| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 3. |
- Rheinbay, E, et al.
(författare)
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Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 102-
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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| 4. |
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| 5. |
- Pustovalova, Y., et al.
(författare)
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NUScon: a community-driven platform for quantitative evaluation of nonuniform sampling in NMR
- 2021
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Ingår i: Magnetic Resonance. - : Copernicus GmbH. - 2699-0016. ; 2:2, s. 843-861
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Tidskriftsartikel (refereegranskat)abstract
- Although the concepts of nonuniform sampling (NUS) and non-Fourier spectral reconstruction in multidimensional NMR began to emerge 4 decades ago (Bodenhausen and Ernst, 1981; Barna and Laue, 1987), it is only relatively recently that NUS has become more commonplace. Advantages of NUS include the ability to tailor experiments to reduce data collection time and to improve spectral quality, whether through detection of closely spaced peaks (i.e., “resolution”) or peaks of weak intensity (i.e., “sensitivity”). Wider adoption of these methods is the result of improvements in computational performance, a growing abundance and flexibility of software, support from NMR spectrometer vendors, and the increased data sampling demands imposed by higher magnetic fields. However, the identification of best practices still remains a significant and unmet challenge. Unlike the discrete Fourier transform, non-Fourier methods used to reconstruct spectra from NUS data are nonlinear, depend on the complexity and nature of the signals, and lack quantitative or formal theory describing their performance. Seemingly subtle algorithmic differences may lead to significant variabilities in spectral qualities and artifacts. A community-based critical assessment of NUS challenge problems has been initiated, called the “Nonuniform Sampling Contest” (NUScon), with the objective of determining best practices for processing and analyzing NUS experiments. We address this objective by constructing challenges from NMR experiments that we inject with synthetic signals, and we process these challenges using workflows submitted by the community. In the initial rounds of NUScon our aim is to establish objective criteria for evaluating the quality of spectral reconstructions. We present here a software package for performing the quantitative analyses, and we present the results from the first two rounds of NUScon. We discuss the challenges that remain and present a roadmap for continued community-driven development with the ultimate aim of providing best practices in this rapidly evolving field. The NUScon software package and all data from evaluating the challenge problems are hosted on the NMRbox platform.
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| 6. |
- Bansal, Sheel, et al.
(författare)
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Practical Guide to Measuring Wetland Carbon Pools and Fluxes
- 2023
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Ingår i: Wetlands (Wilmington, N.C.). - : SPRINGER. - 0277-5212 .- 1943-6246. ; 43:8
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Forskningsöversikt (refereegranskat)abstract
- Wetlands cover a small portion of the world, but have disproportionate influence on global carbon (C) sequestration, carbon dioxide and methane emissions, and aquatic C fluxes. However, the underlying biogeochemical processes that affect wetland C pools and fluxes are complex and dynamic, making measurements of wetland C challenging. Over decades of research, many observational, experimental, and analytical approaches have been developed to understand and quantify pools and fluxes of wetland C. Sampling approaches range in their representation of wetland C from short to long timeframes and local to landscape spatial scales. This review summarizes common and cutting-edge methodological approaches for quantifying wetland C pools and fluxes. We first define each of the major C pools and fluxes and provide rationale for their importance to wetland C dynamics. For each approach, we clarify what component of wetland C is measured and its spatial and temporal representativeness and constraints. We describe practical considerations for each approach, such as where and when an approach is typically used, who can conduct the measurements (expertise, training requirements), and how approaches are conducted, including considerations on equipment complexity and costs. Finally, we review key covariates and ancillary measurements that enhance the interpretation of findings and facilitate model development. The protocols that we describe to measure soil, water, vegetation, and gases are also relevant for related disciplines such as ecology. Improved quality and consistency of data collection and reporting across studies will help reduce global uncertainties and develop management strategies to use wetlands as nature-based climate solutions.
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| 7. |
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| 8. |
- Bölling, T, et al.
(författare)
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Development of Curative Therapies for Ewing Sarcomas by Interdisciplinary Cooperative Groups in Europe.
- 2015
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Ingår i: Klinische Pädiatrie. - : Georg Thieme Verlag KG. - 1439-3824 .- 0300-8630. ; 227:3, s. 108-115
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Forskningsöversikt (refereegranskat)abstract
- Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
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| 9. |
- Chapman, Colin D, et al.
(författare)
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Intranasal Treatment of Central Nervous System Dysfunction in Humans
- 2013
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 30:10, s. 2475-2484
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Forskningsöversikt (refereegranskat)abstract
- One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.
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| 10. |
- Deng, YX, et al.
