Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention.

The avenue of effective migraine therapies blocking calcitonin gene-related peptide (CGRP) transmission is the successful outcome of 35 years of translational research. Developed after short-acting, the small antagonists of the CGRP receptor (the "gepants"), the monoclonal antibodies blocking CGRP or its receptor (CGRP/rec mAbs) have changed the paradigm in migraine treatment. Contrary to the classical acute medications like triptans or nonsteroidal anti-inflammatory drugs (NSAIDs) with a transient effect, they act for long durations exclusively in the peripheral portion of the trigeminovascular system and can thus be assimilated to a durable attack treatment, unlike the classical preventives that chiefly act upstream on the central facets of migraine pathophysiology. Randomized controlled trials (RCT) of eptinezumab, erenumab, fremanezumab and galcanezumab have included collectively several thousands of patients, making them the most extensively studied class of preventive migraine treatments. Their results clearly indicate that CGRP/rec mAbs are significantly superior to placebo and have been comprehensively reviewed by Dodick [Cephalalgia 2019;39(3):445-458]. In this review we will briefly summarize the placebo-subtracted outcomes and number-needed-to-treat (NNT) of these pivotal RCTs and analyze new and post-hoc studies published afterwards focusing on effect size, effect onset and sustainability, response in subgroups of patients, safety and tolerability, and cost-effectiveness. We will also summarize our limited real-world experience with one of the CGRP/rec mAbs. Although methodological differences and lack of direct comparative trials preclude any reliable comparison, the overall impression is that there are only minor differences in efficacy and tolerability profiles between the four monoclonals: the average placebo-subtracted 50% responder rates for reduction in migraine headaches are 21.4% in episodic migraine (NNTs: 4-5), 17.4% in chronic migraine (NNTs: 4-8). Patients with an improvement exceeding 50% are rare, chronic migraineurs with continuous headache are unlikely to be responders and migraine auras are not improved. The effect starts within the first week after administration and is quasi maximal at one month. It is sustained for long time periods and may last for several months after treatment termination. CGRP/rec mAbs are effective even after prior preventive treatment failures and in patients with medication overuse, but the effect size might be smaller. They significantly reduce disability and health care resource utilization. The adverse effect profile of CGRP/rec mAbs is close to that of placebo with few minor exceptions and despite concerns related to the safeguarding role of CGRP in ischemia, no treatment-related vascular adverse events have been reported to date. Putting the CGRP/rec mAbs in perspective with available preventive migraine drug treatments, their major advantage seems not to be chiefly their superior efficacy but their unprecedented efficacy over adverse event ratio. Regarding cost-effectiveness, preliminary pharmaco-economic analyses of erenumab suggest that it is cost-effective for chronic migraine compared to no treatment or to onabotulinumtoxinA, but likely not for episodic migraine unless attack frequency is high, indirect costs are considered and its price is lowered

The BTZ black hole with a time-dependent boundary

The non-rotating BTZ solution is expressed in terms of coordinates that allow for an arbitrary time-dependent scale factor in the boundary metric. We provide explicit expressions for the coordinate transformation that generates this form of the metric, and determine the regions of the complete Penrose diagram that are convered by our parametrization. This construction is utilized in order to compute the stress-energy tensor of the dual CFT on a time-dependent background. We study in detail the expansion of radial null geodesic congruences in the BTZ background for various forms of the scale factor of the boundary metric. We also discuss the relevance of our construction for the holographic calculation of the entanglement entropy of the dual CFT on time-dependent backgrounds.Comment: 14 pages, 13 figures, title changed in journal, conformal diagrams added, references added, final version to appear in Classical and Quantum Gravit

Identification and differential expression dynamics of peach small GTPases encoding genes during fruit development and ripening

The function of monomeric GTPases of the RAS superfamily in fruit development and ripening has been partially characterized. Here the identification of peach (Prunus persica) small GTPases of the RAS superfamily expressed in fruit and the characterization of their expression profiles during fruit development are described. Extensive searches on expressed sequence tag (EST) databases led to the selection of a total of 24 genes from peach encoding proteins with significant similarity to Arabidopsis small GTPases. Sequence similarity analyses and identification of conserved motifs, diagnostic of specific RAS families and subfamilies, enabled bona fide assignment of fourteen PpRAB, seven PpARF/ARL/SAR, two PpROP and one PpRAN GTPases. Transcriptional expression profiles of peach monomeric GTPases, analysed by real-time quantitative reverse transcription-PCR, were obtained for mesocarp samples, collected in two consecutive years. Reproducible patterns of expression could be identified for five peach RAB-encoding genes (PpRABA1-1, PpRABA2, PpRABD2-1, PpRABD2-2, and PpRABC2), two ARFs (PpARFA1-1 and PpARLB1), and two ROPs (PpROP3 and PpROP4). Interestingly, the transient transcriptional up-regulation of PpARF genes and of PpRAB genes of the A and D clades, putatively controlling the exocytic delivery of cell wall components and modifying enzymes, appeared to coincide with peaks of growth speed and sugar accumulation and with the final phases of ripening. To our knowledge, this is the first description of the co-ordinated differential expression of a set of genes encoding small GTPases of the ARF and RAB families which takes place during key moments of fruit development and maturation

