Clinical and epidemiological data suggest that asthma and allergic diseases are associated and may share a common genetic etiology. We analyzed genome-wide SNP data for asthma and allergic diseases ...in 33,593 cases and 76,768 controls of European ancestry from UK Biobank. Two publicly available independent genome-wide association studies were used for replication. We have found a strong genome-wide genetic correlation between asthma and allergic diseases (r
= 0.75, P = 6.84 × 10
). Cross-trait analysis identified 38 genome-wide significant loci, including 7 novel shared loci. Computational analysis showed that shared genetic loci are enriched in immune/inflammatory systems and tissues with epithelium cells. Our work identifies common genetic architectures shared between asthma and allergy and will help to advance understanding of the molecular mechanisms underlying co-morbid asthma and allergic diseases.
Mapping gene networks requires large amounts of transcriptomic data to learn the connections between genes, which impedes discoveries in settings with limited data, including rare diseases and ...diseases affecting clinically inaccessible tissues. Recently, transfer learning has revolutionized fields such as natural language understanding
and computer vision
by leveraging deep learning models pretrained on large-scale general datasets that can then be fine-tuned towards a vast array of downstream tasks with limited task-specific data. Here, we developed a context-aware, attention-based deep learning model, Geneformer, pretrained on a large-scale corpus of about 30 million single-cell transcriptomes to enable context-specific predictions in settings with limited data in network biology. During pretraining, Geneformer gained a fundamental understanding of network dynamics, encoding network hierarchy in the attention weights of the model in a completely self-supervised manner. Fine-tuning towards a diverse panel of downstream tasks relevant to chromatin and network dynamics using limited task-specific data demonstrated that Geneformer consistently boosted predictive accuracy. Applied to disease modelling with limited patient data, Geneformer identified candidate therapeutic targets for cardiomyopathy. Overall, Geneformer represents a pretrained deep learning model from which fine-tuning towards a broad range of downstream applications can be pursued to accelerate discovery of key network regulators and candidate therapeutic targets.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Marine Group I (MGI) Thaumarchaeota are one of the most abundant and cosmopolitan chemoautotrophs within the global dark ocean. To date, no representatives of this archaeal group retrieved from the ...dark ocean have been successfully cultured. We used single cell genomics to investigate the genomic and metabolic diversity of thaumarchaea within the mesopelagic of the subtropical North Pacific and South Atlantic Ocean. Phylogenetic and metagenomic recruitment analysis revealed that MGI single amplified genomes (SAGs) are genetically and biogeographically distinct from existing thaumarchaea cultures obtained from surface waters. Confirming prior studies, we found genes encoding proteins for aerobic ammonia oxidation and the hydrolysis of urea, which may be used for energy production, as well as genes involved in 3-hydroxypropionate/4-hydroxybutyrate and oxidative tricarboxylic acid pathways. A large proportion of protein sequences identified in MGI SAGs were absent in the marine cultures Cenarchaeum symbiosum and Nitrosopumilus maritimus, thus expanding the predicted protein space for this archaeal group. Identifiable genes located on genomic islands with low metagenome recruitment capacity were enriched in cellular defense functions, likely in response to viral infections or grazing. We show that MGI Thaumarchaeota in the dark ocean may have more flexibility in potential energy sources and adaptations to biotic interactions than the existing, surface-ocean cultures.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending ...thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 × 10
). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Genetic Determinants of Aortic Distention Pirruccello, James P.; Rämö, Joel T.; Choi, Seung Hoan ...
Journal of the American College of Cardiology,
04/2023, Volume:
81, Issue:
14
Journal Article
Peer reviewed
As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and ...diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease.
In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain.
We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants.
Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores.
Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This article presents evidence-based clinical recommendations for the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars in children and adolescents. A guideline ...panel convened by the American Dental Association (ADA) Council on Scientific Affairs and the American Academy of Pediatric Dentistry conducted a systematic review and formulated recommendations to address clinical questions in relation to the efficacy, retention, and potential side effects of sealants to prevent dental caries; their efficacy compared with fluoride varnishes; and a head-to-head comparison of the different types of sealant material used to prevent caries on pits and fissures of occlusal surfaces.
This is an update of the ADA 2008 recommendations on the use of pit-and-fissure sealants on the occlusal surfaces of primary and permanent molars. The authors conducted a systematic search in MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and other sources to identify randomized controlled trials reporting on the effect of sealants (available on the US market) when applied to the occlusal surfaces of primary and permanent molars. The authors used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the quality of the evidence and to move from the evidence to the decisions.
