Fostering collaborative research for rare genetic disease: The example of Niemann-Pick type C disease

Rare disease represents one of the most significant issues facing the medical community and health care providers worldwide, yet the majority of these disorders never emerge from their obscurity, drawing little attention from the medical community or the pharmaceutical industry. The challenge therefore is how best to mobilize rare disease stakeholders to enhance basic, translational and clinical research to advance understanding of pathogenesis and accelerate therapy development. Here we describe a rare, fatal brain disorder known as Niemann-Pick type C (NPC) and an innovative research collaborative known as Support of Accelerated Research for NPC (SOAR-NPC) which illustrates one pathway through which knowledge of a rare disease and its possible treatments are being successfully advanced. Use of the “SOAR” mechanism, we believe, offers a blueprint for similar advancement for many other rare disorders

Assessing the applicability of terrestrial laser scanning for mapping englacial conduits

his is an Open Access article, distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike licence (http://creativecommons.org/licenses/by-nc-sa/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the same Creative Commons licence is included and the original work is properly cited. The written permission of Cambridge University Press must be obtained for commercial re-use.The morphology of englacial drainage networks and their temporal evolution are poorly characterised, particularly within cold ice masses. At present, direct observations of englacial channels are restricted in both spatial and temporal resolution. Through novel use of a terrestrial laser scanning (TLS) system, the interior geometry of an englacial channel in Austre Brøggerbreen, Svalbard, was reconstructed and mapped. Twenty-eight laser scan surveys were conducted in March 2016, capturing the glacier surface around a moulin entrance and the uppermost 122 m reach of the adjoining conduit. The resulting point clouds provide detailed 3-D visualisation of the channel with point accuracy of 6.54 mm, despite low (<60%) overall laser returns as a result of the physical and optical properties of the clean ice, snow, hoar frost and sediment surfaces forming the conduit interior. These point clouds are used to map the conduit morphology, enabling extraction of millimetre-to-centimetre scale geometric measurements. The conduit meanders at a depth of 48 m, with a sinuosity of 2.7, exhibiting teardrop shaped cross-section morphology. This improvement upon traditional surveying techniques demonstrates the potential of TLS as an investigative tool to elucidate the nature of glacier hydrological networks, through reconstruction of channel geometry and wall composition.Peer reviewedFinal Published versio

Dysregulated Arginine Metabolism and Cardiopulmonary Dysfunction in Patients with Thalassaemia

Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-min-walk-test, Borg Dyspnoea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanisms of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV) ≥ 2·5 m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase (LDH) levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including LDH, haemoglobin and bilirubin. Thalassaemia patients with a TRV ≥ 2·5 m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in β-thalassaemia

EM-mosaic detects mosaic point mutations that contribute to congenital heart disease.

BackgroundThe contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and cardiovascular tissue has not been determined.MethodsWe developed a new computational method, EM-mosaic (Expectation-Maximization-based detection of mosaicism), to analyze mosaicism in exome sequences derived primarily from blood DNA of 2530 CHD proband-parent trios. To optimize this method, we measured mosaic detection power as a function of sequencing depth. In parallel, we analyzed our cohort using MosaicHunter, a Bayesian genotyping algorithm-based mosaic detection tool, and compared the two methods. The accuracy of these mosaic variant detection algorithms was assessed using an independent resequencing method. We then applied both methods to detect mosaicism in cardiac tissue-derived exome sequences of 66 participants for which matched blood and heart tissue was available.ResultsEM-mosaic detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, suggesting a role in CHD. The estimated true frequency of mosaic variants above 10% mosaicism was 0.14/person in blood and 0.21/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele fraction.ConclusionsWe estimate that ~ 1% of CHD probands have a mosaic variant detectable in blood that could contribute to cardiac malformations, particularly those damaging variants with relatively higher allele fraction. Although blood is a readily available DNA source, cardiac tissues analyzed contributed ~ 5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses

Systems Analysis Implicates WAVE2&nbsp;Complex in the Pathogenesis of&nbsp;Developmental Left-Sided Obstructive&nbsp;Heart Defects.

Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development

Associations of built food environment with body mass index and waist circumference among youth with diabetes

