Developing educational iPhone, Android and Windows smartphone cross-platform apps to facilitate understanding of clinical genomics terminology

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Creation and Worldwide Utilisation of New COVID-19 Online Information Hub for Genetics Health Professionals, Patients and Families

The current COVID-19 pandemic has unfortunately resulted in many significant concerns for individuals with genetic disorders and their relatives, regarding the viral infection and, particularly, its specific implications and additional advisable precautions for individuals affected by genetic disorders. To address this, the resulting requirement for guidance and information for the public and for genetics professionals was discussed among colleagues nationally, on the ScotGEN Steering Committee, and internationally on the Education Committee of the European Society of Human Genetics (ESHG). It was agreed that the creation of an online hub of genetics-related COVID-19 information resources would be particularly helpful. The proposed content, divided into a web page for professionals and a page for patients, was discussed with, and approved by, genetics professionals. The hub was created and provided online at www.scotgen.org.uk and linked from the ESHG’s educational website for genetics and genomics, at www.eurogems.org. The new hub provides links, summary information and representative illustrations for a wide range of selected international resources. The resources for professionals include: COVID-19 research related hubs provided by Nature, Science, Frontiers, and PubMed; clinical guidelines; the European Centre for Disease Prevention and Control; the World Health Organisation; and molecular data sources including coronavirus 3D protein structures. The resources for patients and families include links to many accessible sources of support and relevant information. Since the launch of the pages, the website has received visits from over 50 countries worldwide. Several genetics consultants have commented on usefulness, clarity, readability, and ease of navigation. Visits have originated most frequently in the United Kingdom, Kuwait, Hong Kong, Moldova, United States, Philippines, France, and Qatar. More links have been added since the launch of the hub to include additional international public health and academic resources. In conclusion, an up-to-date online hub has been created and made freely available for healthcare professionals, patients, relatives and the public, providing categorised easily navigated links to a range of worldwide resources related to COVID-19. These pages are receiving a rapidly growing number of return visits and the authors continue to maintain and update the pages’ content, incorporating new developments in this field of enormous worldwide importance

pRNA-stimulated protein kinases and the regulation of transfected glucagon receptors