The guideline panel formulated 3 main recommendations. They concluded that sealants are effective in preventing and arresting pit-and-fissure occlusal carious lesions of primary and permanent molars in children and adolescents compared with the nonuse of sealants or use of fluoride varnishes. They also concluded that sealants could minimize the progression of noncavitated occlusal carious lesions (also referred to as initial lesions) that receive a sealant. Finally, based on the available limited evidence, the panel was unable to provide specific recommendations on the relative merits of 1 type of sealant material over the others.
These recommendations are designed to inform practitioners during the clinical decision-making process in relation to the prevention of occlusal carious lesions in children and adolescents. Clinicians are encouraged to discuss the information in this guideline with patients or the parents of patients. The authors recommend that clinicians reorient their efforts toward increasing the use of sealants on the occlusal surfaces of primary and permanent molars in children and adolescents.
High-throughput metabolomics using liquid chromatography and mass spectrometry (LC/MS) provides a useful method to identify biomarkers of disease and explore biological systems. However, the majority ...of metabolic features detected from untargeted metabolomics experiments have unknown ion signatures, making it critical that data should be thoroughly quality controlled to avoid analyzing false signals. Here, we present a postalignment method relying on intermittent pooled study samples to separate genuine metabolic features from potential measurement artifacts. We apply the method to lipid metabolite data from the PREDIMED (PREvención con DIeta MEDi-terránea) study to demonstrate clear removal of measurement artifacts. The method is publicly available as the R package MetProc, available on CRAN under the GPL-v2 license.
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IJS, KILJ, NUK, PNG, UL, UM
Hypoxia, defined as dissolved oxygen (DO) < 2 mg/L, in the central basin of Lake Erie has been studied since the mid‐1900s. Even so, spatial patterns of hypoxia, and episodic hypoxia in nearshore ...areas where drinking water plant intakes are located, are not well characterized owing to limited observations and short‐term dynamics. We evaluated a physically based, DO model with respect to patterns of hypoxia observed in Lake Erie. The DO model used assigned rates of sediment and water column oxygen demand that were temperature dependent but otherwise spatially and temporally uniform. The DO model was linked to National Oceanic and Atmospheric Administration's (NOAA) Lake Erie Operational Forecasting System hydrodynamic model, an application of the Finite Volume Community Ocean Model (FVCOM). Model temperature and DO were compared with observations from ship‐based studies, real‐time sensor networks and an array of moored sensors that we deployed in 2017. In years with dominant southwesterly winds, persistent downwelling occurred along the south shore, which resulted in a thinner thermocline and earlier initiation of hypoxia along the south shore than the north. Occasional northeast winds temporarily reversed this pattern, causing upwelling along the south shore that brought hypoxic water to nearshore locations and water intakes. The DO model reproduced observed spatial and temporal patterns of hypoxia and revealed locations subject to episodes of hypoxia, including nearshore Ohio, north of Pelee Island, and near the Bass Islands. Model skill was limited in some respects, highlighting the importance of accurate simulation of the thermal structure and spatial patterns of oxygen demand rates.
Plain Language Summary
Hypoxia, defined as dissolved oxygen (DO) < 2 mg/L, results from a combination of physical and biological processes. Hypoxia in Lake Erie reduces habitat and food supply for fish and complicates drinking water treatment. We applied a mathematical model that was driven by weather information (wind and air temperature) and simulated water temperature, currents, and DO. By evaluating whether a model that focused on physical processes could predict hypoxia, we investigated the relative importance of physical versus biological drivers. We compared model temperature and DO with measurements conducted by us and by others. In years with dominant southwesterly winds, persistent downwelling occurred along the south shore, which resulted in a thinner thermocline and earlier initiation of hypoxia along the south shore than the north. Occasional northeast winds temporarily reversed this pattern, causing upwelling along the south shore that brought hypoxic water to nearshore locations and water intakes. The DO model reproduced observed spatial and temporal patterns of hypoxia, indicating the importance of physical drivers, and revealed locations subject to episodes of hypoxia, including nearshore Ohio, north of Pelee Island, and near the Bass Islands.
Key Points
Coastal upwelling influenced spatial and temporal patterns of Lake Erie hypoxia
A physical dissolved oxygen model linked to a numerical ocean model exhibited useful skill
Model bias in dissolved oxygen suggested an east‐west gradient in sediment oxygen demand
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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