A5073246971- Astrophysics and Star Formation Studies
- Folate and B Vitamins Research
- Genomics and Rare Diseases
- Astro and Planetary Science
- Amino Acid Enzymes and Metabolism
- Stellar, planetary, and galactic studies
- Metabolism and Genetic Disorders
- Genetic Associations and Epidemiology
- Genomics and Phylogenetic Studies
- Microbial Metabolic Engineering and Bioproduction
- Cancer, Hypoxia, and Metabolism
- Bioinformatics and Genomic Networks
- Cancer Genomics and Diagnostics
- Solar and Space Plasma Dynamics
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- Molecular Spectroscopy and Structure
- Genomic variations and chromosomal abnormalities
- Advanced Thermodynamic Systems and Engines
- Space Exploration and Technology
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- Ubiquitin and proteasome pathways
- COVID-19 and healthcare impacts
- Astronomy and Astrophysical Research
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University of Toronto
2012-2024
University of Leicester
2021-2024
University of Colorado Denver
2021
Lunenfeld-Tanenbaum Research Institute
2017-2021
Sinai Health System
2019-2021
Mount Sinai Hospital
2017-2020
Method21 December 2017Open Access Transparent process A framework for exhaustively mapping functional missense variants Jochen Weile orcid.org/0000-0003-1628-9390 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada The Donnelly Centre, University of Department Molecular Genetics, Computer Science, Search more papers by this author Song Sun Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden Atina G Cote Jennifer Knapp Marta Verby Joseph C...
The success of personalized genomic medicine depends on our ability to assess the pathogenicity rare human variants, including important class missense variation. There are many challenges in training accurate computational systems, e.g., finding balance between quantity, quality, and bias variant sets used as examples avoiding predictive features that can accentuate effects bias. Here, we describe VARITY, which judiciously exploits a larger reservoir with uncertain accuracy...
For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused variants cystathionine beta-synthase (CBS) gene, most which are rare. With early detection, existing therapies highly effective.Damaging CBS can detected based on their failure to restore growth yeast cells lacking ortholog CYS4. This assay has only been applied reactively, after first...
Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by variants. Further complicating variant interpretation, impacts often depend on environment. An important example this phenomenon MTHFR p.Ala222Val (c.665C>T), which carried half all humans and has a phenotypic impact that depends dietary folate. Here we...
By performing global hydrodynamical simulations of accretion discs with driven turbulence models, we demonstrate that elevated levels induce highly stochastic migration torques on low-mass companions embedded in these discs. This scenario applies to planets migrating within gravito-turbulent regions protoplanetary as well stars and black holes the outskirts active galactic nuclei (AGN) When level is low, linear Lindblad persists background forces its accumulative effect can still dominate...
Abstract Recent studies have shown that the large-scale gas dynamics of protoplanetary disks (PPDs) are controlled by nonideal magnetohydrodynamics (MHD), but how this influences dust is not fully understood. To end, we investigate stability dusty, magnetized subject to Hall effect, which applies planet-forming regions PPDs. We find a novel background drift instability (BDHI) may facilitate planetesimal formation in Hall-effected disk regions. Through combination linear analysis and...
Abstract Background Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns circularity bias have limited previous methods for evaluating comparing predictors. Population-level cohorts genotyped phenotyped participants that not been used in predictor training can facilitate an unbiased benchmarking available methods. Using curated set gene-trait associations with reported rare-variant burden association,...
Significance Many phages use a contractile tail to inject their genomes into the host bacterial cell. These complex assemblages are capable of specifically recognizing cell surface, contracting upon binding, penetrating wall, and creating channel in membrane through which phage genome can pass. Remarkably, bacteria have co-opted tails adapted them protein-injecting nanomachines directed at other even eukaryotic cells. Here, we elucidate composition assembly pathway baseplate...
Abstract Current imaging observations of protoplanetary disks using the Atacama Large Millimeter/submillimeter Array (ALMA) primarily focus on submillimeter wavelength, leaving a gap in effective observational approaches for centimeter-sized dust, which is crucial to issue planet formation. The forthcoming Square Kilometre (SKA) and ngVLA may rectify this deficiency. In paper, we employ multifluid hydrodynamic numerical simulations radiative transfer calculations investigate potential...
Abstract Background Protein-protein interactions (PPIs) create the steps in signaling and regulatory networks central to most fundamental biological processes. It is possible predict these by making use of experimentally determined orthologous other species. Results In this study, prediction PPIs rice was carried out interolog method mapping deduced genes protein supported experimental evidence from reference organisms. We predicted 37112 for 4567 proteins, including 1671 self...
Determining the complete Arabidopsis (Arabidopsis thaliana) protein-protein interaction network is essential for understanding functional organization of proteome. Numerous small-scale studies and a couple large-scale ones have elucidated fraction estimated 300,000 binary interactions in Arabidopsis. In this study, we provide evidence that docking algorithm has ability to identify real using both experimentally determined predicted protein structures. We ranked 0.91 million generated by all...
