| 681. |
- Godoy, Patricio, et al.
(författare)
-
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
-
Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
-
Forskningsöversikt (refereegranskat)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
|
|
| 682. |
|
|
| 683. |
- Greetham, Hazel L., et al.
(författare)
-
Sutterella sterconcanis sp nov., isolated from canine faeces
- 2004
-
Ingår i: INTERNATIONAL JOURNAL OF SYSTEMATIC AND EVOLUTIONARY MICROBIOLOGY. - : Microbiology Society. - 1466-5026 .- 1466-5034. ; 54, s. 1581-1584
-
Tidskriftsartikel (refereegranskat)abstract
- Morphological, biochemical and molecular genetic studies were carried out on an unknown non-spore-forming, Gram-negative, rod-shaped bacterium which was isolated from dog faeces. The bacterium grew under anaerobic conditions, was asaccharolytic, resistant to 20 % (v/v) bile and was oxidase- and urease-negative. Phylogenetic analysis based on comparative 16S rRNA gene sequencing showed that the unidentified bacterium clustered withSutterella wadsworthensis, although a sequence divergence of >5 % indicated that the bacterium from dog faeces represented a previously unrecognized subline within the genus. On the basis of the presented findings, a novel species,Sutterella stercoricanissp. nov., is described. The type strain ofSutterella stercoricanisis 5BAC4T(=CCUG 47620T=CIP 108024T).
|
|
| 684. |
- Guiglion, G., et al.
(författare)
-
The RAdial Velocity Experiment (RAVE) : Parameterisation of RAVE spectra based on convolutional neural networks
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 644
-
Tidskriftsartikel (refereegranskat)abstract
- Context Data-driven methods play an increasingly important role in the field of astrophysics In the context of large spectroscopic surveys of stars, data-driven methods are key in deducing physical parameters for millions of spectra in a short time. Convolutional neural networks (CNNs) enable us to connect observables (e.g. spectra, stellar magnitudes) to physical properties (atmospheric parameters, chemical abundances, or labels in general). Aims. We test whether it is possible to transfer the labels derived from a high-resolution stellar survey to intermediate-resolution spectra of another survey by using a CNN. Methods. We trained a CNN, adopting stellar atmospheric parameters and chemical abundances from APOGEE DR16 (resolution Ra22 500) data as training set labels. As input, we used parts of the intermediate-resolution RAVE DR6 spectra (R ∼ 7500) overlapping with the APOGEE DR16 data as well as broad-band ALLWISE and 2MASS photometry, together with Gaia DR2 photometry and parallaxes. Results. We derived precise atmospheric parameters Teff, log(g), and [M/H], along with the chemical abundances of [Fe/H], [α/M], [Mg/Fe], [Si/Fe], [Al/Fe], and [Ni/Fe] for 420 165 RAVE spectra. The precision typically amounts to 60 K in Teff, 0.06 in log(g) and 0.02-0.04 dex for individual chemical abundances. Incorporating photometry and astrometry as additional constraints substantially improves the results in terms of the accuracy and precision of the derived labels, as long as we operate in those parts of the parameter space that are well-covered by the training sample. Scientific validation confirms the robustness of the CNN results. We provide a catalogue of CNN-Trained atmospheric parameters and abundances along with their uncertainties for 420 165 stars in the RAVE survey. Conclusions. CNN-based methods provide a powerful way to combine spectroscopic, photometric, and astrometric data without the need to apply any priors in the form of stellar evolutionary models. The developed procedure can extend the scientific output of RAVE spectra beyond DR6 to ongoing and planned surveys such as Gaia RVS, 4MOST, and WEAVE. We call on the community to place a particular collective emphasis and on efforts to create unbiased training samples for such future spectroscopic surveys.
|
|
| 685. |
- Heald, Adrian H., et al.
(författare)
-
Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile
- 2021
-
Ingår i: Diabetic Medicine. - : John Wiley & Sons. - 0742-3071 .- 1464-5491. ; 38:9
-
Tidskriftsartikel (refereegranskat)abstract
- AimsChange in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesized that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression.MethodsWe involved people with type 2 diabetes from two UK‐based cohorts: 11,914 individuals with GP follow‐up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross‐sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow‐up time points with 1‐year intervals.ResultsThe ‘favourable adiposity’ genetic score was cross‐sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91kg [0.59,1.23]) and BMI (0.30kg/m2 [0.19,0.40]), but higher high‐density lipoprotein (0.02mmol/L [0.01,0.02]) and lower triglycerides (‐0.04mmol/L [‐0.07,‐0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow‐up.There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62,1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid‐lowering (0.91 [0.86,0.97]) and anti‐hypertensive medication (0.95 [0.91,0.99]).ConclusionsIn individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long‐term and having lower odds of requiring lipid‐lowering or anti‐hypertensive medication in spite of relatively higher adiposity.
|
|
| 686. |
- Holmes, E, et al.
(författare)
-
Therapeutic modulation of microbiota-host metabolic interactions
- 2012
-
Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 4:137, s. 137rv6-
-
Tidskriftsartikel (refereegranskat)abstract
- Abnormal microbial-host metabolic interactions underlying disease provide new targets for therapeutic intervention.
|
|
| 687. |
- Horvath, L., et al.
(författare)
-
Isotope dependence of the type I ELMy H-mode pedestal in JET-ILW hydrogen and deuterium plasmas
- 2021
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 61:4
-
Tidskriftsartikel (refereegranskat)abstract
- The pedestal structure, edge transport and linear MHD stability have been analyzed in a series of JET with the ITER-like wall hydrogen (H) and deuterium (D) type I ELMy H-mode plasmas. The pedestal pressure is typically higher in D than in H at the same input power and gas rate, with the difference mainly due to lower density in H than in D (Maggi et al (JET Contributors) 2018 Plasma Phys. Control. Fusion 60 014045). A power balance analysis of the pedestal has shown that higher inter-ELM separatrix loss power is required in H than in D to maintain a similar pedestal top pressure. This is qualitatively consistent with a set of interpretative EDGE2D-EIRENE simulations for H and D plasmas, showing that higher edge particle and heat transport coefficients are needed in H than in D to match the experimental profiles. It has also been concluded that the difference in neutral penetration between H and D leads only to minor changes in the upstream density profiles and with trends opposite to experimental observations. This implies that neutral penetration has a minor role in setting the difference between H and D pedestals, but higher ELM and/or inter-ELM transport are likely to be the main players. The interpretative EDGE2D-EIRENE simulations, with simultaneous upstream and outer divertor target profile constraints, have indicated higher separatrix electron temperature in H than in D for a pair of discharges at low fueling gas rate and similar stored energy (which required higher input power in H than in D at the same gas rate). The isotope dependence of linear MHD pedestal stability has been found to be small, but if a higher separatrix temperature is considered in H than in D, this could lead to destabilization of peeling-ballooning modes and shrinking of the stability boundary, qualitatively consistent with the reduced pedestal confinement in H.
|
|
| 688. |
|
|
| 689. |
- Jaiswal, Siddhartha, et al.
(författare)
-
Clonal Hematopoiesis and risk of atherosclerotic cardiovascular disease
- 2017
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 377:2, s. 111-121
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear. METHODS We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice. RESULTS In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis. CONCLUSIONS The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.)
|
|
| 690. |
- Kirchhoff, Tomas, et al.
(författare)
-
Breast cancer risk and 6q22.33 : combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
- 2012
-
Ingår i: PLOS ONE. - : Public library of science. - 1932-6203. ; 7:6
-
Tidskriftsartikel (refereegranskat)abstract
- Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
|
|
