths up to ∼200. Paradoxically, R6/2 mice with repeat lengths >300 have a less aggressive phenotype and longer lifespan than those with shorter repeats. The mechanism underlying this phenomenon is unknown. OBJECTIVE: To investigate the consequences of longer repeat lengths on structural changes in the brains of R6/2 mice, especially with regard to progressive atrophy. METHODS: We used longitudinal in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) to compare pathological changes in two strains of R6/2 mice, one with a rapidly progressing disease (250 CAG repeats), and the other with a less aggressive phenotype (350 CAG repeats). RESULTS: We found significant progressive brain atrophy in both 250 and 350 CAG repeat mice, as well as changes in metabolites (glutamine/glutamate, choline and aspartate). Although similar in magnitude, atrophy in the brains of 350 CAG R6/2 mice progressed more slowly than that seen in 250 CAG mice, in line with the milder phenotype and longer lifespan. Interestingly, significant atrophy was detectable in 350 CAG mice as early as 8-12 weeks of age, although behavioural abnormalities in these mice are not apparent before 25-30 weeks. This finding fits well with human data from the PREDICT-HD and TRACK-HD project, where reductions in brain volume were found 10 years in advance of the onset of symptoms. CONCLUSIONS: The similar brain atrophy with a mismatch between onset of brain atrophy and behavioural phenotype in HD mice with 350 repeats will make this mouse particularly useful for modelling early stages of HD pathology.This project was funded by a grant from CHDI Inc.This is the author accepted manuscript. The final version is available from IOS Press at https://doi.org/10.3233/JHD-160208

Aligning Policing and Public Health Promotion: Insights from the World of Foot Patrol

Foot patrol work is rarely described in relation to public health, even though police routinely encounter health risk behaviors and environments. Through a qualitative study of foot patrol policing in violent ‘hotspots’ of Philadelphia, we explore some prospects and challenges associated with bridging security and public health considerations in law enforcement. Noting existing efforts to help advance police officer knowledge of, and attitudes toward health vulnerabilities, we incorporate perspectives from environmental criminology to help advance this bridging agenda. Extending the notion of capable guardianship to understand foot patrol work, we suggest that the way forward for theory, policy, and practice is not solely to rely on changing officer culture and behavior, but rather to advance a wider agenda for enhancing collective guardianship, and especially ‘place management’ for harm reduction in the city

Huntington's disease mouse models online: high-resolution MRI images with stereotaxic templates for computational neuroanatomy.

Magnetic resonance imaging (MRI) has proved to be an ideal modality for non-destructive and highly detailed assessment of structural morphology in biological tissues. Here we used MRI to make a dataset of ex vivo brains from two different rodent models of Huntington's disease (HD), the R6/2 line and the YAC 128 mouse. We are making the whole dataset (399 transgenic HD and wildtype (WT) brains, from mice aged 9-80 weeks) publicly available. These data will be useful, not only to investigators interested in the study of HD, but also to researchers of computational neuroanatomy who may not have access to such large datasets from mouse models. Here we demonstrate a number of uses of such data, for example to produce maps of grey and white matter and cortical thickness. As an example of how the library might provide insights in mouse models of HD, we calculated whole brain grey matter volumes across different age groups with different numbers of cytosine-adenine-guanine (CAG) repeats in a fragment of the gene responsible for HD in humans. (The R6/2 dataset was obtained from an allelic series of R6/2 mice carrying a range of CAG repeat lengths between 109 and 464.) This analysis revealed different trajectories for each fragment length. In particular there was a gradient of decreasing pathology with longer CAG repeat lengths, reflecting our previous findings with behavioural and histological studies. There will be no constraints placed on the use of the datasets included here. The original data will be easily and permanently accessible via the University of Cambridge data repository (http://www.dspace.cam.ac.uk/handle/1810/243361)

ASPIRE-2-PREVENT: a survey of lifestyle, risk factor management and cardioprotective medication in patients with coronary heart disease and people at high risk of developing cardiovascular disease in the UK.

