Investigating The Role Of LBH During Early Embryonic Development In Xenopus Laevis

LBH is a highly conserved protein whose role during vertebrate development is relatively under-studied. In collaboration with the Albertson lab, our lab has previously shown that it is necessary for cranial neural crest cell migration in the zebrafish and in Xenopus laevis. The molecular mechanisms through which it acts are not well understood. In Xenopus, LBH is a maternally deposited protein. As such, studying its role in early development has not been feasible through the morpholino-mediated knockdown techniques that prevent translation of target genes. Recently, a technique for degrading endogenous proteins was developed, called Trim-Away. This was developed in mammalian systems and utilizes the E3 ubiquitin ligase Trim21 in conjunction with an antibody against a protein of interest in order to degrade the protein. In order to observe the effects of a knockdown of LBH during early embryonic development, we sought to modify the technique for use in Xenopus. We injected embryos with mRNA encoding the human form of trim21 along with a monoclonal antibody against LBH that our lab developed (2B8) and tracked degradation of the protein over time, monitoring embryos for any phenotypes arising during early development. Our results demonstrate that Trim-Away can be utilized in Xenopus. LBH depleted embryos display a variety of defects during gastrulation, the process by which the three germ layers are properly organized. These appear to be mainly due to defects in fibronectin fibrillogenesis and mesodermal migration

Mechanistic Study of the Effect of Endothelin SNPs in Microvascular Angina – protocol of the PRIZE Endothelin Sub-Study

Introduction Microvascular angina (MVA) is a common cause of ischemia with non-obstructive coronary arteries (INOCA) and limited therapeutic options are available to those affected. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathophysiology of MVA. A large randomised, double blinded, placebo controlled crossover trial, the PRecIsion medicine with ZibotEntan in microvascular angina (PRIZE) trial is currently underway, investigating an endothelin receptor antagonist – Zibotentan, as a new drug treatment for microvascular angina. The trial uses a 'precision medicine' approach by preferential selection of those with higher ET-1 expression conferred by the PHACTR1 minor G allele single nucleotide polymorphism (SNP). The incidence of this SNP occurs in approximately one third of the population therefore a considerable number of screened patients will be ineligible for randomisation and the treatment phase of the trial. Methods In the PRIZE Endothelin (ET) Sub-Study, patients screened out of the PRIZE trial will be genotyped for other genetic variants in the ET-1 pathway. These will be correlated with phenotypic characteristics including exercise tolerance, angina severity and quantitative measures of microvascular function on cardiovascular MRI as well as mechanistic data on endothelin pathway signalling. Conclusions The study will provide a comprehensive genotype and phenotype bio-resource identifying novel ET-1 genotypes to inform the potential wider use of endothelin receptor antagonists for this indication.Wellcome Trust [WT107715/Z/15/Z, APD], British Heart Foundation [CB, RE/18/6134217], Medical Research Council [CB, MR/S018905/1], ].Jon Moulton Charity Trust [GRA, SPH

Factors influencing national implementation of innovations within community pharmacy : a systematic review applying the consolidated framework for implementation research

Background: To meet emergent healthcare needs, innovations need to be implemented into routine clinical practice. Community pharmacy is increasingly considered a setting through which innovations can be implemented to achieve positive service and clinical outcomes. Small-scale pilot programmes often need scaled up nation-wide to affect population level change. This systematic review aims to identify facilitators and barriers to the national implementation of community pharmacy innovations. Methods: A systematic review exploring pharmacy staff perspectives of the barriers and facilitators to implementing innovations at a national level was conducted. The databases Medline, EMBASE, PsycINFO, CINAHL, and Open Grey were searched and supplemented with additional search mechanisms such as Zetoc alerts. Eligible studies underwent quality assessment, and a directed content analysis approach to data extraction was conducted and aligned to the Consolidated Framework for Implementation Research (CFIR) to facilitate narrative synthesis. Results: Thirty-nine studies were included: 16 were qualitative, 21 applied a questionnaire design, and 2 were mixed methods. Overarching thematic areas spanning across the CFIR domains were pharmacy staff engagement (e.g. their positive and negative perceptions), operationalisation of innovations (e.g. insufficient resources and training), and external engagement (e.g. the perceptions of patients and other healthcare professionals, and their relationship with the community pharmacy). Study participants commonly suggested improvements in the training offered, in the engagement strategies adopted, and in the design and quality of innovations. Conclusions: This study's focus on national innovations resulted in high-level recommendations to facilitate the development of successful national implementation strategies. These include (1) more robust piloting of innovations, (2) improved engagement strategies to increase awareness and acceptance of innovations, (3) promoting whole-team involvement within pharmacies to overcome time constraints, and (4) sufficient pre-implementation evaluation to gauge acceptance and appropriateness of innovations within real-world settings. The findings highlight the international challenge of balancing the professional, clinical, and commercial obligations within community pharmacy practice. A preliminary theory of how salient factors influence national implementation in the community pharmacy setting has been developed, with further research necessary to understand how the influence of these factors may differ within varying contexts. Trial registration: A protocol for this systematic review was developed and uploaded onto the PROSPERO international prospective register of systematic reviews database (Registration number: CRD42016038876)

