Cellular uptake of steroid carrier proteins - mechanisms and implications

Steroid hormones are believed to enter cells solely by free diffusion through the plasma membrane. However, recent studies suggest the existence of cellular uptake pathways for carrier-bound steroids. Similar to the clearance of cholesterol via lipoproteins, these pathways involve the recognition of carrier proteins by endocytic receptors on the surface of target cells, followed by internalization and cellular delivery of the bound sterols. Here, we discuss the emerging concept that steroid hormones can selectively enter steroidogenic tissues by receptor-mediated endocytosis; and we discuss the implications of these uptake pathways for steroid hormone metabolism and action in vivo

Pro-neurotrophins, sortilin, and nociception

Nerve growth factor (NGF) signaling is important in the development and functional maintenance of nociceptors, but it also plays a central role in initiating and sustaining heat and mechanical hyperalgesia following inflammation. NGF signaling in pain has traditionally been thought of as primarily engaging the classic high-affinity receptor tyrosine kinase receptor TrkA to initiate sensitization events. However, the discovery that secreted proforms of nerve NGF have biological functions distinct from the processed mature factors raised the possibility that these proneurotrophins (proNTs) may have distinct function in painful conditions. ProNTs engage a novel receptor system that is distinct from that of mature neurotrophins, consisting of sortilin, a type I membrane protein belonging to the VPS10p family, and its co-receptor, the classic low-affinity neurotrophin receptor p75NTR. Here, we review how this new receptor system may itself function with or independently of the classic TrkA system in regulating inflammatory or neuropathic pain

UK physiotherapists delivering physical activity advice: what are the challenges and possible solutions? A qualitative study

Objectives Despite the known health benefits of physical activity (PA), PA levels are in decline. Healthcare professionals, including physiotherapists, have been identified as ideal conduits to promote PA, yet their knowledge and awareness of PA guidelines are poor. The aims of this study were to explore current knowledge of PA guidelines among UK physiotherapists and identify barriers and possible solutions to delivering PA advice. Design A qualitative approach using semistructured interviews that took place between March and May 2021. Data were analysed with a thematic approach using Braun and Clarke’s six steps. Setting Various inpatient and outpatient clinical settings across six UK regions. Participants Eighteen UK-based physiotherapists managing National Health Service patients were recruited through volunteer sampling in March 2021. Results Five themes and 16 subthemes (shown in parenthesis) were identified as barriers and solutions to delivering PA advice: physiotherapist intrinsic barriers (knowledge, fear/confidence); a lack of emphasis and priority given to PA (time constraints, minimal educational and staff training); patient barriers (compliance, expectations and fear of doing PA); increasing awareness of the PA guidelines (staff training, signposting awareness, use of social media and television campaigns); and optimising delivery (use of visual resources, good communication and approaches involving being individualised and gradual for patients with chronic conditions). Conclusions In this study, physiotherapist participants seemed to have limited awareness of the PA guidelines despite recent updates and were faced with similar barriers to those previously reported in the literature. The solutions suggested could guide strategies to support physiotherapists being able to deliver PA advice. Further research is needed to evaluate the efficiency of any implemented solutions supporting the delivery of PA advice

Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression

Sorting protein-related receptor with A-type repeats (SORLA) is a major risk factor in cellular processes leading to Alzheimer's disease (AD). It acts as sorting receptor for the amyloid precursor protein (APP) that regulates intracellular trafficking and processing into amyloidogenic-beta peptides (Abeta). Overexpression of SORLA in neurons reduces while inactivation of gene expression (as in knock-out mouse models) accelerates amyloidogenic processing and senile plaque formation. The current study aimed at identifying molecular pathways that control SORLA gene transcription in vivo and that may contribute to low levels of receptor expression in the brain of patients with AD. Using screening approaches in primary neurons, we identified brain-derived neurotrophic factor (BDNF) as a major inducer of Sorla that activates receptor gene transcription through the ERK (extracellular regulated kinase) pathway. In line with a physiological role as regulator of Sorla, expression of the receptor is significantly impaired in mouse models with genetic (Bdnf(-/-)) or disease-related loss of BDNF activity in the brain (Huntington's disease). Intriguingly, exogenous application of BDNF reduced Abeta production in primary neurons and in the brain of wild-type mice in vivo, but not in animals genetically deficient for Sorla. These findings demonstrate that the beneficial effects ascribed to BDNF in APP metabolism act through induction of Sorla that encodes a negative regulator of neuronal APP processing

