scholarly journals PIVOTAL: Prioritizing variants of uncertain significance with spatial genomic patterns in the 3D proteome

2020 ◽  
Author(s):  
Siqi Liang ◽  
Matthew Mort ◽  
Peter D. Stenson ◽  
David N. Cooper ◽  
Haiyuan Yu

ABSTRACTVariants of uncertain significance (VUS) have posed an increasingly prominent challenge to clinicians due to their growing numbers and difficulties in making clinical responses to them. Currently there are no existing methods that leverage the spatial relationship of known disease mutations and genomic properties for prioritizing variants of uncertain significance. More importantly, disease genes often associate with multiple clinically distinct diseases, but none of the existing variant prioritization methods provide clues as to the specific type of disease potentially associated with a given variant. We present PIVOTAL, a spatial neighborhood-based method using three-dimensional structural models of proteins, that significantly improves current variant prioritization tools and identifies potential disease etiology of candidate variants on a proteome scale. Using PIVOTAL, we made pathogenicity predictions for over 140,000 VUS and deployed a web application (http://pivotal.yulab.org) that enables users both to explore these data and to perform custom calculations.

1995 ◽  
Vol 131 (2) ◽  
pp. 279-295 ◽  
Author(s):  
Y Urata ◽  
S J Parmelee ◽  
D A Agard ◽  
J W Sedat

We have analyzed the three-dimensional structural details of Drosophila melanogaster polytene chromosome bands and interbands using three-dimensional light microscopy and a novel method of sample preparation that does not involve flattening or stretching the chromosomes. Bands have been visualized in unfixed chromosomes stained with the DNA specific dye 4,6-Diamidino-2-phenylindole (DAPI). Interbands have been visualized using fixed chromosomes that have been immunostained with an antibody to RNA polymerase II. Additionally, these structures have been analyzed using in situ hybridization with probes from specific genetic loci (Notch and white). Bands are seen to be composed of approximately 36 substructural features that measure 0.2-0.4 micron in diameter. We suggest that these substructural features are in fact longitudinal fibers made up of bundles of chromatids. Band shape can be a reproducible characteristic of a particular band and is dependent on the spatial relationship of these bundles, varying from bands with a uniform distribution of bundles to bands with a peripheral concentration of chromatin. Interbands are composed of bundles of chromatids of a similar size and number as those seen in the bands. The distribution of bundles is similar between a band and the neighboring interband, implying that there is a long range organization to the DNA that includes both the coding and the noncoding portions of genes. Finally, we note that the polytene chromosome has a circular shape when viewed in cross section, whether there are one or two homologs present.


1997 ◽  
Vol 37 (1) ◽  
pp. 797 ◽  
Author(s):  
A. Woods

A stereoscopic video system for use with Underwater Remotely Operated Vehicles (ROVs) has been developed by Curtin University's Centre for Marine Science and Technology. The system provides ROV operators with a fully three-dimensional (stereoscopic) view of the ROVs surroundings. This increased perception of depth offers several advantages to both the piloting of ROVs and also to the operation of an ROV manipulator arm.The stereoscopic video system consists of an underwater stereoscopic video camera which fits on the ROV and a stereoscopic display which is installed in the ship-based ROV control room. The system was developed in close cooperation with Woodside Offshore Petroleum which has used the system on their Triton ROV. Three ROVs are currently operated at Woodside's oil fields on Western Australia's North West Shelf.Field use of the system on the Triton ROV has revealed many advantages of stereoscopic video. One of the areas where advantages are particularly evident is in the operation of the manipulator arm. Operators have reported that it is perceptually easier to perform manipulator tasks. This is because the spatial relationship of objects can be immediately identified, making object placement and alignment easier. The system also provides a better understanding of the work site and a perceived improvement in image quality and therefore improved visibility.


2016 ◽  
Vol 63 (1) ◽  
pp. 9-15
Author(s):  
Giulio Santoro ◽  
Fabrizio Vittadello

Imaging modalities such as endorectal ultrasonography (ERUS), pelvic magnetic resonance (MRI) and computed tomography play a fundamental role in evaluating recatl cancer preoperatively, planning surgical procedures, and selecting patients for neoadjuvant therapy. Based on the best available evidence, ERUS is recommended to accurately discriminate between T1 and T2 lesions, for low rectal cancer, defined as 0-5cm from the anal verge, if local excision (with transanal excision of transanal endoscopic microsurgery) is being considered. MRI is the best modality to detect mesorectal fascia invasion and to predict circumferential resection margin involvement. Both modalities have similar limitations in distinguishing metastatic from bening lumph node in the mesorectum. Due to higher panoramicity and multiplanar reconstruction, three-dimensional ERUS allows to visualize the spatial relationship of the rectal tumour in the context of the surrounding structures, improving the accuracy of ultra-sonographic staging. Technological advances and perspectives of ERUS under investigations are represented by real-time colour elastography, Doppler US and contrast-enhanced US.


Author(s):  
Andrew M Glazer ◽  
Giovanni E. Davogustto ◽  
Christian M. Shaffer ◽  
Carlos G Vanoye ◽  
Reshma R. Desai ◽  
...  

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results (RoR) is unclear. In addition, the majority of discovered variants are currently classified as Variants of Uncertain Significance (VUS), limiting clinical actionability. Methods: The eMERGE-III study is a multi-center prospective cohort which included 21,846 participants without prior indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with Electronic Health Record (EHR)-derived phenotypes and follow-up clinical examination. Selected VUS (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had pathogenic or likely pathogenic (P/LP) variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared to non-carriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their EHRs. Fifty four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long QT syndrome), and 12/19 of these diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance (VUS), we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, EHR phenotypes, and in vitro functional studies.