Novel Application of NASA's GEOS-CF CO Forecasting System to ACT-America Airborne Campaign

No abstract availabl

Observing World Cities from Space: Progress and Challenges

No abstract availabl

Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson's disease associated with enhanced autophagy

Protective effects of the telomerase protein TERT have been shown in neurons and brain. We previously demonstrated that TERT protein can accumulate in mitochondria of Alzheimer’s disease (AD) brains and protect from pathological tau in primary mouse neurons. This prompted us to employ telomerase activators in order to boost telomerase expression in a mouse model of Parkinson’s disease (PD) overexpressing human wild type α-synuclein. Our aim was to test whether increased Tert expression levels were able to ameliorate PD symptoms and to activate protein degradation. We found increased Tert expression in brain for both activators which correlated with a substantial improvement of motor functions such as gait and motor coordination while telomere length in the analysed region was not changed. Interestingly, only one activator (TA-65) resulted in a decrease of reactive oxygen species from brain mitochondria. Importantly, we demonstrate that total, phosphorylated and aggregated α-synuclein were significantly decreased in the hippocampus and neocortex of activator-treated mice corresponding to enhanced markers of autophagy suggesting an improved degradation of toxic alpha-synuclein. We conclude that increased Tert expression caused by telomerase activators is associated with decreased α-synuclein protein levels either by activating autophagy or by preventing or delaying impairment of degradation mechanisms during disease progression. This encouraging preclinical data could be translated into novel therapeutic options for neurodegenerative disorders such as PD

Scottish Patient Safety Programme – Pharmacy in Primary Care Collaborative Final Evaluation Report

The Scottish Patient Safety Programme (SPSP) is a national quality improvement initiative which launched in 2008. NHS Scotland collaborated with the Institute of Healthcare Improvement (IHI) on the programme, and the theoretical basis of the implementation process was depicted by Paul Carlile and Clay Christensen, who developed a driver diagram with actionable guidance on how to meet the overarching aim to “Improve Safety of Healthcare Services in Scotland” (1). Within the acute sector a number of successes were achieved: a 7% reduction in hospital standardised mortality rates, a 70% reduction in Clostridium Difficile infection since 2007 and an avoidance of 125000 “bed days” in two years for those over 65 years old (2)

The long-distance relationship between Dirofilaria and the UK: case report and literature review

Over the last two decades, vector-borne pathogens (VBPs) have changed their distribution across the globe as a consequence of a variety of environmental, socioeconomic and geopolitical factors. Dirofilaria immitis and Dirofilaria repens are perfect exemplars of European VBPs of One Health concern that have undergone profound changes in their distribution, with new hotspots of infection appearing in previously non-endemic countries. Some areas, such as the United Kingdom, are still considered non-endemic. However, a combination of climate change and the potential spread of invasive mosquito species may change this scenario, exposing the country to the risk of outbreaks of filarial infections. Only a limited number of non-autochthonous cases have been recorded in the United Kingdom to date. These infections remain a diagnostic challenge for clinicians unfamiliar with these “exotic” parasites, which in turn complicates the approach to treatment and management. Therefore, this review aims to (i) describe the first case of D. repens infection in a dog currently resident in Scotland, (ii) summarise the available literature on Dirofilaria spp. infections in both humans and animals in the United Kingdom and (iii) assess the suitability of the United Kingdom for the establishment of these new VBPs