Creating a sport and exercise medicine undergraduate syllabus: a delphi study

Background Sport and Exercise Medicine (SEM) is a growing speciality in the United Kingdom (UK). This growth has not been replicated in SEM teaching at an undergraduate level and SEM-related topics in schools of medicine in the UK are under-represented. As SEM continues to develop as a specialty it is important to consider how it is embedded at all levels of training. The aim of this project was to establish a consensus on SEM-related skills and knowledge relevant for undergraduate medical students in the UK, ultimately creating a curriculum of learning objectives (LOs). Methods A modified Delphi survey was utilised to seek consensus on LOs suitable for incorporation into UK medical school curricula. An expert panel with adequate knowledge in the field was recruited. The initial curriculum was created by the research team using already established postgraduate SEM curricula. All learning objectives were sent to the expert panel for opinions in phases. Levels of agreement and comments made by the expert panel were reviewed after each phase until a consensus on each learning objective was made. Results The expert panel was made up of 45 individuals, with 35 also completing phase 2 (78% retention rate). The initial curriculum contained 58 learning objectives separated into 9 themes. In phase 1 31% (18/58) were accepted outright, 48% (28/58) were altered and 19% (11/58) were rejected. Two additional learning objectives were added. Of the 49 LOs included in phase 2, 98% (48/49) were accepted. The final curriculum was made up of 9 sub-themes and 48 LOs. Conclusion Sport and Exercise Medicine is a broad ranging and rapidly growing speciality. It is important to establish SEM education in all levels of medical education, including undergraduate level. This is the first published version of a Delphi SEM curriculum for undergraduate medical teaching

Cumulative Human Impacts on Mediterranean and Black Sea Marine Ecosystems: Assessing Current Pressures and Opportunities

Management of marine ecosystems requires spatial information on current impacts. In several marine regions, including the Mediterranean and Black Sea, legal mandates and agreements to implement ecosystem-based management and spatial plans provide new opportunities to balance uses and protection of marine ecosystems. Analyses of the intensity and distribution of cumulative impacts of human activities directly connected to the ecological goals of these policy efforts are critically needed. Quantification and mapping of the cumulative impact of 22 drivers to 17 marine ecosystems reveals that 20% of the entire basin and 60-99% of the territorial waters of EU member states are heavily impacted, with high human impact occurring in all ecoregions and territorial waters. Less than 1% of these regions are relatively unaffected. This high impact results from multiple drivers, rather than one individual use or stressor, with climatic drivers (increasing temperature and UV, and acidification), demersal fishing, ship traffic, and, in coastal areas, pollution from land, accounting for a majority of cumulative impacts. These results show that coordinated management of key areas and activities could significantly improve the condition of these marine ecosystems.JRC.H.1-Water Resource

Measuring diet in primary school children aged 8-11 years: validation of the Child and Diet Evaluation Tool (CADET) with an emphasis on fruit and vegetable intake.

Background/Objectives:The Child And Diet Evaluation Tool (CADET) is a 24-h food diary that measures the nutrition intake of children aged 3-7 years, with a focus on fruit and vegetable consumption. Until now CADET has not been used to measure nutrient intake of children aged 8-11 years. To ensure that newly assigned portion sizes for this older age group were valid, participants were asked to complete the CADET diary (the school and home food diary) concurrently with a 1-day weighed record. Subjects/Methods:A total of 67 children with a mean age of 9.3 years (s.d.: ± 1.4, 51% girls) participated in the study. Total fruit and vegetable intake in grams and other nutrients were extracted to compare the mean intakes from the CADET diary and Weighed record using t-tests and Pearson's r correlations. Bland-Altman analysis was also conducted to assess the agreement between the two methods. Results: Correlations comparing the CADET diary to the weighed record were high for fruit, vegetables and combined fruit and vegetables (r=0.7). The results from the Bland-Altman plots revealed a mean difference of 54 g (95% confidence interval: -88, 152) for combined fruit and vegetables intake. CADET is the only tool recommended by the National Obesity Observatory that has been validated in a UK population and provides nutrient level data on children's diets. Conclusions:The results from this study conclude that CADET can provide high-quality nutrient data suitable for evaluating intervention studies now for children aged 3-11 years with a focus on fruit and vegetable intake

