The phenotypic presentation of adult individuals with SLC6A1-related neurodevelopmental disorders

IntroductionSLC6A1 is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. SLC6A1-neurodevelopmental disorders have a consistent phenotype of mild to severe intellectual disability (ID), epilepsy, language delay and behavioral disorders. This phenotypic description is mainly based on knowledge from the pediatric population.MethodHere, we sought to describe patients with SLC6A1 variants and age above 18 years through the ascertainment of published and unpublished patients. Unpublished patients were ascertained through international collaborations, while previously published patients were collected through a literature search.ResultsA total of 15 adult patients with SLC6A1 variants were included. 9/13 patients had moderate to severe ID (data not available in two). Epilepsy was prevalent (11/15) with seizure types such as absence, myoclonic, atonic, and tonic–clonic seizures. Epilepsy was refractory in 7/11, while four patients were seizure free with lamotrigine, valproate, or lamotrigine in combination with valproate. Language development was severely impaired in five patients. Behavioral disorders were reported in and mainly consisted of autism spectrum disorders and aggressive behavior. Schizophrenia was not reported in any of the patients.DiscussionThe phenotype displayed in the adult patients presented here resembled that of the pediatric cohort with ID, epilepsy, and behavioral disturbances, indicating that the phenotype of SLC6A1-NDD is consistent over time. Seizures were refractory in >60% of the patients with epilepsy, indicating the lack of targeted treatment in SLC6A1-NDDs. With increased focus on repurposing drugs and on the development of new treatments, hope is that the outlook reflected here will change over time. ID appeared to be more severe in the adult patients, albeit this might reflect a recruitment bias, where only patients seen in specialized centers were included or it might be a feature of the natural history of SLC6A1-NDDs. This issue warrants to be explored in further studies in larger cohorts

Communicating product user reviews and ratings in interfaces for e-commerce: a multimodal approach

This paper describes a comparative empirical evaluation study that uses multimodal presentations to communicate review messages in an e-commerce platform. Previous studies demonstrate the effective use of multimodality in different problem domains (e.g. e-learning). In this paper, multimodality and expressive avatars are used to communicate information related to product reviews messages. The data of the reviews was opportunistically collected from Facebook and Twitter. Two independent groups of users were used to evaluate two different presentations of reviews and ratings using as a basis an experimental e- commerce platform. The control group used a text-based with emojis presentation and the experimental group used a multimodal approach based on expressive avatars. Three parameters of usability were measured. These were efficiency, effectiveness, user satisfaction, and user preference. The result showed that the two approaches performed similarly. These findings provide a basis for further experiments in which text, emojis and expressive avatars can be combine to communicate a larger volume of reviews and ratings

Plasma and Muscle Myostatin in Relation to Type 2 Diabetes

OBJECTIVE: Myostatin is a secreted growth factor expressed in skeletal muscle tissue, which negatively regulates skeletal muscle mass. Recent animal studies suggest a role for myostatin in insulin resistance. We evaluated the possible metabolic role of myostatin in patients with type 2 diabetes and healthy controls. DESIGN: 76 patients with type 2 diabetes and 92 control subjects were included in the study. They were matched for age, gender and BMI. Plasma samples and biopsies from the vastus lateralis muscle were obtained to assess plasma myostatin and expression of myostatin in skeletal muscle. RESULTS: Patients with type 2 diabetes had higher fasting glucose (8.9 versus 5.1 mmol/L, P<0.001), plasma insulin (68.2 versus 47.2 pmol/L, P<0.002) and HOMA2-IR (1.6 versus 0.9, P<0.0001) when compared to controls. Patients with type 2 diabetes had 1.4 (P<0.01) higher levels of muscle myostatin mRNA content than the control subjects. Plasma myostatin concentrations did not differ between patients with type 2 diabetes and controls. In healthy controls, muscle myostatin mRNA correlated with HOMA2-IR (r = 0.30, P<0.01), plasma IL-6 (r = 0.34, P<0.05) and VO2 max (r = -0.26, P<0.05), however, no correlations were observed in patients with type 2 diabetes. CONCLUSIONS: This study supports the idea that myostatin may have a negative effect on metabolism. However, the metabolic effect of myostatin appears to be overruled by other factors in patients with type 2 diabetes

Precision tomography of a three-qubit electron-nuclear quantum processor in silicon

Nuclear spins were among the first physical platforms to be considered for quantum information processing, because of their exceptional quantum coherence and atomic-scale footprint. However, their full potential for quantum computing has not yet been realized, due to the lack of methods to link nuclear qubits within a scalable device combined with multi-qubit operations with sufficient fidelity to sustain fault-tolerant quantum computation. Here we demonstrate universal quantum logic operations using a pair of ion-implanted $^{31}$P nuclei in a silicon nanoelectronic device. A nuclear two-qubit controlled-Z gate is obtained by imparting a geometric phase to a shared electron spin, and used to prepare entangled Bell states with fidelities up to 94.2(2.7)%. The quantum operations are precisely characterised using gate set tomography (GST), yielding one-qubit gate fidelities up to 99.93(3)%, two-qubit gate fidelity of 99.21(14)% and two-qubit preparation/measurement fidelities of 98.95(4)%. These three metrics indicate that nuclear spins in silicon are approaching the performance demanded in fault-tolerant quantum processors. We then demonstrate entanglement between the two nuclei and the shared electron by producing a Greenberger-Horne-Zeilinger three-qubit state with 92.5(1.0)% fidelity. Since electron spin qubits in semiconductors can be further coupled to other electrons or physically shuttled across different locations, these results establish a viable route for scalable quantum information processing using nuclear spins.Comment: 27 pages, 14 figures, plus 20 pages supplementary information. v2 includes new and updated references, and minor text change

