Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that are either directed to the muscle nicotinic acetylcholine receptor (AChR) or to the muscle-specific tyrosine kinase ...(MuSK). These autoantibodies define two distinct subforms of the disease-AChR-MG and MuSK-MG. Both AChR and MuSK are expressed on the postsynaptic membrane of the neuromuscular junction (NMJ), which is a highly specialized region of the muscle dedicated to receive and process signals from the motor nerve. Autoantibody binding to proteins of the postsynaptic membrane leads to impaired neuromuscular transmission and muscle weakness. Pro-inflammatory antibodies of the human IgG1 and IgG3 subclass modulate the AChR, cause complement activation, and attract lymphocytes; together acting to decrease levels of the AChR and AChR-associated proteins and to reduce postsynaptic folding. In patients with anti-MuSK antibodies, there is no evidence of loss of junctional folds and no apparent loss of AChR density. Anti-MuSK antibodies are predominantly of the IgG4 isotype, which functionally differs from other IgG subclasses in its anti-inflammatory activity. Moreover, IgG4 undergoes a posttranslational modification termed Fab arm exchange that prevents cross-linking of antigens. These findings suggest that MuSK-MG may be different in etiological and pathological mechanisms from AChR-MG. The effector functions of IgG subclasses on synapse structure and function are discussed in this review.
The Goodpasture antigen-binding protein (GPBP) plays a critical role in brain development. Knockdown of GPBP leads to loss of myelinated tracts in the central nervous system and to extensive ...apoptosis in the brain during early embryogenesis. GPBP was initially identified as a protein associated with the autoantigen in Goodpasture autoimmune syndrome, where it was shown to be a kinase that regulates type IV collagen organization. GPBP isoforms bind and transport ceramide from the endoplasmic reticulum to the Golgi apparatus and are therefore also known as ceramide transporters (CERT). Ceramide dysregulation is involved in autoimmunity and neurodegenerative disorders.
In order to analyze the possible role of GPBP in neuroinflammation and neurodegeneration we studied the basal GPBP expression in normal rat brain. High levels of immunoreactivity were detected in neurons of the cerebral cortex, hippocampal formation, the basal ganglia, the olfactory bulb and nuclei of the thalamus, the hypothalamus and the septal area. Lower expression levels of GPBP were observed widely throughout the brain, suggesting that GPBP plays an important role in central nervous system neuron function.
Melanoma remains the most lethal skin cancer, mainly because of high resistance to therapy. Side population (SP) cells are found in many types of cancer and are usually enriched in therapy-resistant ...as well as tumorigenic cells. Here, we identified a Hoechst dye-effluxing SP in a large series of human melanoma samples representing different progression phases. The SP size did not change with disease stage but was correlated with the prognostic "Breslow's depth" in the primary (cutaneous) tumors. When injected into immunodeficient mice, the SP generated larger tumors than the bulk "main population" (MP) melanoma cells in two consecutive generations, and showed tumorigenic capacity at lower cell numbers than the MP. In addition, the SP reconstituted the heterogeneous composition of the human A375 melanoma cell line, and its clonogenic activity was 2.5-fold higher than that of the MP. Gene-expression analysis revealed upregulated expression in the melanoma SP (versus the MP) of genes associated with chemoresistance and anti-apoptosis. Consistent with these molecular characteristics, the SP increased in proportion when A375 cells were exposed to the melanoma standard chemotherapeutic agent dacarbazine, and to the aggravating condition of hypoxia. In addition, the SP showed enhanced expression of genes related to cell invasion and migration, as well as to putative (melanoma) cancer stem cells (CSC) including ABCB1 and JARID1B. ABCB1 immunoreactivity was detected in a number of tumor cells in human melanomas, and in particular in clusters at the invasive front of the primary tumors. Together, our findings support that the human melanoma SP is enriched in tumorigenic and chemoresistant capacity, considered key characteristics of CSC. The melanoma SP may therefore represent an interesting therapeutic target.