Background: Youth with diabetes are at increased risk for obesity and cardiovascular disease complications. However, less is known about the influence of built food environment on health outcomes in this population. The aim of this study was to explore the associations of accessibility and availability of supermarkets and fast food outlets with Body Mass Index (BMI) z-score and waist circumference among youth with diabetes. Methods: Information on residential location and adiposity measures (BMI z-score and waist circumference) for 845 youths with diabetes residing in South Carolina was obtained from the South Carolina site of the SEARCH for Diabetes in Youth study. Food outlets data obtained from the South Carolina Department of Health and Environmental Control and InfoUSA were merged based on names and addresses of the outlets. The comprehensive data on franchised supermarket and fast food outlets was then used to construct three accessibility and availability measures around each youth’s residence. Results: Increased number and density of chain supermarkets around residence location were associated with lower BMI z-score and waist circumference among youth with diabetes. For instance, for a female child of 10 years of age with height of 54.2 inches and weight of 70.4 pounds, lower supermarket density around residence location was associated with about 2.8–3.2 pounds higher weight, when compared to female child of same age, height and weight with highest supermarket density around residence location. Similarly, lower supermarket density around residence location was associated with a 3.5–3.7 centimeter higher waist circumference, when compared to residence location with the highest supermarket density. The associations of number and density of chain fast food outlets with adiposity measures, however, were not significant. No significant associations were observed between distance to the nearest supermarket and adiposity measures. However, contrary to our expectation, increased distance to the nearest fast food outlet was associated with higher BMI z-score, but not with waist circumference. Conclusions: Food environments conducive to healthy eating may significantly influence health behaviors and outcomes. Efforts to increase the availability of supermarkets providing options/selections for health-promoting foods may significantly improve the dietary intake and reduce adiposity among youth with diabetes

The Malthusian Paradox: performance in an alternate reality game

The Malthusian Paradox is a transmedia alternate reality game (ARG) created by artists Dominic Shaw and Adam Sporne played by 300 participants over three months. We explore the design of the game, which cast players as agents of a radical organisation attempting to uncover the truth behind a kidnapping and a sinister biotech corporation, and highlight how it redefined performative frames by blurring conventional performer and spectator roles in sometimes discomforting ways. Players participated in the game via a broad spectrum of interaction channels, including performative group spectacles and 1-to-1 engagements with game characters in public settings, making use of low- and high-tech physical and online artefacts including bespoke and third party websites. Players and game characters communicated via telephony and social media in both a designed and an ad-hoc manner. We reflect on the production and orchestration of the game, including the dynamic nature of the strong episodic narrative driven by professionally produced short films that attempted to respond to the actions of players; and the difficulty of designing for engagement across hybrid and temporally expansive performance space. We suggest that an ARG whose boundaries are necessarily unclear affords rich and emergent, but potentially unsanctioned and uncontrolled, opportunities for interactive performance, which raises significant challenges for design

Spatial patterning of supermarkets and fast food outlets with respect to neighborhood characteristics

A large body of literature has reported differences in exposure to environments supporting either healthy (e.g. supermarkets) or unhealthy (e.g. fast food outlets) dietary choices by neighborhood characteristics. We explored the associations of both supermarkets and fast food outlets availability with neighborhood characteristics, and clustering of these two outlet types in a largely rural state. Compared to block groups without a supermarket, those with a supermarket had a significantly higher income, higher housing value, larger population with high school education and above, lower minority population and lower population living below poverty even after controlling for urbanicity and population density of census block groups. Surprisingly, a similar relationship was found for block groups with and without fast food outlets. This was due to spatial co-occurrence and clustering of fast food outlets around supermarket locations. Hence, future studies exploring the associations of food environment with diet or diet-related health outcome should concurrently examine all aspects of food environment (healthy and unhealthy)

Loss of Singleminded-2s in the Mouse Mammary Gland Induces an Epithelial-Mesenchymal Transition Associated with Up-Regulation of Slug and Matrix Metalloprotease 2

The short splice variant of the basic helix-loop-helix Per-Arnt-Sim transcription factor Singleminded-2, SIM2s, has been implicated in development and is frequently lost or reduced in primary breast tumors. Here, we show that loss of Sim2s causes aberrant mouse mammary gland ductal development with features suggestive of malignant transformation, including increased proliferation, loss of polarity, down-regulation of E-cadherin, and invasion of the surrounding stroma. Additionally, knockdown of SIM2s in MCF-7 breast cancer cells contributed to an epithelial-mesenchymal transition (EMT) and increased tumorigenesis. In both Sim2(−/−) mammary glands and SIM2s-depleted MCF7 cells, these changes were associated with increased SLUG and MMP2 levels. SIM2s protein was detectable on the SLUG promoter, and overexpression of SIM2s repressed expression from a SLUG-controlled reporter in a dose-dependent manner. To our knowledge, SIM2s is the first protein shown to bind and repress the SLUG promoter, providing a plausible explanation for the development role and breast tumor-suppressive activity of SIM2s. Together, our results suggest that SIM2s is a key regulator of mammary-ductal development and that loss of SIM2s expression is associated with an invasive, EMT-like phenotype

Bridging Alone: Religious Conservatism, Marital Homogamy, and Voluntary Association Membership

This study characterizes social insularity of religiously conservative American married couples by examining patterns of voluntary associationmembership. Constructing a dataset of 3938 marital dyads from the second wave of the National Survey of Families and Households, the author investigates whether conservative religious homogamy encourages membership in religious voluntary groups and discourages membership in secular voluntary groups. Results indicate that couples’ shared affiliation with conservative denominations, paired with beliefs in biblical authority and inerrancy, increases the likelihood of religious group membership for husbands and wives and reduces the likelihood of secular group membership for wives, but not for husbands. The social insularity of conservative religious groups appears to be reinforced by homogamy—particularly by wives who share faith with husbands