Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders

A physician targeted intervention improves prescribing in chronic heart failure in general medical units

Abstract Background Despite strong evidence for beta-blockers and angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in chronic heart failure (CHF), they have been under-utilised especially in general medical units. We aim to evaluate the effectiveness and feasibility of a physician-targeted quality improvement intervention with education and feedback on the prescription of beta-blockers and ACEI/ARB for CHF management in an inpatient setting. Methods We conducted an interrupted time series study between January 2009 and February 2012. A two-stage intervention was implemented. Between November 2009 and January 2011, a structured physician-oriented education program was undertaken. From February 2011, quarterly performance feedback was provided to each medical unit by a senior clinician. Medical notes of patients admitted with CHF under general medical units before and during the intervention were prospectively audited. Main outcomes were beta-blockers and ACEI/ARB prescription rates, and 180-day readmission rates for CHF. Results Four hundred and sixty-eight patients were included in this study. Structured education program was associated with a significant rise in beta-blockers prescription rates from a baseline of 60 to 92% (p = 0.003), but a non-sustained rise in ACEI/ARB prescription. Regular performance feedback resulted in a further sustained increase in ACEI/ARB prescription rates from 62 to 93% (p = 0.028) and a positive trend for beta-blockers with rates maintained at 89%. There was a reduction in 180-day readmission rates that correlated with the improvements in beta-blocker (p = 0.030) and ACEI/ARB (p = 0.035) prescription. Conclusion Implementation of a structured education program with regular performance feedback was durable and was associated with improvements in appropriate prescribing and an observed decrease in CHF-related readmissions

Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders

Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

The mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders

Community Consensus Guidelines to Support FAIR Data Standards in Clinical Research Studies in Primary Mitochondrial Disease

Primary mitochondrial diseases (PMD) are genetic disorders with extensive clinical and molecular heterogeneity where therapeutic development efforts have faced multiple challenges. Clinical trial design, outcome measure selection, lack of reliable biomarkers, and deficiencies in long-term natural history data sets remain substantial challenges in the increasingly active PMD therapeutic development space. Developing "FAIR" (findable, accessible, interoperable, reusable) data standards to make data sharable and building a more transparent community data sharing paradigm to access clinical research metadata are the first steps to address these challenges. This collaborative community effort describes the current landscape of PMD clinical research data resources available for sharing, obstacles, and opportunities, including ways to incentivize and encourage data sharing among diverse stakeholders. This work highlights the importance of, and challenges to, developing a unified system that enables clinical research structured data sharing and supports harmonized data deposition standards across clinical consortia and research groups. The goal of these efforts is to improve the efficiency and effectiveness of drug development and improve understanding of the natural history of PMD. This initiative aims to maximize the benefit for PMD patients, research, industry, and other stakeholders while acknowledging challenges related to differing needs and international policies on data privacy, security, management, and oversight

Development of an Objective Autism Risk Index Using Remote Eye Tracking

Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD), and numerous studies have identified abnormal attention patterns in ASD. The primary aim of the present study was to create an objective, eye tracking-based autism risk index

Bi-local Construction of Sp(2N)/dS Higher Spin Correspondence

We derive a collective field theory of the singlet sector of the Sp(2N) sigma model. Interestingly the hamiltonian for the bilocal collective field is the same as that of the O(N) model. However, the large-N saddle points of the two models differ by a sign. This leads to a fluctuation hamiltonian with a negative quadratic term and alternating signs in the nonlinear terms which correctly reproduces the correlation functions of the singlet sector. Assuming the validity of the connection between O(N) collective fields and higher spin fields in AdS, we argue that a natural interpretation of this theory is by a double analytic continuation, leading to the dS/CFT correspondence proposed by Anninos, Hartman and Strominger. The bi-local construction gives a map into the bulk of de Sitter space-time. Its geometric pseudospin-representation provides a framework for quantization and definition of the Hilbert space. We argue that this is consistent with finite N grassmanian constraints, establishing the bi-local representation as a nonperturbative framework for quantization of Higher Spin Gravity in de Sitter space.Comment: 1 figur

A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies

Leukodystrophies (LD) and genetic leukoencephalopathies (gLE) are disorders that result in white matter abnormalities in the central nervous system (CNS). Magnetic resonance (MR) imaging (MRI) has dramatically improved and systematized the diagnosis of LDs and gLEs, and in combination with specific clinical features, such as Addison’s disease in Adrenoleukodystrophy or hypodontia in Pol-III related or 4H leukodystrophy, can often resolve a case with a minimum of testing. The diagnostic odyssey for the majority LD and gLE patients, however, remains extensive – many patients will wait nearly a decade for a definitive diagnosis and at least half will remain unresolved. The combination of MRI, careful clinical evaluation and next generation genetic sequencing holds promise for both expediting the diagnostic process and dramatically reducing the number of unresolved cases. Here we present a workflow detailing the Global Leukodystrophy Initiative (GLIA) consensus recommendations for an approach to clinical diagnosis, including salient clinical features suggesting a specific diagnosis, neuroimaging features and molecular genetic testing. We also discuss recommendations on the use of broad-spectrum next-generation sequencing in instances of ambiguous MRI or clinical findings. We conclude with a proposal for systematic trials of genome-wide agnostic testing as a first line diagnostic in LDs and gLEs given the increasing number of genes associated with these disorders

Common data elements for clinical research in mitochondrial disease: a National Institute for Neurological Disorders and Stroke project

Objectives The common data elements (CDE) project was developed by the National Institute of Neurological Disorders and Stroke (NINDS) to provide clinical researchers with tools to improve data quality and allow for harmonization of data collected in different research studies. CDEs have been created for several neurological diseases; the aim of this project was to develop CDEs specifically curated for mitochondrial disease (Mito) to enhance clinical research. Methods Nine working groups (WGs), composed of international mitochondrial disease experts, provided recommendations for Mito clinical research. They initially reviewed existing NINDS CDEs and instruments, and developed new data elements or instruments when needed. Recommendations were organized, internally reviewed by the Mito WGs, and posted online for external public comment for a period of eight weeks. The final version was again reviewed by all WGs and the NINDS CDE team prior to posting for public use

Probe Branes, Time-dependent Couplings and Thermalization in AdS/CFT

We present holographic descriptions of thermalization in conformal field theories using probe D-branes in AdS X S space-times. We find that the induced metrics on Dp-brane worldvolumes which are rotating in an internal sphere direction have horizons with characteristic Hawking temperatures even if there is no black hole in the bulk AdS. The AdS/CFT correspondence applied to such systems indeed reveals thermal properties such as Brownian motions and AC conductivities in the dual conformal field theories. We also use this framework to holographically analyze time-dependent systems undergoing a quantum quench, where parameters in quantum field theories, such as a mass or a coupling constant, are suddenly changed. We confirm that this leads to thermal behavior by demonstrating the formation of apparent horizons in the induced metric after a certain time.Comment: LaTeX, 47 pages, 14 figures; Typos corrected and references added (v2); minor corrections, references added(v3