Molecular misreading: The occurrence of frameshift proteins in different diseases

Neuronal homoeostasis requires a constant balance between biosynthetic and catabolic processes. Eukaryotic cells primarily use two distinct mechanisms for degradation: the proteasome and autophagy of aggregates by the lysosomes. We focused on the UPS (ubiquitin-proteasome system). As a result of molecular misreading, misframed UBB (ubiquitin B) (UBB+1) is generated. UBB+1 accumulates in the neuritic plaques and neurofibrillary tangles in all patients with AD (Alzheimer's disease) and in the neuronal and glial hallmarks of other tauopathies and in polyglutamine diseases such as Huntington's disease. UBB+1 is not present in synucleinopathies such as Parkinson's disease. We showed that UBB+1 causes UPS dysfunction, aggregation and apoptotic cell death. UBB+1 is also present in non-neurological cells, hepatocytes of the diseased liver and in muscles during inclusion body myositis. Other frequently occurring (age-related) diseases such as Type 2 (non-insulin-dependent) diabetes mellitus are currently under investigation. These findings point to the importance of the UPS in diseases and open new avenues for target identification of the main players of the UPS. Treatment of these diseases with tools (e.g. viral RNA interference constructs) to intervene with specific targets is the next step

Assessing publication rates from medical students' mandatory research projects in the Netherlands: a follow-up study of 10 cohorts of medical students

Objectives The medical field is facing a clinician-scientist shortage. Medical schools could foster the clinician-scientist workforce by offering students research opportunities. Most medical schools offer elective research programmes. Subsequently, a subset of doctors graduates without any research experience. Mandatory research projects may be more sufficient to develop clinician-scientist, but take more supervision and curricular time. There is limited insight in the scientific outcomes of mandatory research experiences. This study aims to examine publication rates of a mandatory research experience, identify factors associated with publication, and includes postgraduate research engagement. Design and setting Prospective follow-up study involving 10 cohorts of medical students' mandatory research projects from Leiden University Medical Center. Participants All medical students who conducted their research project between 2008 and 2018 (n=2329) were included. Main outcome measure Publication rates were defined as peer-reviewed scientific publications, including research papers, reviews, and published meeting abstracts. Postgraduate research engagement was defined as research participation and dissemination of research at scientific conferences or in journals. Results In total, 644 (27.7%) of all mandatory research experiences resulted in publication, with students mainly as first (n=984, 42.5%) or second author (n=587, 25.3%) and above world average citation impact (mean normalised journal score 1.29, mean normalised citation score 1.23). Students who conducted their research in an academic centre (adjusted OR 2.82; 95% CI 2.10 to 3.77), extended their research (adjusted OR 1.73; 95% CI 1.35 to 2.20), were involved in an excellency track (adjusted OR 2.08; 95% CI 1.44 to 3.01), or conducted clinical (adjusted OR 2.08; 95% CI 1.15 to 3.74) or laboratory (adjusted OR 2.16; 95% CI 1.16 to 4.01) research published their research more often. Later as junior doctors, this group significantly more often disseminate their research results at scientific conferences (adjusted OR 1.89; 95% CI 1.11 to 3.23) or in journals (adjusted OR 1.98; 95% CI 1.14 to 3.43). Conclusions Our findings suggest that a significant subset of hands-on mandatory research projects with flexible learning pathways result in tangible research output with proper impact and that such successful experiences can be considered as diving board towards a research-oriented career.Clinical epidemiolog

Thermal Density Functional Theory in Context

This chapter introduces thermal density functional theory, starting from the ground-state theory and assuming a background in quantum mechanics and statistical mechanics. We review the foundations of density functional theory (DFT) by illustrating some of its key reformulations. The basics of DFT for thermal ensembles are explained in this context, as are tools useful for analysis and development of approximations. We close by discussing some key ideas relating thermal DFT and the ground state. This review emphasizes thermal DFT's strengths as a consistent and general framework.Comment: Submitted to Spring Verlag as chapter in "Computational Challenges in Warm Dense Matter", F. Graziani et al. ed

SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Differences in post mortem stability of sex steroid receptor immunoreactivity in rat brain

Difficulties in demonstrating sex steroid receptors in the human brain by immunohistochemistry (IHC) may depend on postmortem delay and a long fixation time. The effect of different postmortem times was therefore studied in rat brain kept in the skull at room temperature for 0, 6, or 24 hr after death. After a long fixation for 20 days, hypothalami were embedded in paraffin and sections were immunohistochemically stained for androgen receptor (AR), estrogen receptor-alpha (ER), or progesterone receptor (PR). Retrieving the antigenic sites by microwave pretreatment was essential to obtain successful IHC in all groups studied. In general, immunoreactivity was restricted to the cell nuclei. However, the intensity of the staining appeared to be strongly dependent on the different receptor antigens and postmortem time. Both AR and ER but not PR immunoreactivity were decreased after immersion-fixation compared to the perfused sections at time point zero. In brains fixed by immersion, all three receptors decreased gradually with increasing postmortem time, and ER became hardly detectable after 24 hr postmortem. The results of these experiments show that, with the protocol used, postmortem variables and lengthy fixation do not, in principle, prevent sex steroid receptor IHC in human material. The outcome of the immunostaining, however, might be strongly dependent on the epitopes and/or antibody use