Axonal endoplasmic reticulum tubules control local translation via P180/RRBP1-mediated ribosome interactions.

Local mRNA translation in axons is critical for the spatiotemporal regulation of the axonal proteome. A wide variety of mRNAs are localized and translated in axons; however, how protein synthesis is regulated at specific subcellular sites in axons remains unclear. Here, we establish that the axonal endoplasmic reticulum (ER) supports axonal translation in developing rat hippocampal cultured neurons. Axonal ER tubule disruption impairs local translation and ribosome distribution. Using nanoscale resolution imaging, we find that ribosomes make frequent contacts with axonal ER tubules in a translation-dependent manner and are influenced by specific extrinsic cues. We identify P180/RRBP1 as an axonally distributed ribosome receptor that regulates local translation and binds to mRNAs enriched for axonal membrane proteins. Importantly, the impairment of axonal ER-ribosome interactions causes defects in axon morphology. Our results establish a role for the axonal ER in dynamically localizing mRNA translation, which is important for proper neuron development.

Long-Term Outcomes of Liver Transplantation for the Management of Neuroendocrine Neoplasms: A Systematic Review.

Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review of studies published in PubMed, Scopus and OVID until 1 July 2021, we summarise and critically appraise the existing literature regarding this modality, with a special focus on long-term outcomes data where possible. Fourteen studies were identified that reported outcomes from the use of liver transplantation for metastatic neuroendocrine neoplasms. No randomised trials were identified. Generally, indications and selection criteria were poorly articulated, with the notable exception of studies using the Milan criteria. The median 5-year overall survival was 65% (ranging from 36% to 97.2%, 11 studies), and the median 10-year overall survival was 50% (ranging from 46.1% to 88.8%, 3 studies). One additional study focussed on treatments and outcomes following post-transplant recurrence. No studies reported outcomes past 10 years. Further follow-up of the largest series with explicit selection criteria will deepen our understanding of the role that transplantation has to play in this setting.

Value of a UK medical degree for international students (VISION): a cross-sectional study.

OBJECTIVES: It is estimated that NHS staff consist of over 200 different nationalities, with a reported 30.7% of doctors holding a nationality other than British. Despite this, international medical students represent 7.5% of all medical students studying in the UK and pay on average, 4-6 times more in tuition fees when compared with the £9250 per annum (Great British Pounds (£) in 2021) paid by home students. This study's aim and objective are to evaluate the perception of the financial cost and value of the UK medical degree for international students and their motivations for pursuing such a degree. METHODS: This is a cross-sectional observational study enquiring about international premedical, medical and medical school graduates' perception of the value of the UK medical degree and factors influencing their decision to study in the UK.A questionnaire was developed and distributed to 24 medical schools and 64 secondary schools both internationally and across the UK. RESULTS: A total of 352 responses from 56 nationalities were recorded. 96% of international students identified clinical and academic opportunities as the most important factors to study medicine in the UK, closely followed by quality of life (88%). The least important factor was family reasons, with 39% of individuals identifying this factor. Only 4.82% of graduates in our study considered leaving the UK after training. Overall, 54% of students felt the UK degree was value for money. This belief was significantly higher in premedical students compared with existing students and graduates (71% vs 52% and 20%, p<0.001 for all comparisons). CONCLUSION: The quality of medical education and international prestige are attractive factors for international students to study medicine in the UK. However, further work is needed to ascertain reasons for the differing perceptions of the value by international students at different stages in their clinical training.

What are the impacts of recent changes in UK core surgical training application on current and prospective applicants?