2020 ◽  
Vol 23 (6) ◽  
pp. 1213-1238
Author(s):  
Vlada Vladimirovna Kugurakova ◽  
Gulnara Faritovna Sahibgareeva ◽  
An' Zung Nguyen ◽  
Andrey Maksimovich Astafiev

The article is devoted to our approaches to processing text in natural language to clarify the specific spatial relationship of objects and three-dimensional frame-by-frame visualization. The proposed approach allows us to show how the explicit constraints of the extracted spatial relationships affect and makes it possible to create possible layouts of objects on the scene. Natural language interpretations for spatial knowledge can generate three-dimensional scenes, which in turn are necessary to translate the scriptwriter's intent into the design of video games. The work also takes into account the rules of directing to create successful shots. Among them, accounting for the plan, camera rotation, as well as compositional nuances.


1984 ◽  
Vol 25 (3) ◽  
pp. 237-241 ◽  
Author(s):  
K.-E. Fredfeldt ◽  
H. H. Holm ◽  
J. F. Pedersen

Simple experiments which form the basis for a true 3-D demonstration of sectional images are presented and a method for genuine 3-D display of dynamic ultrasound images is described. Eight ultrasound images are recorded with a slightly different angulation of the transducer. The images are extracted from the video signal from a conventional ultrasound scanner and stored in eight digital memories. After recording, each image is displayed on an oscilloscope screen, which is viewed via a fast oscillating mirror. The position of the mirror determines which of the eight images are to be displayed and thereby ensures a correct spatial relationship of the images, resulting in a true 3-D scan presentation.


2020 ◽  
Vol 13 (5) ◽  
pp. 424-434
Author(s):  
Chee Jian Pua ◽  
Nevin Tham ◽  
Calvin W.L. Chin ◽  
Roddy Walsh ◽  
Chiea Chuen Khor ◽  
...  

Background: To assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry. Methods: We sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies. Results: Singaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P <0.0001) but an excess of variants of uncertain significance (24%, P <0.0001), as compared to Whites (pathogenic/likely pathogenic: 31%, excess of variants of uncertain significance: 7%). Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls (TNNI3:p.R79C, Singaporean controls AF=0.0055, P =0.0057, genome aggregation database-East Asian AF=0.0062, P =0.0086; TNNT2:p.R286H, Singaporean controls AF=0.0017, P <0.0001, genome aggregation database-East Asian AF=0.0009, P <0.0001). Both these variants have conflicting annotations in ClinVar and are of low penetrance (TNNI3:p.R79C, 0.7%; TNNT2:p.R286H, 2.7%) but are predicted to be deleterious by computational tools. In population controls, TNNI3:p.R79C carriers had significantly thicker left ventricular walls compared with noncarriers while its etiological fraction is limited (0.70 [95% CI, 0.35–0.86]) and thus TNNI3:p.R79C is considered variant of uncertain significance. Mutant TNNT2:p.R286H iPSC-CMs (induced pluripotent stem cells derived cardiomyocytes) show hypercontractility, increased metabolic requirements, and cellular hypertrophy and the etiological fraction (0.93 [95% CI, 0.83–0.97]) support the likely pathogenicity of TNNT2:p.R286H. Conclusions: As compared with Whites, Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall. This highlights the need for greater study of HCM genetics in non-White populations.


Author(s):  
Ruth V.W. Dimlich

Mast cells in the dura mater of the rat may play a role in cerebral pathologies including neurogenic inflammation (vasodilation; plasma extravasation) and headache pain . As has been suggested for other tissues, dural mast cells may exhibit a close spatial relationship to nerves. There has been no detailed ultrastructural description of mast cells in this tissue; therefore, the goals of this study were to provide this analysis and to determine the spatial relationship of mast cells to nerves and other components of the dura mater in the rat.Four adult anesthetized male Wistar rats (290-400 g) were fixed by perfusion through the heart with 2% glutaraldehyde and 2.8% paraformaldehyde in a potassium phosphate buffer (pH 7.4) for 30 min. The head of each rat was removed and stored in fixative for a minimum of 24 h at which time the dural coverings were removed and dissected into samples that included the middle meningeal vasculature. Samples were routinely processed and flat embedded in LX 112. Thick (1 um) sections from a minimum of 3 blocks per rat were stained with toluidine blue (0.5% aqueous).


1998 ◽  
Vol 10 (1-3) ◽  
pp. 100-108 ◽  
Author(s):  
Alicia Colson ◽  
Ross Parry

This article argues that the analysis of a threedimensional image demanded a three-dimensional approach. The authors realise that discussions of images and image processing inveterately conceptualise representation as being flat, static, and finite. The authors recognise the need for a fresh acuteness to three-dimensionality as a meaningful – although problematic – element of visual sources. Two dramatically different examples are used to expose the shortcomings of an ingrained two-dimensional approach and to facilitate a demonstration of how modern (digital) techniques could sanction new historical/anthropological perspectives on subjects that have become all too familiar. Each example could not be more different in their temporal and geographical location, their cultural resonance, and their historiography. However, in both these visual spectacles meaning is polysemic. It is dependent upon the viewer's spatial relationship to the artifice as well as the spirito-intellectual viewer within the community. The authors postulate that the multi- faceted and multi-layered arrangement of meaning in a complex image could be assessed by working beyond the limitations of the two-dimensional methodological paradigm and by using methods and media that accommodated this type of interconnectivity and representation.


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