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| 5. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 6. |
- Erickson, C. M., et al.
(författare)
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KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD
- 2019
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:16
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Tidskriftsartikel (refereegranskat)abstract
- Objective To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated beta-amyloid (A beta) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on A beta burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on A beta was different among KL-VS heterozygotes compared to noncarriers. APOE4 carriers exhibited greater A beta burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on A beta load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0.001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher A beta burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated A beta aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.
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| 8. |
- Yang, H., et al.
(författare)
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Preliminary Characterization of Submarine Basalt Magnetic Mineralogy Using Amplitude-Dependence of Magnetic Susceptibility
- 2024
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Ingår i: Geochemistry, Geophysics, Geosystems. - 1525-2027. ; 25:2
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Tidskriftsartikel (refereegranskat)abstract
- The past ∼200 million years of Earth's geomagnetic field behavior have been recorded within oceanic basalts, many of which are only accessible via scientific ocean drilling. Obtaining the best possible paleomagnetic measurements from such valuable samples requires an a priori understanding of their magnetic mineralogies when choosing the most appropriate protocol for stepwise demagnetization experiments (either alternating field or thermal). Here, we present a quick, and non-destructive method that utilizes the amplitude-dependence of magnetic susceptibility to screen submarine basalts prior to choosing a demagnetization protocol, whenever conducting a pilot study or other detailed rock-magnetic characterization is not possible. We demonstrate this method using samples acquired during International Ocean Discovery Program Expedition 391. Our approach is rooted in the observation that amplitude-dependent magnetic susceptibility is observed in basalt samples whose dominant magnetic carrier is multidomain titanomagnetite (∼TM60–65, (Ti0.60–0.65Fe0.35–0.40)Fe2O4). Samples with low Ti contents within titanomagnetite or samples that have experienced a high degree of oxidative weathering do not display appreciable amplitude dependence. Due to their low Curie temperatures, basalts that possess amplitude-dependence should ideally be demagnetized either using alternating fields or via finely-spaced thermal demagnetization heating steps below 300°C. Our screening method can enhance the success rate of paleomagnetic studies of oceanic basalt samples.
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- Berntsen, Peter, 1974, et al.
(författare)
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Biomechanical effects of environmental and engineered particles on human airway smooth muscle cells
- 2010
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Ingår i: Journal of the Royal Society Interface. - : The Royal Society. - 1742-5689 .- 1742-5662. ; 7:Suppl 3
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Tidskriftsartikel (refereegranskat)abstract
- The past decade has seen significant increases in combustion-generated ambient particles, which contain a nanosized fraction (less than 100 nm), and even greater increases have occurred in engineered nanoparticles (NPs) propelled by the booming nanotechnology industry. Although inhalation of these particulates has become a public health concern, human health effects and mechanisms of action for NPs are not well understood. Focusing on the human airway smooth muscle cell, here we show that the cellular mechanical function is altered by particulate exposure in a manner that is dependent upon particle material, size and dose. We used Alamar Blue assay to measure cell viability and optical magnetic twisting cytometry to measure cell stiffness and agonist-induced contractility. The eight particle species fell into four categories, based on their respective effect on cell viability and on mechanical function. Cell viability was impaired and cell contractility was decreased by (i) zinc oxide (40-100 nm and less than 44 mu m) and copper(II) oxide (less than 50 nm); cell contractility was decreased by (ii) fluorescent polystyrene spheres (40 nm), increased by (iii) welding fumes and unchanged by (iv) diesel exhaust particles, titanium dioxide (25 nm) and copper(II) oxide (less than 5 mu m), although in none of these cases was cell viability impaired. Treatment with hydrogen peroxide up to 500 mu M did not alter viability or cell mechanics, suggesting that the particle effects are unlikely to be mediated by particle-generated reactive oxygen species. Our results highlight the susceptibility of cellular mechanical function to particulate exposures and suggest that direct exposure of the airway smooth muscle cells to particulates may initiate or aggravate respiratory diseases.