Core Surgical Training (CST) is a 2-year UK training programme, designed to provide junior doctors interested in surgery with formal training and to introduce them to various surgical specialties. The selection process is divided into two stages. In the portfolio stage, applicants submit a score based on a published self-assessment guidance. Only candidates whose scores remain higher than the cut-off after verification will proceed to the interview stage. Finally, jobs are allocated according to the overall performance of both stages. Despite the rising number of applicants, the number of job vacancies remains largely similar. Hence, the intensity of competition has increased over the past few years. The competitive ratio increased from 2.8:1 in 2019 to 4.6:1 in 2021. Hence, several changes have been implemented in the CST application process, with the aim to combat this trend. The recurring changes in the CST application process have sparked considerable discussions among applicants. The effect of the changes on the current and prospective applicants is yet to be explored. This letter aims to highlight the changes and discuss the potential impacts. The CST application from 2020 to 2022 has been compared to identify the changes implemented throughout the years. Specific changes have been highlighted. The impact of changes in the CST application process on applicants has been divided into 'pros' and 'cons' sections. Recently, many specialties have shifted from portfolio-based assessment to Multiple Specialty Recruitment Assessments. In contrast, CST application preserves its emphasis on holistic assessment and academic excellence. However, the application process could be further refined for more impartial recruitment. This would ultimately help alleviate the challenging situation of staff shortage, increase the number of specialist doctors, reduce waiting time for elective surgeries and most importantly, provide better care for our patients in the NHS.

The most influential COVID-19 articles: A systematic review.

Background: Since December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),causative pathogen of coronavirus disease 2019 (COVID-19), has triggered a pandemic with challenges for health care systems around the world. Researchers have studied and published on the subject of SARS-CoV-2 and the disease extensively. What is the significance of articles published, shared and cited in the early stages of such a pandemic? Materials and methods: A systematic literature search in a time frame of 12 months and analysis rating using Principle Component Analysis (PCA) and Multiple Factor Analysis (MFA) were performed. Results: The 100 most cited COVID-19 articles were identified. The majority of these articles were from China (n = 54), followed by United States of America (USA) (n = 21) and United Kingdom (UK) (n = 8). All articles were published in high-ranked, peer-reviewed journals, with research focusing onthe the diagnosis, transmission and therapy of COVID-19. The level of evidence of the 100 most cited COVID-19 articles on average was low. Conclusion: In the early stages of a pandemic, new and innovative research can emerge and be highly cited, regardless of the level of evidence.

What are the impacts of recent changes in UK core surgical training application on current and prospective applicants?

Core Surgical Training (CST) is a 2-year UK training programme, designed to provide junior doctors interested in surgery with formal training and to introduce them to various surgical specialties. The selection process is divided into two stages. In the portfolio stage, applicants submit a score based on a published self-assessment guidance. Only candidates whose scores remain higher than the cut-off after verification will proceed to the interview stage. Finally, jobs are allocated according to the overall performance of both stages. Despite the rising number of applicants, the number of job vacancies remains largely similar. Hence, the intensity of competition has increased over the past few years. The competitive ratio increased from 2.8:1 in 2019 to 4.6:1 in 2021. Hence, several changes have been implemented in the CST application process, with the aim to combat this trend. The recurring changes in the CST application process have sparked considerable discussions among applicants. The effect of the changes on the current and prospective applicants is yet to be explored. This letter aims to highlight the changes and discuss the potential impacts. The CST application from 2020 to 2022 has been compared to identify the changes implemented throughout the years. Specific changes have been highlighted. The impact of changes in the CST application process on applicants has been divided into 'pros' and 'cons' sections. Recently, many specialties have shifted from portfolio-based assessment to Multiple Specialty Recruitment Assessments. In contrast, CST application preserves its emphasis on holistic assessment and academic excellence. However, the application process could be further refined for more impartial recruitment. This would ultimately help alleviate the challenging situation of staff shortage, increase the number of specialist doctors, reduce waiting time for elective surgeries and most importantly, provide better care for our patients in the NHS.

Real-time three-dimensional tracking of single vesicles reveals abnormal motion and pools of synaptic vesicles in neurons of Huntington's disease mice.

Although defective synaptic transmission was suggested to play a role in neurodegenerative diseases, the dynamics and vesicle pools of synaptic vesicles during neurodegeneration remain elusive. Here, we performed real-time three-dimensional tracking of single synaptic vesicles in cortical neurons from a mouse model of Huntington's disease (HD). Vesicles in HD neurons had a larger net displacement and radius of gyration compared with wild-type neurons. Vesicles with high release probability (Pr) were interspersed with low-Pr vesicles in HD neurons, whereas high-Pr vesicles were closer to fusion sites than low-Pr in wild-type neurons. Non-releasing vesicles in HD neurons had an abnormally high prevalence of irregular oscillatory motion. These abnormal dynamics and vesicle pools were rescued by overexpressing Rab11, and the abnormal irregular oscillatory motion was rescued by jasplakinolide. Our studies reveal the abnormal dynamics and pools of synaptic vesicles in the early stages of HD, suggesting a possible pathogenic mechanism of neurodegenerative diseases.

