| 1. |
- 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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| 2. |
- Gundersen, P., et al.
(författare)
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The response of methane and nitrous oxide fluxes to forest change in Europe
- 2012
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 9:10, s. 3999-4012
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Tidskriftsartikel (refereegranskat)abstract
- Forests in Europe are changing due to interactions between climate change, nitrogen (N) deposition and new forest management practices. The concurrent impact on the forest greenhouse gas (GHG) balance is at present difficult to predict due to a lack of knowledge on controlling factors of GHG fluxes and response to changes in these factors. To improve the mechanistic understanding of the ongoing changes, we studied the response of soil–atmosphere exchange of nitrous oxide (N2O) and methane (CH4) at twelve experimental or natural gradient forest sites, representing anticipated future forest change. The experimental manipulations, one or more per site, included N addition (4 sites), changes of climate (temperature, 1 site; precipitation, 2 sites), soil hydrology (3 sites), harvest intensity (1 site), wood ash fertilisation (1 site), pH gradient in organic soil (1 site) and afforestation of cropland (1 site). On average, N2O emissions increased by 0.06 ± 0.03 (range 0–0.3) g N2O-N m−2 yr−1 across all treatments on mineral soils, but the increase was up to 10 times higher in an acidic organic soil. Soil moisture together with mineral soil C / N ratio and pH were found to significantly influence N2O emissions across all treatments. Emissions were increased by elevated N deposition, especially in interaction with increased soil moisture. High pH reduced the formation of N2O, even under otherwise favourable soil conditions. Oxidation (uptake) of CH4 was on average reduced from 0.16 ± 0.02 to 0.04 ± 0.05 g CH4-C m−2 yr−1 by the investigated treatments. The CH4 exchange was significantly influenced by soil moisture and soil C / N ratio across all treatments, and CH4 emissions occurred only in wet or water-saturated conditions. For most of the investigated forest manipulations or natural gradients, the response of both N2O and CH4 fluxes was towards reducing the overall GHG forest sink. The most resilient forests were dry Mediterranean forests, as well as forests with high soil C / N ratio or high soil pH. Mitigation strategies may focus on (i) sustainable management of wet forest areas and forested peatlands, (ii) continuous forest cover management, (iii) reducing atmospheric N input and, thus, N availability, and (iv) improving neutralisation capacity of acid soils (e.g. wood ash application).
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| 3. |
- Metcalfe, Daniel B., et al.
(författare)
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Impacts of experimentally imposed drought on leaf respiration and morphology in an Amazon rain forest
- 2010
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Ingår i: Functional Ecology. - : Wiley. - 0269-8463 .- 1365-2435. ; 24:3, s. 524-533
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Tidskriftsartikel (refereegranskat)abstract
- P>1. The Amazon region may experience increasing moisture limitation over this century. Leaf dark respiration (R) is a key component of the Amazon rain forest carbon (C) cycle, but relatively little is known about its sensitivity to drought. 2. Here, we present measurements of R standardized to 25 degrees C and leaf morphology from different canopy heights over 5 years at a rain forest subject to a large-scale through-fall reduction (TFR) experiment, and nearby, unmodified Control forest, at the Caxiuana reserve in the eastern Amazon. 3. In all five post-treatment measurement campaigns, mean R at 25 degrees C was elevated in the TFR forest compared to the Control forest experiencing normal rainfall. After 5 years of the TFR treatment, R per unit leaf area and mass had increased by 65% and 42%, respectively, relative to pre-treatment means. In contrast, leaf area index (L) in the TFR forest was consistently lower than the Control, falling by 23% compared to the pre-treatment mean, largely because of a decline in specific leaf area (S). 4. The consistent and significant effects of the TFR treatment on R, L and S suggest that severe drought events in the Amazon, of the kind that may occur more frequently in future, could cause a substantial increase in canopy carbon dioxide emissions from this ecosystem to the atmosphere.
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| 4. |
- Kimlicka, L., et al.
(författare)
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The Cardiac Ryanodine Receptor N-Terminal Region Contains an Anion Binding Site that Is Targeted by Disease Mutations
- 2013
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Ingår i: Structure. - : Elsevier BV. - 0969-2126. ; 21:8, s. 1440-1449
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Tidskriftsartikel (refereegranskat)abstract
- Ryanodine receptors (RyRs) are calcium release channels located in the membrane of the endoplasmic and sarcoplasmic reticulum and play a major role in muscle excitation-contraction coupling. The cardiac isoform (RyR2) is the target for >150 mutations that cause catecholaminergic polymorphic ventricular tachycardia (CPVT) and other conditions. Here, we present the crystal structure of the N-terminal region of RyR2 (1-547), an area encompassing 29 distinct disease mutations. The protein folds up in three individual domains, which are held together via a central chloride anion that shields repulsive positive charges. Several disease mutant versions of the construct drastically destabilize the protein. The R420Q disease mutant causes CPVT and ablates chloride binding. The mutation results in reorientations of the first two domains relative to the third domain. These conformational changes likely activate the channel by destabilizing intersubunit interactions that are disrupted upon channel opening.
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| 6. |
- Rodrigues Gomes, Joao Carlos, et al.
(författare)
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Cleavage of the Vesicular GABA Transporter under Excitotoxic Conditions Is Followed by Accumulation of the Truncated Transporter in Nonsynaptic Sites.
- 2011
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Ingår i: The Journal of Neuroscience : the official journal of the Society for Neuroscience. - 1529-2401. ; 31:12, s. 4622-4635
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Tidskriftsartikel (refereegranskat)abstract
- GABA is the major inhibitory neurotransmitter in the CNS and changes in GABAergic neurotransmission affect the overall activity of neuronal networks. The uptake of GABA into synaptic vesicles is mediated by the vesicular GABA transporter (VGAT), and changes in the expression of the transporter directly regulate neurotransmitter release. In this work we investigated the changes in VGAT protein levels during ischemia and in excitotoxic conditions, which may affect the demise process. We found that VGAT is cleaved by calpains following excitotoxic stimulation of hippocampal neurons with glutamate, giving rise to a stable truncated cleavage product (tVGAT). VGAT cleavage was also observed after transient middle cerebral artery occlusion in mice, a cerebral ischemia model, and following intrahippocampal injection of kainate, but no effect was observed in transgenic mice overexpressing calpastatin, a calpain inhibitor. Incubation of isolated cerebrocortical synaptic vesicles with recombinant calpain also induced the cleavage of VGAT and formation of stable tVGAT. Immunoblot experiments using antibodies targeting different regions of VGAT and N-terminal sequencing analysis showed that calpain cleaves the transporter in the N-terminal region, at amino acids 52 and 60. Immunocytochemistry of GABAergic striatal neurons expressing GFP fusion proteins with the full-length VGAT or tVGAT showed that cleavage of the transporter induces a loss of synaptic delivery, leading to a homogeneous distribution of the protein along neurites. Our results show that excitotoxicity downregulates full-length VGAT, with a concomitant generation of tVGAT, which is likely to affect GABAergic neurotransmission and may influence cell death during ischemia.
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| 7. |
- Saglio, Giuseppe, et al.
(författare)
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Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.
- 2010
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Ingår i: The New England journal of medicine. - 1533-4406. ; 362:24, s. 2251-9
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Tidskriftsartikel (refereegranskat)abstract
- Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
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