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Individuals with Neurofibromatosis type 1 (NF1) experience a high degree of motor problems. The cerebellum plays a pivotal role in motor functioning and the NF1 gene is highly expressed in cerebellar Purkinje cells. However, it is not well understood to what extent NF1 affects cerebellar functioning and how this relates to NF1 motor functioning. Therefore, we subjected global Nf1+/− mice to a cerebellar-specific associative learning task, called Pavlovian eyeblink conditioning. Additionally, we assessed general motor function and muscle strength in Nf1+/− mice. To our surprise, we found that Nf1+/− mice showed a moderately increased learning rate of conditioned eyeblink responses, as well as improved accuracy in the adaptive timing of the eyeblink responses. Locomotion, balance, general motor function, and muscle strength were not affected in Nf1+/− mice. Together, our results support the view that cerebellar function in Nf1+/− mice is unimpaired.

Sustainability has a molecular basis that suggests a central role for chemistry in addressing today’s challenges to Earth and societal systems, and this role requires educators to see chemical reactions and processes as integral parts of dynamic and interconnected systems. Despite this prospect, few accessible resources are available for students and educators to facilitate systems thinking in chemistry for sustainability. We have developed an interactive digital learning tool (https://planetaryboundaries.kcvs.ca) based on the Planetary Boundaries sustainability framework, that uses interactive visualizations to help users better understand Earth system sustainability challenges and helps chemists and educators connect substances, reactions, and chemistry concepts to sustainability science. The tool highlights the fundamental role that chemistry plays in regulating the individual biophysical Earth system processes and in determining their control variables. It incorporates key features of a systems thinking framework by illustrating the dynamic interconnections among the processes and their control variables and demonstrates change of the Earth system over time. Finally, the interactive tool provides educators with accessible entry points to support the integration of chemistry curriculum content with sustainability considerations.

We formulate and solve a generalized inverse Navier-Stokes problem for the joint velocity field reconstruction and boundary segmentation of noisy flow velocity images. To regularize the problem we use a Bayesian framework with Gaussian random fields. This allows us to estimate the uncertainties of the unknowns by approximating their posterior covariance with a quasi-Newton method. We first test the method for synthetic noisy images of 2D flows and observe that the method successfully reconstructs and segments the noisy synthetic images with a signal-to-noise ratio (SNR) of 3. Then we conduct a magnetic resonance velocimetry (MRV) experiment to acquire images of an axisymmetric flow for low ($\simeq 6$) and high ($>30$) SNRs. We show that the method is capable of reconstructing and segmenting the low SNR images, producing noiseless velocity fields and a smooth segmentation, with negligible errors compared with the high SNR images. This amounts to a reduction of the total scanning time by a factor of 27. At the same time, the method provides additional knowledge about the physics of the flow (e.g. pressure), and addresses the shortcomings of MRV (low spatial resolution and partial volume effects) that otherwise hinder the accurate estimation of wall shear stresses. Although the implementation of the method is restricted to 2D steady planar and axisymmetric flows, the formulation applies immediately to 3D steady flows and naturally extends to 3D periodic and unsteady flows., WD Amrstrong, Cambridge Trusts

This document is an addition to the research protocol forThe GLasses Against transmission of SARS-CoV-2 in the communitY (GLASSY) trial. The RCT has been registered in Clinical Trials(NCT05217797). This document was posted online before the analysis of the data took place.

Recent studies of Victorinus by Stephen Andrew Cooper, Ellen Scully, Lenka Karfíková and Werner Steinmann have highlighted the need to read the philosophical treatises more closely alongside explicitly theological and exegetical work. But the approach of these authors reflects significantly divergent goals, from reading his work to defend an almost Lutheran emphasis on sola fide, or rather differently, in terms of a ‘physicalist’ approach on universal implications of Christ’s role as Logos. Appreciating the work of Cooper and Karfíková, the present treatment is focused on a recent article by Scully, questioning her understanding of Victorinus on the interconnection of cosmology and soteriology to present the human Christ in terms of a Platonic form.

Thousand and one amino‐acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen‐activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant‐negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems., In this study we expand the cohort of individuals with a neurodevelopmental disorder, carrying a de novo variant in TAOK1 (a), thereby further defining the neurodevelopmental disorder caused by TAOK1 malfunctioning. Using both in vivo (b) and in vitro (c) functional assays, we provide evidence that increased as well as decreased levels of TAOK1 cause disruption of neuronal development, showing that TAOK1 plays an important role in neuronal function. Additionally, our data suggests that both gain of function as well as loss of function mutations are potentially causative for the TAOK1‐related neurodevelopmental disorder.

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by deletion (~75%) or mutation (~10%) of the ubiquitin E3 ligase A (UBE3A) gene, which encodes a HECT type E3 ubiquitin protein ligase. Although the critical substrates of UBE3A are unknown, previous studies have suggested a critical role of nuclear UBE3A in AS pathophysiology. Here, we investigated to what extent UBE3A missense mutations disrupt UBE3A subcellular localization as well as catalytic activity, stability and protein folding. Our functional screen of 31 UBE3A missense mutants revealed that UBE3A mislocalization is the predominant cause of UBE3A dysfunction, accounting for 55% of the UBE3A mutations tested. The second major cause (29%) is a loss of E3-ubiquitin ligase activity, as assessed in an Escherichia coli in vivo ubiquitination assay. Mutations affecting catalytic activity are found not only in the catalytic HECT domain, but also in the N-terminal half of UBE3A, suggesting an important contribution of this N-terminal region to its catalytic potential. Together, our results show that loss of nuclear UBE3A E3 ligase activity is the predominant cause of UBE3A-linked AS. Moreover, our functional analysis screen allows rapid assessment of the pathogenicity of novel UBE3A missense variants which will be of particular importance when treatments for AS become available.

