Characterising trees and hyperbolic spaces by their boundaries

We use the language of proper CAT(-1) spaces to study thick, locally compact trees, the real, complex and quaternionic hyperbolic spaces and the hyperbolic plane over the octonions. These are rank 1 Euclidean buildings, respectively rank 1 symmetric spaces of non-compact type. We give a uniform proof that these spaces may be reconstructed using the cross ratio on their visual boundary, bringing together the work of Tits and Bourdon.Comment: 15 pages, 5 figure

Coloured graphical models and their symmetries

Coloured graphical models are Gaussian statistical models determined by an undirected coloured graph. These models can be described by linear spaces of symmetric matrices. We outline a relationship between the symmetries of the graph and the linear forms that vanish on the reciprocal variety of the model. In particular, we give four families for which such linear forms are completely described by symmetries

How fast could a mermaid swim?

This paper investigates the potential swimming speed of the popular mythical creature, the mermaid. In order to calculate this speed, the motion of swimming was considered and the assumption that the tail of the mermaid would swim and produce the same amount of power as a bottle-nose dolphin’s tail during swimming. Through the consideration of the forces of thrust, the power generated by one stroke and drag, the speed was calculated at 5.93 ms-1

Patients, Professionals and the Internet: Renegotiating the Healthcare Encounter

The aim of this research was to examine how patient use of internet information impinges on the utilisation of healthcare services. The research had the following objectives: + to quantify the extent, and patterns, of patients use of the internet as a health information resource and identify the factors leading to variations in behaviour. + to identify the search strategies employed by patients in accessing internet health information internet and the evaluative approaches used in assessing information quality. + to analyse the content and dynamics of virtual health communities and how participation in such communities is integrated into engagement with health services. + to document the evolving nature of patient-professional interaction arising from patient access to health information and the subsequent format of the healthcare encounter. + to assess the effect of changing patient access to information and changes in the healthcare encounter on patterns of patient decision making and health behaviours

Relationship-centred care for people living with dementia in care homes

Dementia is a progressive degenerative disease, typically affecting older adults for which there is currently no cure. Dementia is characterised by progressive impairment to several cognitive functions including memory and orientation, practical abilities and mood changes, all of which can impact personality and social relationships. The theory of social death has been explored for people living with dementia as the ability to maintain social interactions are threatened leading to a loss of social identity and exclusion and withdrawal from the wider community. A relationship-centred care approach has been recommended to improve care for older people in long-term care, aiming to create environments conducive to relationships, considering the needs of the person living with dementia and also the staff and family members involved in their care. The ‘Senses Framework’ by Nolan was designed to promote relationships, acknowledging the experiences of all parties across six senses: security, continuity, belonging, purpose, fulfilment and significance. Utilising the Senses Framework has the potential to sustain meaningful relationships by fostering a sense of value and empowerment. This Rapid Evidence Summary aims to explore the evidence assessing the benefits of a relationship triad approach (Senses Framework and other relationship-centred care approaches) in long term care settings (including care homes) for people living with dementia. Nine primary studies and one systematic review were identified. The benefits of using a relationship-centred approach were mapped under each of the senses described within the Senses Framework, detailed separately for people living with dementia, relatives and care home staff. For people living with dementia, interventions using touch and music increased the sense of security and belonging reducing neuropsychiatric conditions such as agitation and aggression. Memory boxes were used to support a sense of significance and continuity and significant moments from the past brought pleasure and enabled meaningful conversations. For relatives and staff, improved communication and relationships increased confidence and trust and by working together they found that they could exert more influence and could develop into a powerful force for change

Localized immune surveillance of primary melanoma in the skin deciphered through executable modeling

While skin is a site of active immune surveillance, primary melanomas often escape detection. Here, we have developed an in silico model to determine the local cross-talk between melanomas and Langerhans cells (LCs), the primary antigen-presenting cells at the site of melanoma development. The model predicts that melanomas fail to activate LC migration to lymph nodes until tumors reach a critical size, which is determined by a positive TNF-α feedback loop within melanomas, in line with our observations of murine tumors. In silico drug screening, supported by subsequent experimental testing, shows that treatment of primary tumors with MAPK pathway inhibitors may further prevent LC migration. In addition, our in silico model predicts treatment combinations that bypass LC dysfunction. In conclusion, our combined approach of in silico and in vivo studies suggests a molecular mechanism that explains how early melanomas develop under the radar of immune surveillance by LC

The social cohesion investment: Local areas that invested in social cohesion programmes are faring better in the midst of the Covid-19 pandemic