Previous observations had suggested that the reduction in glucagon-stimulated adenylyl cyclase activity that was elicited by challenge of hepatocytes with phorbol 12- myristate 13-acetate (PMA) may have been mediated by the action of protein kinase C. In order to gain further insight into the nature of the protein kinase species which conferred such an inhibitory effect in these cells, I used a model system consisting of COS-7 cells transiently transfected so as to overexpress glucagon receptors. In these cells glucagon elicited a profound, dose-dependent, increase in the intracellular cAMP concentration with an EC50 of 1.8+/-0.4 nM glucagon. This value was comparable to those reported previously for the response observed in intact hepatocytes. In the transfected cells, levels of cAMP accumulation were maximal after approximately 10 minutes of stimulation with glucagon and thereafter remained stably elevated. These studies were undertaken in the presence of the non-selective phosphodiesterase inhibitor, IBMX, which elicited an inhibition of >96% of total cAMP phosphodiesterase (PDE) activity in these cells. Glucagon challenge of the transfected COS-7 cells failed to elicit a significant stimulation of IP3 production. However, in the presence of 0.3% (v/v) butan-1-ol, the hormone elicited an increase in the level of [3H]-PtdOH, although not of [3H]-PtdBut, suggesting that the hydrolysis of PtdCho by PLC, but not by PLD, was stimulated by glucagon in these cells. Intriguingly, in contrast to previous observations made using hepatocytes, treatment with PMA did not inhibit the ability of glucagon to increase intracellular cAMP levels in these transfected cells. Furthermore, PMA-induced inhibition of the response was not conferred by varying the quantity of transfected DNA or by treating with the potent protein phosphatase inhibitor, okadaic acid. Nor was it observed following the co-transfection of the cells with cDNAs encoding various protein kinase C isoforms (PKC-alpha, PKC-betaII and PKC-epsilon) or the PMA-activated G-protein receptor kinases, GRK2 and GRK3. A striking PMA-induced inhibition (51%) of the glucagon-stimulated cAMP accumulation was, however, observed in COS-7 cells which had been co-transfected with a cDNA encoding the novel diacyl glycerol/phorbol ester-stimulated protein kinase, protein kinase D (PKD). This PMA-induced inhibitory effect in these co-transfected COS-7 cells was dependent upon the catalytic activity of the kinase since PMA failed to elicit a reduction in glucagon-stimulated cAMP accumulation in COS-7 cells which had been co-transfected with the glucagon receptor and a kinase-inactive form of PKD. Moreover, the effect appeared to be directed at the level of cAMP synthesis rather than its degradation as studies of homogenate cAMP PDE activity showed no change in total PDE activity and IBMX was able to inhibit a similar fraction of the total activity. In the transfected cells, treatment with PMA did not inhibit either [125I]-glucagon binding or GTP-induced glucagon dissociation. Furthermore, the intracellular cAMP accumulation elicited by either cholera toxin or forskolin was not reduced by treatment with the phorbol ester. No statistically significant PMA-induced reduction in the isoprenaline-stimulated cAMP accumulation was detectable in COS-7 cells transfected with PKD and either the beta2AR or the beta3AR. This is consistent with the possibility that, in the co-transfected COS cells in which the inhibitory effect is observed, PKD phosphorylates the glucagon receptor itself. PKD transcripts were detected in RNA isolated from hepatocytes but not from COS-7 cells. Transcripts for GRK2 were present in hepatocytes but not in COS-7 cells, whilst transcripts for GRK3 were not found in either cell type. Immunoblotting studies indicated that PKC-alpha, PKC-betaII and PKC-epsilon were expressed both in hepatocytes and in COS-7 cells, although the level of PKC-betaII appeared to be lower in the latter cell type. Such studies also indicated that the levels of PKC-alpha, PKC-betaII, PKC-epsilon and PKC-zeta in hepatocytes isolated from streptozotocin diabetic rats were 1.4-2.0 fold higher than in hepatocytes obtained from healthy control animals. In contrast, the level of PKD-specific transcript in hepatocytes and adipose tissue appeared to be markedly reduced in diabetic rats, and was restored by insulin treatment. It is suggested that PKD may play a role in the regulation of glucagon-stimulated adenylate cyclase activity in vivo and that the loss, in the diabetic state, of such a regulatory mechanism might constitute an important factor in the pathogenesis of hyperglycaemia

Cardiac disorders and structural brain abnormalities are commonly associated with hypospadias in children with neurodevelopmental disorders

Ther objective of our study was to use an established cohort of boys to investigate common patterns of malformations in those with hypospadias. We performed a retrospective review of the phenotype of participants in the Deciphering Developmental Disorders Study with neurodevelopmental delay and an 'Abnormality of the genital system'. This group was divided into two subgroups: those with hypospadias and without hypospadias. Associated phenotypes of the two subgroups were compared and analysed. Of the 166 Deciphering Developmental Disorders participants with hypospadias and neurodevelopmental delay, 47 (28%) had cardiovascular and 40 (24%) had structural brain abnormalities. The rate of cardiovascular abnormalities in those with neurodevelopmental delay and genital abnormalities other than hypospadias (N = 645) was lower at 19% (P = 0.001). In addition, structural brain malformations were higher at 24% in the hypospadias group versus 15% in the group without hypospadias (P = 0.002). The constellation of these features occured at a higher rate in the hypospadias group versus the no hypospadias group (P = 0.038). In summary, this is the first study to indicate that cardiovascular and brain abnormalities are frequently encountered in association with hypospadias in children with neurodevelopmental disorders. Not only do these associations provide insight into the underlying aetiology but also they highlight the multisystem involvement in conditions with hypospadias