OBJECTIVE: To determine in patients with coronary heart disease (CHD) and people at high risk of developing cardiovascular disease (CVD) whether the Joint British Societies' guidelines on CVD prevention (JBS2) are followed in everyday clinical practice. DESIGN: A cross-sectional survey was undertaken of medical records and patient interviews and examinations at least 6 months after the recruiting event or diagnosis using standardised instruments and a central laboratory for measurement of lipids and glucose. SETTINGS: The ASPIRE-2-PREVENT survey was undertaken in 19 randomly selected hospitals and 19 randomly selected general practices in 12 geographical regions in England, Northern Ireland, Wales and Scotland. PATIENTS: In hospitals, 1474 consecutive patients with CHD were identified and 676 (25.6% women) were interviewed. In general practice, 943 people at high CVD risk were identified and 446 (46.5% women) were interviewed. RESULTS: The prevalence of risk factors in patients with CHD and high-risk individuals was, respectively: smoking 14.1%, 13.3%; obesity 38%, 50.2%; not reaching physical activity target 83.3%, 85.4%; blood pressure ≥130/80 mm Hg (patients with CHD and self-reported diabetes) or ≥140/85 mm Hg (high-risk individuals) 46.9%, 51.3%; total cholesterol ≥4 mmol/l 52.6%, 78.7%; and diabetes 17.8%, 43.8%. CONCLUSIONS: The potential among patients with CHD and individuals at high risk of developing CVD in the UK to achieve the JBS2 lifestyle and risk factor targets is considerable. CVD prevention needs a comprehensive multidisciplinary approach, addressing all aspects of lifestyle and risk factor management. The challenge is to engage and motivate cardiologists, physicians and other health professionals to routinely practice high quality preventive cardiology in a healthcare system which must invest in prevention

Scaling down an insect-size microrobot, HAMR-VI into HAMR-Jr

Here we present HAMR-Jr, a \SI{22.5}{\milli\meter}, \SI{320}{\milli\gram} quadrupedal microrobot. With eight independently actuated degrees of freedom, HAMR-Jr is, to our knowledge, the most mechanically dexterous legged robot at its scale and is capable of high-speed locomotion (\SI{13.91}{bodylengths~\second^{-1}}) at a variety of stride frequencies (\SI{1}{}-\SI{200}{\hertz}) using multiple gaits. We achieved this using a design and fabrication process that is flexible, allowing scaling with minimum changes to our workflow. We further characterized HAMR-Jr's open-loop locomotion and compared it with the larger scale HAMR-VI microrobot to demonstrate the effectiveness of scaling laws in predicting running performance.Comment: IEEE International Conference on Robotics and Automation 2020 (accepted

How does a transforming landscape influence bird breeding success?

Context The conversion of agricultural landscapes to tree plantations is a major form of landscape transformation worldwide, but its effects on biodiversity, particularly key population processes like reproductive success, are poorly understood. Objectives We compared bird breeding success between woodland remnants surrounded by maturing stands of plantation Radiata Pine and a matched set of woodland remnants in semi-cleared grazing land. Methods Our study was conducted in the Nanangroe region in south-eastern New South Wales, Australia. Using repeated field measurements, we quantified bird breeding success in 23 woodland remnants; 13 surrounded by Radiata Pine plantations and 10 on farms where remnants were surrounded by semi-cleared grazing land. We matched the attributes of native remnant patches between two types of matrix. Results We found that: (1) rates of nesting success of smaller-bodied birds in woodland remnants surrounded by grazing land were significantly higher than in woodland remnants surrounded by pine plantations; and (2) taxa with domed nests were more successful at nesting than species that constructed open cup/bowl nests in woodland remnants within farmlands. Conclusions Our findings suggest that bird breeding success in remnant woodland patches is significantly diminished as a result of the conversion of semi-cleared grazing land to pine plantations

Adaptation to experimental jet-lag in R6/2 mice despite circadian dysrhythmia.