Decreased BDNF Release in Cortical Neurons of a Knock-in Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an increase in CAG repeats in the Huntingtin gene (HTT). The striatum is one of the most vulnerable brain regions in HD, and altered delivery of BDNF to the striatum is believed to underlie this high vulnerability. However, the delivery of BDNF to the striatum in HD remains poorly understood. Here, we used real-time imaging to visualize release of BDNF from cortical neurons cultured alone or co-cultured with striatal neurons. BDNF release was significantly decreased in the cortical neurons of zQ175 mice (a knock-in model of HD), and total internal reflection fluorescence microscopy revealed several release patterns of single BDNF-containing vesicles, with distinct kinetics and prevalence, in co-cultured cortical HD neurons. Notably, a smaller proportion of single BDNF-containing vesicles underwent full release in HD neurons than in wild-type neurons. This decreased release of BDNF in cortical neurons might lead to decreased BDNF levels in the striatum because the striatum receives BDNF mainly from the cortex. In addition, we observed a decrease in the total travel length and speed of BDNF-containing vesicles in HD neurons, indicating altered transport of these vesicles in HD. Our findings suggest a potential mechanism for the vulnerability of striatal neurons in HD and offer new insights into the pathogenic mechanisms underlying the degeneration of neurons in HD.

Altered Synaptic Vesicle Release and Ca2+ Influx at Single Presynaptic Terminals of Cortical Neurons in a Knock-in Mouse Model of Huntington's Disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the huntingtin (HTT) gene, which leads to progressive loss of neurons starting in the striatum and cortex. One possible mechanism for this selective loss of neurons in the early stage of HD is altered neurotransmission at synapses. Despite the recent finding that presynaptic terminals play an important role in HD, neurotransmitter release at synapses in HD remains poorly understood. Here, we measured synaptic vesicle release in real time at single presynaptic terminals during electrical field stimulation. We found the increase in synaptic vesicle release at presynaptic terminals in primary cortical neurons in a knock-in mouse model of HD (zQ175). We also found the increase in Ca2+ influx at presynaptic terminals in HD neurons during the electrical stimulation. Consistent with increased Ca2+-dependent neurotransmission in HD neurons, the increase in vesicle release and Ca2+ influx was rescued with Ca2+ chelators or by blocking N-type voltage-gated Ca2+ channels, suggesting N-type voltage-gated Ca2+ channels play an important role in HD. Taken together, our results suggest that the increased synaptic vesicles release due to increased Ca2+ influx at presynaptic terminals in cortical neurons contributes to the selective neurodegeneration of these neurons in early HD and provide a possible therapeutic target.

Correlation between compositional and mechanical properties of human mesenchymal stem cell-collagen microspheres during chondrogenic differentiation.

Mesenchymal stem cell (MSC)-based engineering is promising for cartilage repair. However, the compositional mechanical relationship of the engineered structures has not been extensively studied, given the importance of such relationship in native cartilage tissues. In this study, a novel human MSC-collagen microsphere system was used to study the compositional mechanical relationship during in vitro chondrogenic differentiation using histological and biochemical methods and a microplate compression assay. The mechanical property was found positively correlating with newly deposited cartilage-relevant matrices, glycosaminoglycan, and type II collagen, and with the collagen crosslinker density, in agreement with the presence of thick collagen bundles upon structural characterization. On the other hand, the mechanical property negatively correlates with type I collagen and total collagen, suggesting that the initial collagen matrix scaffold of the microsphere system was being remodeled by the differentiating human MSCs. This study also demonstrated the application of a simple, sensitive, and nondestructive tool for monitoring the progression of chondrogenic differentiation of MSCs in tissue-engineered constructs and therefore contributes to future development of novel cartilage repair strategies.