Abstract Mean-motion resonances (MMRs) form through convergent disc migration of planet pairs, which may be disrupted by dynamical instabilities after protoplanetary (PPD) dispersal. This scenario is supported recent analysis TESS data showing that neighboring pairs in younger planetary systems are closer to resonance. To study stability MMRs during migration, we perform hydrodynamical simulations migrating PPDs, comparing the effect laminar viscosity and realistic turbulence. We find stable...
ABSTRACT The traditional paradigm of viscosity-dominated evolution protoplanetary discs has been recently challenged by existence magnetized disc winds. However, distinguishing wind-driven and turbulence-driven accretion through observations difficult. In this study, we present a novel approach to identifying their separate contribution angular momentum transport studying the gap ring morphology planet-forming in ALMA continuum. We model gap-opening process planets with both viscous 2D...
Planets open deep gaps in protoplanetary discs when their mass exceeds a gap opening mass, $M_{\rm gap}$. We use one- and two-dimensional simulations to study planet with angular momentum transport powered by MHD disc winds. parameterise the efficiency of wind through dimensionless parameter $\alpha_{\rm dw}$, which is an analogue turbulent viscosity v}$. find that magnetised winds are much less efficient counteracting tidal torques than turbulence is. For astrophysically realistic values...
ALMA has spatially resolved over 200 annular structures in protoplanetary discs, many of which are suggestive the presence planets. Constraining mass these putative planets is quite degenerate for it depends on disc physical properties, and simplicity a steady-state often assumed whereby planet position kept fixed there constant source dust at outer edge disc. Here we argue against this approach by demonstrating how dynamics can lift degeneracies such models. We take main parameters from...
Abstract Over 200 protoplanetary disk systems have been resolved by the Atacama Large Millimeter/submillimeter Array (ALMA), and vast majority suggest presence of planets. The dust gaps in transition disks are considered evidence giant planets sculpting gas under appropriate viscosity. However, unusually high accretion rates many T Tauri stars hosting challenge this theory. As only currently observed with turbulence, rate (∼10 −8.3 M ⊙ yr −1 ) DM Tau indicates strong turbulence within...
ABSTRACT Accretion of protoplanetary discs (PPDs) could be driven by magnetohydrodynamic disc winds rather than turbulent viscosity. With a dynamical prescription for angular momentum transport induced winds, we perform 2D simulations PPDs to systematically investigate the rate and direction planet migration in windy disc. We find that strength influences corotation region similarly ‘desaturation’ effect The magnitude torque depend sensitively on hierarchy between radial advection time-scale...
The promise of personalized genomic medicine depends on our ability to assess the functional impact rare sequence variation. Multiplexed assays can experimentally measure missense variants a massive scale. However, even after such assays, many remain poorly measured. Here we describe software pipeline and application impute missing information in determined variant effect maps.
Abstract Next generation sequencing has become a common tool in the diagnosis of genetic diseases. However, for vast majority variants that are discovered, clinical interpretation is not available. Variant effect mapping allows functional effects many single amino acid to be characterized parallel. Here, we combine multiplexed assays with machine learning assess substitutions human intellectual disability-associated gene, GDI1 . We show resulting variant map can used discriminate pathogenic...
Abstract Although we now routinely sequence human genomes, can confidently identify only a fraction of the variants that have functional impact. Here developed deep mutational scanning framework produces exhaustive maps for missense by combining random codon-mutagenesis and multiplexed variation assays with computational imputation refinement. We applied this to four proteins corresponding six genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin...
Abstract Success in precision medicine depends on our ability to determine which rare human genetic variants have functional effects. Classical homocystinuria—characterized by elevated homocyst(e)ine plasma and urine—is caused primarily-rare the cystathionine beta-synthase ( CBS ) gene. About half of patients respond vitamin B 6 therapy. With early detection newborns, existing therapies are highly effective. Functional variants, especially those that , can be detected based their restore...
This paper explores the continuous-time limit of a class Quasi Score-Driven (QSD) models that characterize volatility. As sampling frequency increases and time interval tends to zero, model weakly converges stochastic volatility where two Brownian motions are correlated, thereby capturing leverage effect in market. Subsequently, we identify necessary condition for non-degenerate correlation is distribution driving innovations differs from computing score, at least one being asymmetric. We...
Accretion of protoplanetary discs (PPDs) could be driven by MHD disc winds rather than turbulent viscosity. With a dynamical prescription for angular momentum transport induced winds, we perform 2D simulations PPDs to systematically investigate the rate and direction planet migration in windy disc. We find that strength influences corotation region similarly "desaturation" effect The magnitude torque depend sensitively on hierarchy between radial advection timescale across horseshoe due wind...