LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson's disease and dementia with Lewy bodies

Loss-of-function variants in the low-density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with autosomal-dominant Parkinson's disease (PD), PD dementia, and dementia with Lewy bodies (DLB). Moreover, LRP10 variants have been found in individuals diagnosed with progressive supranuclear palsy and amyotrophic lateral sclerosis. Despite this genetic evidence, little is known about the expression and function of LRP10 protein in the human brain under physiological or pathological conditions. To better understand how LRP10 variants lead to neurodegeneration, we first performed an in-depth characterisation of LRP10 expression in post-mortem brains and human-induced pluripotent stem cell (iPSC)-derived astrocytes and neurons from control subjects. In adult human brain, LRP10 is mainly expressed in astrocytes and neurovasculature but undetectable in neurons. Similarly, LRP10 is highly expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived neurons. In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). Furthermore, although LRP10 expression and localisation in the substantia nigra of most idiopathic PD and DLB patients and LRP10 variant carriers diagnosed with PD or DLB appeared unchanged compared to control subjects, significantly enlarged LRP10-positive vesicles were detected in a patient carrying the LRP10 p.Arg235Cys variant. Last, LRP10 was detected in Lewy bodies (LB) at late maturation stages in brains from idiopathic PD and DLB patients and in LRP10 variant carriers. In conclusion, high LRP10 expression in non-neuronal cells and undetectable levels in neurons of control subjects indicate that LRP10-mediated pathogenicity is initiated via cell non-autonomous mechanisms, potentially involving the interaction of LRP10 with SORL1 in vesicle trafficking pathways. Together with the specific pattern of LRP10 incorporation into mature LBs, these data support an important mechanistic role for disturbed vesicle trafficking and loss of LRP10 function in neurodegenerative diseases

A Simple Approach for COnsumption and RElease (CORE) Analysis of Metabolic Activity in Single Mammalian Embryos

Non-invasive assay of the consumption and release of metabolites by individual human embryos could allow selection at the cleavage stage of development and facilitate Single Embryo Transfer in clinical IVF but will require simple, high throughput, sensitive methods applicable to small volume samples. A rapid, simple, non-invasive method has therefore been devised using a standard fluorescence plate reader, and used to measure the consumption of pyruvate and glucose, and release of lactate by single bovine embryos at all stages of preimplantation development in culture; amino acid profiles have been determined using HPLC. Early embryos with an ‘intermediate’ level (6.14±0.27 pmol/embryo/h) of pyruvate uptake were associated with the highest rate (68.3%) of blastocyst development indicating that a mid “optimum” range of pyruvate consumption correlates with high viability in this bovine model

Dynamics of career choice among students in undergraduate medical courses. A BEME systematic review : BEME Guide No. 33

Introduction: Due to the lack of a theoretically embedded overview of the recent literature on medical career decision-making, this study provides an outline of these dynamics. Since differences in educational routes to the medical degree likely affect career choice dynamics, this study focuses on medical career decision-making in educational systems with a Western European curriculum structure.Methods: A systematic search of electronic databases (Medline, Embase) was conducted from January 2008 to November 2014. A panel of seven independent reviewers performed the data extraction, quality assessment and data synthesis using the Bland-Meurer model of medical specialty choice as a reference.Results: Fifty-seven studies met the inclusion criteria for the review. Factors associated with specialty preference or career choice can be classified in five main categories: (1) medical school characteristics (e.g., curriculum structure), (2) student characteristics (e.g., age, personality), (3) student values (e.g., personal preference), (4) career needs to be satisfied (e.g., expected income, status, and work-life balance), and (5) perception of specialty characteristics (e.g., extracurricular or curricular experiences). Especially career needs and perceptions of specialty characteristics are often associated with medical career decision-making.Conclusion: Our results support that medical career decisions are formed by a matching of perceptions of specialty characteristics with personal needs. However, the process of medical career decision-making is not yet fully understood. Besides identifying possible predictors, future research should focus on detecting interrelations between hypothesized predictors and identify the determinants and interrelations at the various stages of the medical career decision-making process