Half a century ago, Harry Angelman reported three patients with overlapping clinical features, now well known as Angelman syndrome. Angelman syndrome is caused by mutations affecting the maternally inherited UBE3A gene, which encodes an E3‐ubiquitin ligase that is critical for typical postnatal brain development. Emerging evidence indicates that UBE3A plays a particularly important role in the nucleus. However, the critical substrates that are controlled by UBE3A remain elusive, which hinders the search for effective treatments. Moreover, given the multitude of signalling mechanisms that are derailed, it is unlikely that targeting a single pathway is going to be very effective. Therefore, expectations are very high for approaches that aim to restore UBE3A protein levels. A particular promising strategy is an antisense oligonucleotide approach, which activates the silenced paternal UBE3A gene. When successful, such treatments potentially offer a disease‐modifying therapy for Angelman syndrome and several other neurodevelopmental disorders. What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain.Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus.Trials using antisense oligonucleotides to restore UBE3A levels are continuing., What this paper adds Loss of UBE3A affects multiple signalling pathways in the brain.Emerging evidence suggests that UBE3A plays a critical role in the cell nucleus.Trials using antisense oligonucleotides to restore UBE3A levels are continuing.

Descriptions of the clinical features of Angelman syndrome (AS) have mainly been focused on children. Here, we describe the evolution of the clinical phenotypes of AS in adulthood, using clinical data from 95 individuals (mean age 31.6 years, median 29.0 years, range 18–83 years), with genetically confirmed AS. Data was collected through physical examination and inspection of medical records, combined with questionnaires and interviews. Adults with AS experience substantial debilitating health problems. Constipation, reflux, visual problems, scoliosis, behavioral and sleeping problems occurred frequently and require appropriate attention. Epilepsy was reported in 57% of adults, negatively affecting the level of functioning. Non‐convulsive status epilepticus was not observed in the adults, however some individuals developed prolonged episodes of rhythmic shaking while awake. A decline in mobility was noted in the majority of adults. A minority of adults with AS showed microcephaly. Taken together, this first phenotypic study of adults with AS to include in person interviews with care‐givers and physical examination of patients, including the eldest adult reported to date, provides important insight in the development of the syndrome into adulthood. This knowledge is required to improve care for adult individuals with AS and to evaluate future therapies for this group.

Data analysis plan for Samtale med fastlegen som tiltak for å øke vaksinasjonsdekningen, studieprotokoll [Conversation with GP to increase vaccine coverage, study protocol(10.5281/zenodo.6381858)

Contains fulltext : 252067.pdf (Publisher’s version ) (Closed access) PURPOSE: To demonstrate that splenic artery embolization (SAE) is more cost-effective than splenectomy from a societal perspective in the Netherlands. MATERIALS AND METHODS: Patient-level data obtained from the SPLENIQ study were used to populate a health economic model and were supplemented with expert opinion when necessary. Propensity score matching was used to correct for baseline differences in injury severity scores. The health economic model consisted of 3 health states (complications after intervention, SAE failure, and recovery) and a dead state. Model outcomes were incremental quality-adjusted life years (QALYs) and incremental costs of SAE over splenectomy. The Dutch health economic guidelines were followed. The model used a lifetime time horizon. Uncertainty was assessed using probabilistic sensitivity analysis and scenario analyses. RESULTS: Patients undergoing SAE had a higher life expectancy than patients undergoing splenectomy. Incremental QALYs were 3.1 (mostly explained by difference in life expectancy), and incremental costs were euro34,135 (explained by costs related to medical consumption and lost productivity in additional life years), leading to an incremental cost-effectiveness ratio of euro11,010 per QALY. SAE was considered cost-effective in >95% of iterations using a threshold of euro20,000 per QALY. CONCLUSIONS: SAE results in more QALYs than splenectomy. Intervention costs for SAE are lower than that for splenectomy, but medical consumption and productivity costs in later years are higher for SAE due to better survival. SAE was found to be cost-effective compared with splenectomy under appropriate Dutch cost-effectiveness thresholds.

Study protocol for a randomised trial in Norway: General practitioner phone calls to increase COVID-19 vaccine uptake among high-risk patients. Protocol was finalised 07.12.2021 and registered in clinicaltrials.gov 08.12.2021.

Study protocol for a randomised trialin Norway:General practitioner phone calls to increase COVID-19 vaccine uptake among high-risk patients. Protocol was finalised 07.12.2021 and registered in clinicaltrials.gov 08.12.2021.

Background: Working from home has in many countries been a strongly advised infection prevention during the COVID-19 pandemic. However, we have not found evidence that this intervention influences the transmission of SARS-CoV-2 or other respiratory agents. Randomized trials are needed to assess if working from home reduce the risk of respiratory infections or outbreaks among employees. Methods: Randomized two-arm multi-period crossover superiority trial. We will recruit 3-5 large firms with over 2000 eligible participants, located in Oslo and neighbouring municipalities. All consenting employees in the selected organizations are eligible to participate in the trial. The organizations can define in advance certain key personnel that cannot take part in the trial. The participants will be randomized (1:1) to either i) mainly work from home in 4 weeks, and then at the office in 4 weeks, or ii) first work in the office in 4 weeks and then at home. Our primary outcome will be the proportion of participants who report having symptoms of respiratory disease during the trial period (self-reported). Given a dropout rate of 50%, we assume we need to enrol > 5500 participants to be able to detect a 50% reduction in the risk of COVID-19. Discussion: We expect there to be some bias in the self-reporting of symptoms of respiratory disease, since participants allocated to the going to the office group, will need to consider every day if they feel healthy, while participants staying at home will not have to consider this. Thus, we plan to look only at symptoms above a certain threshold