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Author(s): Naomi R. Latorraca [sup.1] [sup.2] [sup.3] [sup.4] , Jason K. Wang [sup.2] , Brian Bauer [sup.5] , Raphael J. L. Townshend [sup.2] , Scott A. Hollingsworth [sup.1] [sup.2] [sup.3] [...], Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear.sup.1,2. Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail--which bind distinct surfaces on arrestin--can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site-directed fluorescence spectroscopy. The effect of the receptor core on arrestin conformation is mediated primarily by interactions of the intracellular loops of the receptor with the arrestin body, rather than the marked finger-loop rearrangement that is observed upon receptor binding. In the absence of a receptor, arrestin frequently adopts active conformations when its own C-terminal tail is disengaged, which may explain why certain arrestins remain active long after receptor dissociation. Our results, which suggest that diverse receptor binding modes can activate arrestin, provide a structural foundation for the design of functionally selective ('biased') GPCR-targeted ligands with desired effects on arrestin signalling.Molecular dynamics simulations and site-directed fluorescence spectroscopy show that the transmembrane core and cytoplasmic tail of G-protein-coupled receptors independently and cooperatively activate arrestin.

Early in human embryonic development, it is unclear how amniotic sac formation is regulated. Here, the authors use a human pluripotent stem cell-based model, termed the post-implantation amniotic sac embryoid, to recapitulate early embryogenic events of human amniotic sac development.

Abstract Background New approaches are required to address the needs of complex undiagnosed diseases patients. These approaches include clinical genomic diagnostic pipelines, utilizing intra- and multi-disciplinary platforms, as well as specialty-specific genomic clinics. Both are advancing diagnostic rates. However, complementary cross-disciplinary approaches are also critical to address those patients with multisystem disorders who traverse the bounds of multiple specialties and remain undiagnosed despite existing intra-specialty and genomic-focused approaches. The diagnostic possibilities of undiagnosed diseases include genetic and non-genetic conditions. The focus on genetic diseases addresses some of these disorders, however a cross-disciplinary approach is needed that also simultaneously addresses other disorder types. Herein, we describe the initiation and summary outcomes of a public health system approach for complex undiagnosed patients - the Undiagnosed Diseases Program-Western Australia (UDP-WA). Results Briefly the UDP-WA is: i) one of a complementary suite of approaches that is being delivered within health service, and with community engagement, to address the needs of those with severe undiagnosed diseases; ii) delivered within a public health system to support equitable access to health care, including for those from remote and regional areas; iii) providing diagnoses and improved patient care; iv) delivering a platform for in-service and real time genomic and phenomic education for clinicians that traverses a diverse range of specialties; v) retaining and recapturing clinical expertise; vi) supporting the education of junior and more senior medical staff; vii) designed to integrate with clinical translational research; and viii) is supporting greater connectedness for patients, families and medical staff. Conclusion The UDP-WA has been initiated in the public health system to complement existing clinical genomic approaches; it has been targeted to those with a specific diagnostic need, and initiated by redirecting existing clinical and financial resources. The UDP-WA supports the provision of equitable and sustainable diagnostics and simultaneously supports capacity building in clinical care and translational research, for those with undiagnosed, typically rare, conditions.

Global-scale land cover characterization has advanced from a spatial resolution of 1 × 1° in the mid-1990s to 30 × 30 m resolution to date. However, some mapping challenges exist persistently regardless of the increasing spatial resolution. Data fusion has been proved as an effective way of improving land cover characterization. Here we applied a machine learning-based data integration approach for improving global-scale forest cover characterization. The approach employed six coarse-resolution (250–1000 m) global land cover maps as input and various regional, higher-resolution land cover data-sets as reference to build regression tree models per continent. The average error of 10-fold cross validation of the regression tree models varied between 7.70 and 15.68% forest cover and the r2 varied between 0.76 and 0.94, indicating the robustness of the trained models. As a result of data fusion, the synthesized global forest cover map was more accurate than any input global product. We also showed that other major vegetative land cover types such as cropland, woodland, grassland, and wetland all exhibit similar magnitude of discrepancies as forest among existing land cover maps. Our developed method, because of its type- and scale-invariant feature, can be implemented for other land cover types for improving their global characterization. The ensemble approach can also be internalized for improving data quality when generating a global land cover product, where multiple versions can be produced and subsequently integrated.