Local conservation scores without a priori assumptions on neutral substitution rates

<p>Abstract</p> <p>Background</p> <p>Comparative genomics aims to detect signals of evolutionary conservation as an indicator of functional constraint. Surprisingly, results of the ENCODE project revealed that about half of the experimentally verified functional elements found in non-coding DNA were classified as unconstrained by computational predictions. Following this observation, it has been hypothesized that this may be partly explained by biased estimates on neutral evolutionary rates used by existing sequence conservation metrics. All methods we are aware of rely on a comparison with the neutral rate and conservation is estimated by measuring the deviation of a particular genomic region from this rate. Consequently, it is a reasonable assumption that inaccurate neutral rate estimates may lead to biased conservation and constraint estimates.</p> <p>Results</p> <p>We propose a conservation signal that is produced by local Maximum Likelihood estimation of evolutionary parameters using an optimized sliding window and present a Kullback-Leibler projection that allows multiple different estimated parameters to be transformed into a conservation measure. This conservation measure does not rely on assumptions about neutral evolutionary substitution rates and little a priori assumptions on the properties of the conserved regions are imposed. We show the accuracy of our approach (KuLCons) on synthetic data and compare it to the scores generated by state-of-the-art methods (phastCons, GERP, SCONE) in an ENCODE region. We find that KuLCons is most often in agreement with the conservation/constraint signatures detected by GERP and SCONE while qualitatively very different patterns from phastCons are observed. Opposed to standard methods KuLCons can be extended to more complex evolutionary models, e.g. taking insertion and deletion events into account and corresponding results show that scores obtained under this model can diverge significantly from scores using the simpler model.</p> <p>Conclusion</p> <p>Our results suggest that discriminating among the different degrees of conservation is possible without making assumptions about neutral rates. We find, however, that it cannot be expected to discover considerably different constraint regions than GERP and SCONE. Consequently, we conclude that the reported discrepancies between experimentally verified functional and computationally identified constraint elements are likely not to be explained by biased neutral rate estimates.</p

The Aarhus red giants challenge: II. Stellar oscillations in the red giant branch phase

[Contact] The large quantity of high-quality asteroseismic data that have been obtained from space-based photometric missions and the accuracy of the resulting frequencies motivate a careful consideration of the accuracy of computed oscillation frequencies of stellar models, when applied as diagnostics of the model properties.[Aims] Based on models of red-giant stars that have been independently calculated using different stellar evolution codes, we investigate the extent to which the differences in the model calculation affect the model oscillation frequencies and other asteroseismic diagnostics.[Methods] For each of the models, which cover four different masses and different evolution stages on the red-giant branch, we computed full sets of low-degree oscillation frequencies using a single pulsation code and, from these frequencies, typical asteroseismic diagnostics. In addition, we carried out preliminary analyses to relate differences in the oscillation properties to the corresponding model differences.[Results] In general, the differences in asteroseismic properties between the different models greatly exceed the observational precision of these properties. This is particularly true for the nonradial modes whose mixed acoustic and gravity-wave character makes them sensitive to the structure of the deep stellar interior and, hence, to details of their evolution. In some cases, identifying these differences led to improvements in the final models presented here and in Paper I; here we illustrate particular examples of this.[Conclusions] Further improvements in stellar modelling are required in order fully to utilise the observational accuracy to probe intrinsic limitations in the modelling and improve our understanding of stellar internal physics. However, our analysis of the frequency differences and their relation to stellar internal properties provides a striking illustration of the potential, in particular, of the mixed modes of red-giant stars for the diagnostics of stellar interiors.Funding for the Stellar Astrophysics Centre is provided by The Danish National Research Foundation (Grant agreement No. DNRF106). The research was supported by the ASTERISK project (ASTERoseismic Investigations with SONG and Kepler) funded by the European Research Council (Grant agreement No. 267864). This research was supported in part by the National Science Foundation under Grant No. NSF PHY-1748958. VSA acknowledges support from VILLUM FONDEN (research grant 10118) and the Independent Research Fund Denmark (Research grant 7027-00096B). DS is the recipient of an Australian Research Council Future Fellowship (project number FT1400147). SC acknowledges support from Premiale INAF MITiC, from INAF “Progetto mainstream” (PI: S. Cassisi), and grant AYA2013-42781P from the Ministry of Economy and Competitiveness of Spain. AMS is partially supported by grants ESP2017-82674-R (Spanish Government) and 2017-SGR-1131 (General-itat de Catalunya). TC acknowledges support from the European Research Council AdG No 320478-TOFU and the STFC Consolidated Grant ST/R000395/1. SH received funding for this research from the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no 338251 (StellarAges). AM acknowledges the support of the Government of India, Department of Atomic Energy, under Project No. 12-R&D-TFR-6.04-0600. DB is supported in the form of work contract FCT/MCTES through national funds and by FEDER through COMPETE2020 in connection to these grants: UID/FIS/04434/2019; PTDC/FIS-AST/30389/2017 & POCI-01-0145-FEDER-030389