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| 10. |
- Darst, B. F., et al.
(författare)
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Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-beta Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease
- 2017
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 55:2, s. 473-484
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-beta (A beta) deposition and neurodegeneration: A beta clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral A beta deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid A beta deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.
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| 12. |
- Thoram, S., et al.
(författare)
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Nature and Origin of Magnetic Lineations Within Valdivia Bank : Ocean Plateau Formation by Complex Seafloor Spreading
- 2023
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Ingår i: Geophysical Research Letters. - 0094-8276. ; 50:13
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Tidskriftsartikel (refereegranskat)abstract
- Valdivia Bank (VB) is a Late Cretaceous oceanic plateau formed by volcanism from the Tristan-Gough hotspot at the Mid-Atlantic Ridge (MAR). To better understand its origin and evolution, magnetic data were used to generate a magnetic anomaly grid, which was inverted to determine crustal magnetization. The magnetization model reveals quasi-linear polarity zones crossing the plateau and following expected MAR paleo-locations, implying formation by seafloor spreading over ∼4 Myr during the formation of anomalies C34n-C33r. Paleomagnetism and biostratigraphy data from International Ocean Discovery Program Expedition 391 confirm the magnetic interpretation. Anomaly C33r is split into two negative bands, likely by a westward ridge jump. One of these negative anomalies coincides with deep rift valleys, indicating their age and mechanism of formation. These findings imply that VB originated by seafloor spreading-type volcanism during a plate reorganization, not from a vertical stack of lava flows as expected for a large volcano.
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| 14. |
- Schultz, Stephanie A, et al.
(författare)
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Cardiorespiratory Fitness Attenuates the Influence of Amyloid on Cognition.
- 2015
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Ingår i: Journal of the International Neuropsychological Society : JINS. - 1469-7661. ; 21:10, s. 841-50
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to examine cross-sectionally whether higher cardiorespiratory fitness (CRF) might favorably modify amyloid-β (Aβ)-related decrements in cognition in a cohort of late-middle-aged adults at risk for Alzheimer's disease (AD). Sixty-nine enrollees in the Wisconsin Registry for Alzheimer's Prevention participated in this study. They completed a comprehensive neuropsychological exam, underwent 11C Pittsburgh Compound B (PiB)-PET imaging, and performed a graded treadmill exercise test to volitional exhaustion. Peak oxygen consumption (VO2peak) during the exercise test was used as the index of CRF. Forty-five participants also underwent lumbar puncture for collection of cerebrospinal fluid (CSF) samples, from which Aβ42 was immunoassayed. Covariate-adjusted regression analyses were used to test whether the association between Aβ and cognition was modified by CRF. There were significant VO2peak*PiB-PET interactions for Immediate Memory (p=.041) and Verbal Learning & Memory (p=.025). There were also significant VO2peak*CSF Aβ42 interactions for Immediate Memory (p<.001) and Verbal Learning & Memory (p<.001). Specifically, in the context of high Aβ burden, that is, increased PiB-PET binding or reduced CSF Aβ42, individuals with higher CRF exhibited significantly better cognition compared with individuals with lower CRF. In a late-middle-aged, at-risk cohort, higher CRF is associated with a diminution of Aβ-related effects on cognition. These findings suggest that exercise might play an important role in the prevention of AD. (JINS, 2015, 21, 841-850).
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| 15. |
- Weiss, M., et al.