BackgroundDiagnostic imaging for low back pain (LBP) without any indication of a serious underlying cause does not improve patient outcomes. However, there is still overuse of imaging, especially at ...emergency departments (EDs). Although evidence-based guidelines for LBP and radicular pain management exist, a protocol for use at the ED in the Belgian University Hospitals Leuven was not available, resulting in high practice variation. The present paper aims to describe the process from protocol development to the iterative implementation approach and explore how it has influenced practice.MethodsIn accordance with a modified ‘knowledge-to-action’ framework, five steps took place within the iterative bottom-up implementation process: (1) identification of the situation that requires the implementation of evidence based recommendations, (2) context analysis, (3) development of an implementation plan, (4) evaluation and (5) sustainability of the implemented practice recommendations. Two potential barriers were identified: the high turnover of attending specialists at the ED and patients’ and general practicioners’ expectations that might overrule the protocol. These were tackled by educational sessions for staff, patient brochures, an information campaign and symposium for general practitioners.ResultsThe rate of imaging of the lumbar spine decreased from over 25% of patients to 15.0%–16.4% for CT scans and 19.0%–21.8% for X-rays after implementation, but started to fluctuate again after 3 years. After introducing a compulsory e-learning before rotation and catchy posters in the ED staff rooms, rates decreased to 14.0%–14.6% for CT scan use and 12.7–13.5% for X-ray use.ConclusionsImplementation of a new protocol in a tertiary hospital ED with high turn over of rotating trainees is a challenge and requires ongoing efforts to ensure sustainability. Rates of imaging represent an indirect though useful indicator. We have demonstrated that it is possible to implement a protocol that includes demedicalisation in an ED environment and to observe changes in indicator results.
We developed a self-assessment tool for computing students in higher education to measure their Creative Problem Solving skills. Our survey encompasses 7 dimensions of creativity, based on existing ...validated scales and conducted focus groups. These are: technical knowledge, communication, constraints, critical thinking, curiosity, creative state of mind, and creative techniques. Principal axis factor analysis groups the dimensions into three overarching constructs: ability, mindset, and interaction. The results of a pilot study (n = 269) provide evidence for its psychometric qualities, making it a useful instrument for educational researchers to investigate students' creative skills.
Quantifying the contribution of the various processes that influence population genetic structure is important, but difficult. One of the reasons is that no single measure appropriately quantifies ...all aspects of genetic structure. An increasing number of studies is analysing population structure using the statistic D, which measures genetic differentiation, next to GST, which quantifies the standardized variance in allele frequencies among populations. Few studies have evaluated which statistic is most appropriate in particular situations. In this study, we evaluated which index is more suitable in quantifying postglacial divergence between three‐spined stickleback (Gasterosteus aculeatus) populations from Western Europe. Population structure on this short timescale (10 000 generations) is probably shaped by colonization history, followed by migration and drift. Using microsatellite markers and anticipating that D and GST might have different capacities to reveal these processes, we evaluated population structure at two levels: (i) between lowland and upland populations, aiming to infer historical processes; and (ii) among upland populations, aiming to quantify contemporary processes. In the first case, only D revealed clear clusters of populations, putatively indicative of population ancestry. In the second case, only GST was indicative for the balance between migration and drift. Simulations of colonization and subsequent divergence in a hierarchical stepping stone model confirmed this discrepancy, which becomes particularly strong for markers with moderate to high mutation rates. We conclude that on short timescales, and across strong clines in population size and connectivity, D is useful to infer colonization history, whereas GST is sensitive to more recent demographic events.
A reported mixed opioid agonist – neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3′,5′-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new ...dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat.
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•Hybrid opioid agonist – neurokinin 1 receptor antagonist ligands.•In vitro and in vivo evaluation for treatment of acute and neuropathic pain.•Hybrid 22 performs well in both acute and neuropathic pain models.
We developed a self-assessment tool for computing students in higher education to measure their Creative Problem Solving skills. Our survey encompasses 7 dimensions of creativity, based on existing ...validated scales and conducted focus groups. These are: technical knowledge, communication, constraints, critical thinking, curiosity, creative state of mind, and creative techniques. Principal axis factor analysis groups the dimensions into three overarching constructs: ability, mindset, and interaction. The results of a pilot study (n = 269) provide evidence for its psychometric qualities, making it a useful instrument for educational researchers to investigate students' creative skills.
This report documents the program and the outcomes of Dagstuhl Seminar 23241 "Scalable Analysis of Probabilistic Models and Programs". The seminar brought together researchers from probabilistic ...graphical models, verification of probabilistic programming languages, and probabilistic planning. The communities bring vastly different perspectives on the methods and goals of inference under uncertainty. In this seminar, we worked towards a common understanding of how the different angles yield subtle differences in the problem statements and how the different methods provide different strengths and weaknesses. The report describes the different areas, the activities during the seminar including hot topics that were vividly discussed, and an overview of the technical talks.
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