Entanglement Entropy from a Holographic Viewpoint

The entanglement entropy has been historically studied by many authors in order to obtain quantum mechanical interpretations of the gravitational entropy. The discovery of AdS/CFT correspondence leads to the idea of holographic entanglement entropy, which is a clear solution to this important problem in gravity. In this article, we would like to give a quick survey of recent progresses on the holographic entanglement entropy. We focus on its gravitational aspects, so that it is comprehensible to those who are familiar with general relativity and basics of quantum field theory.Comment: Latex, 30 pages, invited review for Classical and Quantum Gravity, minor correction

AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans

A primary electron beam facility at CERN -- eSPS Conceptual design report

The design of a primary electron beam facility at CERN is described. The study has been carried out within the framework of the wider Physics Beyond Colliders study. It re-enables the Super Proton Synchrotron (SPS) as an electron accelerator, and leverages the development invested in Compact Linear Collider (CLIC) technology for its injector and as an accelerator research and development infrastructure. The facility would be relevant for several of the key priorities in the 2020 update of the European Strategy for Particle Physics, such as an electron-positron Higgs factory, accelerator R\&D, dark sector physics, and neutrino physics. In addition, it could serve experiments in nuclear physics. The electron beam delivered by this facility would provide access to light dark matter production significantly beyond the targets predicted by a thermal dark matter origin, and for natures of dark matter particles that are not accessible by direct detection experiments. It would also enable electro-nuclear measurements crucial for precise modelling the energy dependence of neutrino-nucleus interactions, which is needed to precisely measure neutrino oscillations as a function of energy. The implementation of the facility is the natural next step in the development of X-band high-gradient acceleration technology, a key technology for compact and cost-effective electron/positron linacs. It would also become the only facility with multi-GeV drive bunches and truly independent electron witness bunches for plasma wakefield acceleration. A second phase capable to deliver positron witness bunches would make it a complete facility for plasma wakefield collider studies. [...

Expression Patterns of Genes Involved in Sugar Metabolism and Accumulation during Apple Fruit Development

Both sorbitol and sucrose are imported into apple fruit from leaves. The metabolism of sorbitol and sucrose fuels fruit growth and development, and accumulation of sugars in fruit is central to the edible quality of apple. However, our understanding of the mechanisms controlling sugar metabolism and accumulation in apple remains quite limited. We identified members of various gene families encoding key enzymes or transporters involved in sugar metabolism and accumulation in apple fruit using homology searches and comparison of their expression patterns in different tissues, and analyzed the relationship of their transcripts with enzyme activities and sugar accumulation during fruit development. At the early stage of fruit development, the transcript levels of sorbitol dehydrogenase, cell wall invertase, neutral invertase, sucrose synthase, fructokinase and hexokinase are high, and the resulting high enzyme activities are responsible for the rapid utilization of the imported sorbitol and sucrose for fruit growth, with low levels of sugar accumulation. As the fruit continues to grow due to cell expansion, the transcript levels and activities of these enzymes are down-regulated, with concomitant accumulation of fructose and elevated transcript levels of tonoplast monosaccharide transporters (TMTs), MdTMT1 and MdTMT2; the excess carbon is converted into starch. At the late stage of fruit development, sucrose accumulation is enhanced, consistent with the elevated expression of sucrose-phosphate synthase (SPS), MdSPS5 and MdSPS6, and an increase in its total activity. Our data indicate that sugar metabolism and accumulation in apple fruit is developmentally regulated. This represents a comprehensive analysis of the genes involved in sugar metabolism and accumulation in apple, which will serve as a platform for further studies on the functions of these genes and subsequent manipulation of sugar metabolism and fruit quality traits related to carbohydrates

Team climate, intention to leave and turnover among hospital employees: Prospective cohort study