Unfrustrated Qudit Chains and their Ground States

We investigate chains of 'd' dimensional quantum spins (qudits) on a line with generic nearest neighbor interactions without translational invariance. We find the conditions under which these systems are not frustrated, i.e. when the ground states are also the common ground states of all the local terms in the Hamiltonians. The states of a quantum spin chain are naturally represented in the Matrix Product States (MPS) framework. Using imaginary time evolution in the MPS ansatz, we numerically investigate the range of parameters in which we expect the ground states to be highly entangled and find them hard to approximate using our MPS method.Comment: 5 pages, 5 figures. Typos correcte

MRI radiomic features are independently associated with overall survival in soft tissue sarcoma

Purpose: Soft tissue sarcomas (STS) represent a heterogeneous group of diseases, and selection of individualized treatments remains a challenge. The goal of this study was to determine whether radiomic features extracted from magnetic resonance (MR) images are independently associated with overall survival (OS) in STS. Methods and Materials: This study analyzed 2 independent cohorts of adult patients with stage II-III STS treated at center 1 (N = 165) and center 2 (N = 61). Thirty radiomic features were extracted from pretreatment T1-weighted contrast-enhanced MR images. Prognostic models for OS were derived on the center 1 cohort and validated on the center 2 cohort. Clinical-only (C), radiomics-only (R), and clinical and radiomics (C+R) penalized Cox models were constructed. Model performance was assessed using Harrell\u27s concordance index. Results: In the R model, tumor volume (hazard ratio [HR], 1.5) and 4 texture features (HR, 1.1-1.5) were selected. In the C+R model, both age (HR, 1.4) and grade (HR, 1.7) were selected along with 5 radiomic features. The adjusted c-indices of the 3 models ranged from 0.68 (C) to 0.74 (C+R) in the derivation cohort and 0.68 (R) to 0.78 (C+R) in the validation cohort. The radiomic features were independently associated with OS in the validation cohort after accounting for age and grade (HR, 2.4; Conclusions: This study found that radiomic features extracted from MR images are independently associated with OS when accounting for age and tumor grade. The overall predictive performance of 3-year OS using a model based on clinical and radiomic features was replicated in an independent cohort. Optimal models using clinical and radiomic features could improve personalized selection of therapy in patients with STS

The Near-Linear Regime of Gravitational Waves in Numerical Relativity

We report on a systematic study of the dynamics of gravitational waves in full 3D numerical relativity. We find that there exists an interesting regime in the parameter space of the wave configurations: a near-linear regime in which the amplitude of the wave is low enough that one expects the geometric deviation from flat spacetime to be negligible, but nevertheless where nonlinearities can excite unstable modes of the Einstein evolution equations causing the metric functions to evolve out of control. The implications of this for numerical relativity are discussed.Comment: 10 pages, 2 postscript figures, revised tex

Dynamics of Gravitational Waves in 3D: Formulations, Methods, and Tests

The dynamics of gravitational waves is investigated in full 3+1 dimensional numerical relativity, emphasizing the difficulties that one might encounter in numerical evolutions, particularly those arising from non-linearities and gauge degrees of freedom. Using gravitational waves with amplitudes low enough that one has a good understanding of the physics involved, but large enough to enable non-linear effects to emerge, we study the coupling between numerical errors, coordinate effects, and the nonlinearities of the theory. We discuss the various strategies used in identifying specific features of the evolution. We show the importance of the flexibility of being able to use different numerical schemes, different slicing conditions, different formulations of the Einstein equations (standard ADM vs. first order hyperbolic), and different sets of equations (linearized vs. full Einstein equations). A non-linear scalar field equation is presented which captures some properties of the full Einstein equations, and has been useful in our understanding of the coupling between finite differencing errors and non-linearites. We present a set of monitoring devices which have been crucial in our studying of the waves, including Riemann invariants, pseudo-energy momentum tensor, hamiltonian constraint violation, and fourier spectrum analysis.Comment: 34 pages, 14 figure