UK Nurses Delivering Physical Activity Advice: What Are the Challenges and Possible Solutions? A Qualitative Study

There are a multitude of health benefits gained from regular physical activity (PA). Currently, PA advice implementation from NHS nurses is inadequate despite their ever-increasing role in lifestyle and preventive medicine. By assessing their knowledge of current PA guidance, this study proposed to investigate the issues with regular PA advice being given and expand upon nurses’ proposed barriers and solutions. A qualitative approach using semi structured interviews was undertaken between March and August 2023 involving 13 NHS nurses. Thematic analysis was undertaken using Braun and Clarke’s six step approach. Four themes and fifteen subthemes emerged as barriers and solutions in delivering PA advice. Intrinsic barriers included a lack of nurse knowledge on the topic and PA being seen as an afterthought. Extrinsic barriers included time pressures and a lack of staff engagement. Solutions involved increasing staff awareness of guidelines through teaching, policy, encouraging staff to be active and optimising PA advice delivery through a piecemeal approach and utilising online and visual resources. This study displayed an insight into nurses’ thoughts on their consultations with patients regarding PA, and proposed several barriers and solutions. Further work is needed to improve nurses’ PA knowledge and to assess the proposed strategies to improve its delivery

The pro-neurotrophin receptor sortilin is a major neuronal apolipoprotein E receptor for catabolism of amyloid-β peptide in the brain

Apolipoprotein E (APOE) is the major risk factor for sporadic Alzheimer's disease. Among other functions, APOE is proposed to sequester neurotoxic amyloid-{beta} (A{beta}) peptides in the brain, delivering them to cellular catabolism via neuronal APOE receptors. Still, the receptors involved in this process remain controversial. Here, we identified the pro-neurotrophin receptor sortilin as major endocytic pathway for clearance of APOE/A{beata} complexes in neurons. Sortilin binds APOE with high affinity. Lack of receptor expression in mice results in accumulation of APOE and of A{beta} in the brain and in aggravated plaque burden. Also, primary neurons lacking sortilin exhibit significantly impaired uptake of APOE/A{beta} complexes despite proper expression of other APOE receptors. Despite higher than normal brain APOE levels, sortilin-deficient animals display anomalies in brain lipid metabolism (e.g., accumulation of sulfatides) seen in APOE-deficient mice, indicating functional deficiency in cellular APOE uptake pathways. Together, our findings identified sortilin as an essential neuronal pathway for APOE-containing lipoproteins in vivo and suggest an intriguing link between A{beta} catabolism and pro-neurotrophin signaling converging on this receptor

Retromer binds the FANSHY sorting motif in SorLA to regulate amyloid precursor protein sorting and processing

sorLA is a sorting receptor for amyloid precursor protein (APP) genetically linked to Alzheimer's disease (AD). Retromer, an adaptor complex in the endosome-to-Golgi retrieval pathway, has been implicated in APP transport because retromer deficiency leads to aberrant APP sorting and processing and levels of retromer proteins are altered in AD. Here we report that sorLA and retromer functionally interact in neurons to control trafficking and amyloidogenic processing of APP. We have identified a sequence (FANSHY) in the cytoplasmic domain of sorLA that is recognized by the VPS26 subunit of the retromer complex. Accordingly, we characterized the interaction between the retromer complex and sorLA and determined the role of retromer on sorLA-dependent sorting and processing of APP. Mutations in the VPS26 binding site resulted in receptor redistribution to the endosomal network, similar to the situation seen in cells with VPS26 knockdown. The sorLA mutant retained APP-binding activity but, as opposed to the wild-type receptor, misdirected APP into a distinct non-Golgi compartment, resulting in increased amyloid processing. In conclusion, our data provide a molecular link between reduced retromer expression and increased amyloidogenesis as seen in patients with sporadic AD