<p>Abstract</p> <p>Background</p> <p>In hospitals, the costs of employee turnover are substantial and intentions to leave among staff may manifest as lowered performance. We examined whether team climate, as indicated by clear and shared goals, participation, task orientation and support for innovation, predicts intention to leave the job and actual turnover among hospital employees.</p> <p>Methods</p> <p>Prospective study with baseline and follow-up surveys (2–4 years apart). The participants were 6,441 (785 men, 5,656 women) hospital employees under the age of 55 at the time of follow-up survey. Logistic regression with generalized estimating equations was used as an analysis method to include both individual and work unit level predictors in the models.</p> <p>Results</p> <p>Among stayers with no intention to leave at baseline, lower self-reported team climate predicted higher likelihood of having intentions to leave at follow-up (odds ratio per 1 standard deviation decrease in team climate was 1.6, 95% confidence interval 1.4–1.8). Lower co-worker assessed team climate at follow-up was also association with such intentions (odds ratio 1.8, 95% confidence interval 1.4–2.4). Among all participants, the likelihood of actually quitting the job was higher for those with poor self-reported team climate at baseline. This association disappeared after adjustment for intention to leave at baseline suggesting that such intentions may explain the greater turnover rate among employees with low team climate.</p> <p>Conclusion</p> <p>Improving team climate may reduce intentions to leave and turnover among hospital employees.</p

Understanding the Interplay Among Regulatory Self-Efficacy, Moral Disengagement, and Academic Cheating Behaviour During Vocational Education: A Three-Wave Study

The literature has suggested that to understand the diffusion of unethical conduct in the workplace, it is important to investigate the underlying processes sustaining engagement in misbehaviour and to study what occurs during vocational education. Drawing on social-cognitive theory, in this study, we longitudinally examined the role of two opposite dimensions of the self-regulatory moral system, regulatory self-efficacy and moral disengagement, in influencing academic cheating behaviour. In addition, in line with the theories highlighting the bidirectional relationship between cognitive processes and behaviour, we aimed to also examine the reciprocal influence of behaviour on these dimensions over time. Overall, no previous studies have examined the longitudinal interplay between these variables. The sample included 866 (62.8% female) nursing students who were assessed three times annually from the beginning of their vocational education. The findings from a cross-lagged model confirmed that regulatory self-efficacy and moral disengagement have opposite influences on cheating behaviour, that regulatory self-efficacy negatively influences not only the engagement in misconduct but also the justification mechanisms that allow the divorce between moral standards and action, and that moral disengagement and cheating behaviour reciprocally support each other over time. Specifically, not only did moral disengagement influence cheating behaviour even when controlling for its prior levels, but also cheating behaviour affected moral disengagement one year later, controlling for its prior levels. These findings suggest that recourse to wrongdoing could gradually lead to further normalising this kind of behaviour and morally desensitising individuals to misconduct

The ubiquitin proteasome system in neuropathology

The ubiquitin proteasome system (UPS) orchestrates the turnover of innumerable cellular proteins. In the process of ubiquitination the small protein ubiquitin is attached to a target protein by a peptide bond. The ubiquitinated target protein is subsequently shuttled to a protease complex known as the 26S proteasome and subjected to degradative proteolysis. The UPS facilitates the turnover of proteins in several settings. It targets oxidized, mutant or misfolded proteins for general proteolytic destruction, and allows for the tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. In neuropathology, alteration of the UPS, or mutations in UPS target proteins may result in signaling abnormalities leading to the initiation or progression of tumors such as astrocytomas, hemangioblastomas, craniopharyngiomas, pituitary adenomas, and medulloblastomas. Dysregulation of the UPS may also contribute to tumor progression by perturbation of DNA replication and mitotic control mechanisms, leading to genomic instability. In neurodegenerative diseases caused by the expression of mutant proteins, the cellular accumulation of these proteins may overload the UPS, indirectly contributing to the disease process, e.g., sporadic Parkinsonism and prion diseases. In other cases, mutation of UPS components may directly cause pathological accumulation of proteins, e.g., autosomal recessive Parkinsonism and spinocerebellar ataxias. Defects or dysfunction of the UPS may also underlie cognitive disorders such as Angelman syndrome, Rett syndrome and autism, and muscle and nerve diseases, e.g., inclusion body myopathy and giant axon neuropathy. This paper describes the basic biochemical mechanisms comprising the UPS and reviews both its theoretical and proven involvement in neuropathological diseases. The potential for the UPS as a target of pharmacological therapy is also discussed