Category: Ankle, Ankle Arthritis Introduction/Purpose: Ankle replacements (TAR) have evolved significantly over the past 10 years. While most TAR systems reference the medial gutter to set axial tibial component rotation, newer CT scan-based patient specific instrumentation (PSI) allows any rotational position to be set, and this is commonly set to bisect the medial and lateral gutter lines. It is still not yet known which alignment technique is optimal. Methods: We initiated a prospective cohort analysis of 22 consecutive cases using the Prophecy® 3D PSI guide (Wright Medical Technologies, Memphis, TN). There were four foot and ankle fellowship trained surgeons practicing from two referral centers. Every procedure had an intra-operative photograph taken from the knee looking down to the ankle after both the attachment of the PSI guide to the tibia and the insertion of the standard medial gutter fork. The axial rotational angle between both was measured and compared to the Prophecy® pre-operative plan. Statistical analysis was performed using the student’s T-test for paired distribution and descriptive statistics given the number of cases (N=22). Results: The primary outcome of this study was to assess the correlation between the pre-operative medial gutter line drawn on the Prophecy plan and the intra-operative medial gutter fork angle. The Pearson R correlation value was 0.54 (p = 0.53). The average difference between the pre-operative medial gutter line on the Prophecy® plan and the intra-operative gutter fork was -0.46 [95% CI -2.04 – 1.10]. This could mean that the medial gutter fork is on average slightly more internally rotated than templated medial gutter line. However, the average of the absolute differences between the preoperative medial gutter line and the intraoperative medial gutter fork was 2.69 degrees. Of the 22 cases, 11 were within 2 degrees and 17 were within 4 degrees. Conclusion: The medial gutter line on Prophecy® PSI pre-operative TAR plans is a moderately good representation of the intra- operative medial gutter fork position used in standard TAR instrumentation. Based on this, using the Prophecy® default which sets the tibial implant axial rotation to bisect the medial and lateral gutter lines will typically lead to greater external rotation of the tibial component compared to standard TAR instrumentation which aligns the tibial component to the medial gutter fork. Further work needs to be done to better understand which of these axial alignment options, or potentially others, is optimal.

Category: Ankle, Ankle Arthritis Introduction/Purpose: The Infinity (Wright medical) total ankle replacement (TAR) has become the most implanted ankle replacement in the UK with a 30.1% share in the most recent 2016 England and Wales NJR 14th report. It is a fixed bearing implant utilising an anterior approach and radiological guidance to aid alignment, and is approved for use in the UK as an uncemented implant. Methods: Since introducing the Infinity TAR in June 2014, all implants from two centres in the UK; The Royal Devon and Exeter Hospital NHS Foundation Trust and Northumbria NHS Healthcare Trust, have been followed up prospectively. 113 implants are included with 2 year minimum follow-up, average follow-up being 33 months (24-52). Pre- and post-operative demographic, radiographic and functional outcomes were collected including Visual Analogue Score (VAS), Manchester Oxford foot questionnaire (MOxFQ, UK validated patient reported outcome score) EQ5D (validated quality of life score). Complexity was assessed using COFAS pre-operative grade. Results: Implant survivorship was 93.8% at 2 years minimum. Median age was 68 (42-92), male: female 72:41. Mean MOxFQ improved by 28, mean EQ5D by 1.4 and mean VAS by 7. 16 cases had planned additional procedures, 5 required intra-operative medial malleolar fixation. There have been 2 revisions for deep infection, 2 for implant subsidence, 1 for instability and 2 for unexplained pain (6.2%). 5 patients have required further surgery to the ankle and hindfoot with implant retention (4.4%). 3 patients have asymptomatic tibial cysts (3.4%) and 1 patient has an asymptomatic talar cyst (0.9%) - there is no evidence of progression or loosening. Conclusion: We report favourable early functional, radiographic and survivorship outcomes of this implant in the UK population.

Musician-teacher identity is a "work-in-progress" spanning a career lifetime, yet little research appears to explore how this culminative development occurs, particularly from an individualized musician-teacher viewpoint. Using a qualitative epistemology, the author examines autoethnographic vignettes of life experience to highlight how changes of aging, work environments, and personal circumstances guide such a musician-teacher's journey. A "rivers of experience" approach, combined with several frames of reference, uncovers epiphanic moments showing how local and international contexts shape musician-teacher identity. Given the enormous changes in education over the past 40 years, and the changing, challenging world of Covid-19, this article is a timely and needed catalyst for others to reflect on their own experiences as they look to their futures. [ABSTRACT FROM AUTHOR]

Aims: Planning regulations have been used to prevent the over-proliferation of hot food takeaways, minimising the impact of local obesogenic environments. To help mitigate the effects of lockdown, the UK government introduced temporary changes in March 2020 to Planning Regulations for England, allowing food retailers to open for takeaway services beyond 'ancillary' level without needing to apply for planning permission through permitted development rights (PDR). Businesses are required to notify their local authority (LA) when they implement PDRs. To better understand the impact of regulations on the policy and practice of key professional groups, Public Health England commissioned Teesside University to undertake scoping research in the North East of England. Methods: A focus group and interviews were conducted with 15 professionals from 7 of 12 North East LAs. Professions included Planners, Public Health Leads, Environmental Health Officers and Town Centre Managers. Data were analysed using a codebook thematic analysis approach. An interpretation meeting with some participants was conducted. Results: LAs were not aware of most businesses notifying them of new regulation adherence despite taking up PDRs, but were considered low-priority with many lacking formal recording procedures. There were concerns about health consequences of the changes, and consensus relating to ongoing issues with capacity across all professional groups, largely due to the continuing pandemic and absence of a strategy out of temporary measures. Concerns existed around ensuring cessation of restaurants trading as takeaways, and hygiene inspections backlog. Many (personally) saw new takeaways as a lifeline, offering broader menus and preserving local economies. Conclusion: Lack of information around the number of restaurants/pubs using PDR to trade as takeaway services, ongoing capacity issues of LAs and, at the time, the absence of a strategy post regulation changes, meant there were high levels of uncertainty regarding the impacts of these temporary measures. [ABSTRACT FROM AUTHOR]