Research has consistently observed that social cohesion (the strength of relationship between the individual and the state, and between individuals and their fellow citizens) rises in the aftermath of natural disasters or mass tragedies. However, this sense of “coming together” is often short-lived and comes back to pre-disaster level within a matter of weeks. But what happened in the UK as the Covid-19 pandemic progressed? The first stages of the Covid-19 pandemic saw an extraordinary increase in kindness and social connection with people organising spontaneously to support those affected through neighbourhood support groups, reaching out to isolated community members through telephone calls, and the ‘clap for carers’. However, as months pass social tensions appear to be rising again, along with increasing distrust of central government. Minority ethnic and religious communities have been accused of spreading the virus by not taking recommendations seriously, as have younger people – potentially fuelling increased tensions between groups within and across local communities. As the impact of the pandemic persists, so do the challenges for local authorities. Strong connections, local community knowledge and good relations have already proved important for local test, track and trace systems and to tailor health messages for diverse local groups and communities. With winter and tighter lockdown rules both imminent, we believe cohesion and integration will remain crucial in helping communities through the next six months and beyond. The “Beyond Us & Them” research project funded by the Nuffield Foundation aims to track people’s perceptions of social cohesion in different places in the UK. An important feature of the project is that we collect the views of people living in six different local authority areas (five of which are a part of the government Integration Area programme and all of which have invested in social cohesion over the last two years), as well as other places and regions. This brief report presents headline findings on trust and cohesion from comparisons between these local authority areas versus other places in the UK. These included broadly representative samples from Scotland, Wales and Kent (the most densely populated non-metropolitan county in England). We found that people in the six local authority areas were significantly less cynical about both national and local politicians and more accepting of government decisions and guidelines. They also reported stronger and better social relationships with other citizens, and warmer feelings towards immigrants compared to other areas. Taken together these findings indicate stronger social cohesion in the six local authority areas, despite the fact that respondents from these areas reported higher levels of concern and were experiencing higher local infection rates

Biochemical characterization of protease activity of Nsp3 from SARS-CoV-2 and its inhibition by nanobodies

Of the 16 non-structural proteins (Nsps) encoded by SARS CoV-2, Nsp3 is the largest and plays important roles in the viral life cycle. Being a large, multidomain, transmembrane protein, Nsp3 has been the most challenging Nsp to characterize. Encoded within Nsp3 is the papain-like protease domain (PLpro) that cleaves not only the viral polypeptide but also K48-linked polyubiquitin and the ubiquitin-like modifier, ISG15, from host cell proteins. We here compare the interactors of PLpro and Nsp3 and find a largely overlapping interactome. Intriguingly, we find that near full length Nsp3 is a more active protease compared to the minimal catalytic domain of PLpro. Using a MALDI-TOF based assay, we screen 1971 approved clinical compounds and identify five compounds that inhibit PLpro with IC50s in the low micromolar range but showed cross reactivity with other human deubiquitinases and had no significant antiviral activity in cellular SARS-CoV-2 infection assays. We therefore looked for alternative methods to block PLpro activity and engineered competitive nanobodies that bind to PLpro at the substrate binding site with nanomolar affinity thus inhibiting the enzyme. Our work highlights the importance of studying Nsp3 and provides tools and valuable insights to investigate Nsp3 biology during the viral infection cycle

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia.

Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice

Modelling the impact of larviciding on the population dynamics and biting rates of Simulium damnosum (s.l.): implications for vector control as a complementary strategy for onchocerciasis elimination in Africa

Background: In 2012, the World Health Organization set goals for the elimination of onchocerciasis transmission by 2020 in selected African countries. Epidemiological data and mathematical modelling have indicated that elimination may not be achieved with annual ivermectin distribution in all endemic foci. Complementary and alternative treatment strategies (ATS), including vector control, will be necessary. Implementation of vector control will require that the ecology and population dynamics of Simulium damnosum sensu lato be carefully considered. Methods: We adapted our previous SIMuliid POPulation dynamics (SIMPOP) model to explore the impact of larvicidal insecticides on S. damnosum (s.l.) biting rates in different ecological contexts and to identify how frequently and for how long vector control should be continued to sustain substantive reductions in vector biting. SIMPOP was fitted to data from large-scale aerial larviciding trials in savannah sites (Ghana) and small-scale ground larviciding trials in forest areas (Cameroon). The model was validated against independent data from Burkina Faso/Côte d’Ivoire (savannah) and Bioko (forest). Scenario analysis explored the effects of ecological and programmatic factors such as pre-control daily biting rate (DBR) and larviciding scheme design on reductions and resurgences in biting rates. Results: The estimated efficacy of large-scale aerial larviciding in the savannah was greater than that of ground-based larviciding in the forest. Small changes in larvicidal efficacy can have large impacts on intervention success. At 93% larvicidal efficacy (a realistic value based on field trials), 10 consecutive weekly larvicidal treatments would reduce DBRs by 96% (e.g. from 400 to 16 bites/person/day). At 70% efficacy, and for 10 weekly applications, the DBR would decrease by 67% (e.g. from 400 to 132 bites/person/day). Larviciding is more likely to succeed in areas with lower water temperatures and where blackfly species have longer gonotrophic cycles. Conclusions: Focal vector control can reduce vector biting rates in settings where a high larvicidal efficacy can be achieved and an appropriate duration and frequency of larviciding can be ensured. Future work linking SIMPOP with onchocerciasis transmission models will permit evaluation of the impact of combined anti-vectorial and anti-parasitic interventions on accelerating elimination of the disease