(författare)
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Contribution of dynamic vegetation phenology to decadal climate predictability
- 2014
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Ingår i: Journal of Climate. - 1520-0442. ; 27:22, s. 8563-8577
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Tidskriftsartikel (refereegranskat)abstract
- In this study, the impact of coupling and initializing the leaf area index from the dynamic vegetation model Lund-Potsdam-Jena General Ecosystem Simulator (LPJ-GUESS) is analyzed on skill of decadal predictions in the fully coupled atmosphere-land-ocean-sea ice model, the European Consortium Earth System Model (EC-Earth). Similar to the impact of initializing the model with the observed oceanic state, initializing the leaf area index (LAI) fields obtained from an offline LPJ-GUESS simulation forced by the observed atmospheric state leads to a systematic drift.A different treatment of the water and soil moisture budget in LPJ-GUESS is a likely cause of this drift. The coupled system reduces the cold bias of the reference model over land by reducing LAI (and the associated evaporative cooling), particularly outside the growing season. The coupling with the interactive vegetation module implies more degrees of freedom in the coupled model, which generates more noise that can mask a portion of the extra signal that is generated. The forecast reliability improves marginally, particularly early in the forecast. Ranked probability skill scores are also improved slightly in most areas analyzed, but the signal is not fully coherent over the forecast interval because of the relatively low number of ensemble members. Methods to remove the LAI drift and allow coupling of other variables probably need to be implemented before significant forecast skill can be expected.
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- Mauersberger, C, et al.
(författare)
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Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation
- 2022
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Ingår i: Nature cardiovascular research. - : Springer Science and Business Media LLC. - 2731-0590. ; 1:12, s. 1174-1186
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Tidskriftsartikel (refereegranskat)abstract
- Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here, by using histology, flow cytometry and intravital microscopy, we show that functional loss of sGC in platelets of atherosclerosis-prone Ldlr−/− mice contributes to atherosclerotic plaque formation, particularly via increasing in vivo leukocyte adhesion to atherosclerotic lesions. In vitro experiments revealed that supernatant from activated platelets lacking sGC promotes leukocyte adhesion to endothelial cells (ECs) by activating ECs. Profiling of platelet-released cytokines indicated that reduced platelet angiopoietin-1 release by sGC-depleted platelets, which was validated in isolated human platelets from carriers of GUCY1A1 risk alleles, enhances leukocyte adhesion to ECs. Importantly, pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced leukocyte recruitment and atherosclerotic plaque formation in atherosclerosis-prone Ldlr−/− mice. Therefore, pharmacological sGC stimulation might represent a potential therapeutic strategy to prevent and treat CAD.
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- Winkler, MJ, et al.
(författare)
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Functional investigation of the coronary artery disease gene SVEP1
- 2020
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Ingår i: Basic research in cardiology. - : Springer Science and Business Media LLC. - 1435-1803 .- 0300-8428. ; 115:6, s. 67-
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Tidskriftsartikel (refereegranskat)abstract
- A missense variant of the sushi, von Willebrand factor type A, EGF and pentraxin domain containing protein 1 (SVEP1) is genome-wide significantly associated with coronary artery disease. The mechanisms how SVEP1 impacts atherosclerosis are not known. We found endothelial cells (EC) and vascular smooth muscle cells to represent the major cellular source of SVEP1 in plaques. Plaques were larger in atherosclerosis-prone Svep1 haploinsufficient (ApoE−/−Svep1+/−) compared to Svep1 wild-type mice (ApoE−/−Svep1+/+) and ApoE−/−Svep1+/− mice displayed elevated plaque neutrophil, Ly6Chigh monocyte, and macrophage numbers. We assessed how leukocytes accumulated more inside plaques in ApoE−/−Svep1+/− mice and found enhanced leukocyte recruitment from blood into plaques. In vitro, we examined how SVEP1 deficiency promotes leukocyte recruitment and found elevated expression of the leukocyte attractant chemokine (C-X-C motif) ligand 1 (CXCL1) in EC after incubation with missense compared to wild-type SVEP1. Increasing wild-type SVEP1 levels silenced endothelial CXCL1 release. In line, plasma Cxcl1 levels were elevated in ApoE−/−Svep1+/− mice. Our studies reveal an atheroprotective role of SVEP1. Deficiency of wild-type Svep1 increased endothelial CXCL1 expression leading to enhanced recruitment of proinflammatory leukocytes from blood to plaque. Consequently, elevated vascular inflammation resulted in enhanced plaque progression in Svep1 deficiency.
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