The R6/2 transgenic mouse model of Huntington's disease (HD) shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks). R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau) of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD

Geospatial statistics elucidate competing geological controls on natural CO2 seeps in Italy

Site selection for the geological storage of CO 2 for long timespans requires an understanding of the controls on containment, migration, and surface seepage of subsurface CO 2 fluids. Evidence of natural CO 2 migration from depth to the surface is documented at 270 sites from Italy, a prolific CO 2 province. Previous studies indicate that CO 2 delivery to and from buried structures that host CO 2 accumulations is fault controlled but competing controls on the CO 2 flow pathways affect the location and style of CO 2 release. Here, we conduct a meta-analysis using a novel geospatial approach to statistically determine the relationship between the geological setting and structures and the CO 2 seep spatial distribution and characteristics (morphological type, flux, and temperature) in Central Italy. We find that seep distribution differs on two spatial scales corresponding to the geological setting. On large scales (>5 km), seeps are isotropically distributed and align with regional structures such as anticlines, decollements, and extensional faults. On local scales (<5 km), seeps cluster and align with subsidiary geologic structures, including faults and lithological boundaries. The detailed location and flux of seeps within clusters are influenced by the regional structural domain: in the Tyrrhenian, seeps tend to be located along fault traces, whereas seeps are located as springs in the tip and ramp regions of fault scarps in the Apennines. Thus, our geospatial approach evidences, at a regional scale, how macrocrustal fluid flow is governed by deep extensional and compressional features but once CO 2 reaches shallower structures, it evidences how smaller scale features and hydrogeological factors distribute the CO 2 fluids in the near surface, dependent on the geological setting. This work not only demonstrates useful application of a novel geospatial approach to characterize competing crustal controls on CO 2 flow at different scales but also informs the design of appropriate site characterization and surface monitoring programs at engineered carbon stores

Why are sustainable practices often elusive? The role of information flow in the management of networked human-environment interactions

Analyzing the spatial and temporal properties of information flow with a multi-century perspective could illuminate the sustainability of human resource-use strategies. This paper uses historical and archaeological datasets to assess how spatial, temporal, cognitive, and cultural limitations impact the generation and flow of information about ecosystems within past societies, and thus lead to tradeoffs in sustainable practices. While it is well understood that conflicting priorities can inhibit successful outcomes, case studies from Eastern Polynesia, the North Atlantic, and the American Southwest suggest that imperfect information can also be a major impediment to sustainability. We formally develop a conceptual model of Environmental Information Flow and Perception (EnIFPe) to examine the scale of information flow to a society and the quality of the information needed to promote sustainable coupled natural-human systems. In our case studies, we assess key aspects of information flow by focusing on food web relationships and nutrient flows in socio-ecological systems, as well as the life cycles, population dynamics, and seasonal rhythms of organisms, the patterns and timing of species’ migration, and the trajectories of human-induced environmental change. We argue that the spatial and temporal dimensions of human environments shape society's ability to wield information, while acknowledging that varied cultural factors also focus a society's ability to act on such information. Our analyses demonstrate the analytical importance of completed experiments from the past, and their utility for contemporary debates concerning managing imperfect information and addressing conflicting priorities in modern environmental management and resource use

Right Ventricular Dysfunction in the R6/2 Transgenic Mouse Model of Huntington's Disease is Unmasked by Dobutamine

Background: Increasingly, evidence from studies in both animal models and patients suggests that cardiovascular dysfunction is important in HD. Previous studies measuring function of the left ventricle (LV) in the R6/2 mouse model have found a clear cardiac abnormality, albeit with preserved LV systolic function. It was hypothesized that an impairment of RV function might play a role in this condition via mechanisms of ventricular interdependence.Objective: To investigate RV function in the R6/2 mouse model of Huntington's disease (HD).Methods: Cardiac cine- magnetic resonance imaging (MRI) was used to determine functional parameters in R6/2 mice. In a first experiment, these parameters were derived longitudinally to determine deterioration of cardiac function with disease progression. A second experiment compared the response to a stress test (using dobutamine) of wildtype and early-symptomatic R6/2 mice. Results: There was progressive deterioration of RV systolic function with age in R6/2 mice. Furthermore, beta-adrenergic stimulation with dobutamine revealed RV dysfunction in R6/2 mice before any overt symptoms of the disease were apparent.Conclusions: This work adds to accumulating evidence of cardiovascular dysfunction in R6/2 mice, describing for the first time the involvement of the right ventricle. Cardiovascular dysfunction should be considered, both when treatment strategies are being designed, and when searching for biomarkers for HD