(författare)
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Spatial profiling of chromatin accessibility in mouse and human tissues
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7926, s. 375-
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Tidskriftsartikel (refereegranskat)abstract
- Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context1. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping2–5, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry6 and microfluidic deterministic barcoding5. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.
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| 11. |
- Freiherr, Jessica, et al.
(författare)
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Intranasal Insulin as a Treatment for Alzheimer's Disease : A Review of Basic Research and Clinical Evidence
- 2013
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Ingår i: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 27:7, s. 505-514
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Forskningsöversikt (refereegranskat)abstract
- Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism-such as insulin resistance in obesity, type 2 diabetes and AD-and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.
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| 12. |
- Maxwell, Tania L., et al.
(författare)
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Global dataset of soil organic carbon in tidal marshes
- 2023
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Ingår i: Scientific Data. - : Springer Nature. - 2052-4463. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Tidal marshes store large amounts of organic carbon in their soils. Field data quantifying soil organic carbon (SOC) stocks provide an important resource for researchers, natural resource managers, and policy-makers working towards the protection, restoration, and valuation of these ecosystems. We collated a global dataset of tidal marsh soil organic carbon (MarSOC) from 99 studies that includes location, soil depth, site name, dry bulk density, SOC, and/or soil organic matter (SOM). The MarSOC dataset includes 17,454 data points from 2,329 unique locations, and 29 countries. We generated a general transfer function for the conversion of SOM to SOC. Using this data we estimated a median (± median absolute deviation) value of 79.2 ± 38.1 Mg SOC ha−1 in the top 30 cm and 231 ± 134 Mg SOC ha−1 in the top 1 m of tidal marsh soils globally. This data can serve as a basis for future work, and may contribute to incorporation of tidal marsh ecosystems into climate change mitigation and adaptation strategies and policies.
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| 13. |
- Sellman, Stefan, 1984-
(författare)
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Quantifying Risk in Epidemiological and Ecological Contexts
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The rates of globalization and growth of the human population puts ever increasing pressure on the agricultural sector to intensify and grow more complex, and with this intensification comes an increased risk of outbreaks of infectious livestock diseases. At the same time, and for the same reasons, the detrimental effect that humans have on other species with which we share the environment has never been more apparent, as the current rates of species loss from ecological communities rival those of ancient mass extinction events. In order to find ways to lessen the effects of and eventually solve such problems we need ways to quantify the risks involved, something that can be difficult when for instance the sheer size or sensitivity of the systems makes practical experimentation unsuitable. For these situations mathematical models have become invaluable tools due to their flexibility and noninvasiveness. This thesis presents four works involving the quantification of risk in livestock epidemic and ecological contexts using mathematical models. Two of them deal with extinctions of species within model ecological communities, and how species interactions play a role in the identity of the lost species following perturbations to specific species (Papers I and II). The other two regard how the spatial layout of the underlying population of livestock premises affect the risk of foot and mouth disease outbreaks among farms in the USA, and how models of such outbreaks can be optimized to improve their usefulness (Papers III and IV).Ecological communities consist of species and the often intricate pattern of interactions between them. These interspecies connections can propagate effects caused by disturbances in one end of the network, through the community via the links, to other parts of the network. In some cases, a reduction in the abundance of one species can cause the extinction of a second species before the first species disappears, something called functional extinction. Despite this, many conservation efforts revolve around simply keeping populations of single species at a high enough level for their own survival. In a model setting, the study of Paper I explores and attempts to quantify how common such functional extinctions are in relation to the alternative outcome that a perturbed species itself becomes extinct. This is done by first constructing stable model food webs describing predator-prey interactions of up to 50 species, parameterized through allometric relationships between metabolic processes and body size. Then the smallest amount of extra mortality that can be applied to each and every species in the web before any species become extinct is determined. The study shows that in these model communities, more often than not (>80%) another species, rather than the species that is subjected to the additional mortality will be the one to become extinct first.The approach of Paper I is taken further in Paper II by applying the same methodology to ecological networks that include mixtures of both antagonistic (predator-prey) and mutualistic (e.g. pollination and seed dispersal) interactions. The results further reinforce the findings of Paper I, and show that ecological networks containing a mixture of antagonistic and mutualistic interactions are more sensitive to functional extinctions than purely antagonistic or purely mutualistic ones, an important finding considering the diversity of interaction types in natural systems. Furthermore, the type of species found to have the lowest threshold before becoming functionally extinct were those with a mixture of interaction types, such as pollinating insects. Both Paper I and II consolidate the notion that when doing conservation work it is important to have the entire community in mind by considering the population sizes that are viable from a multi-species perspective, rather than just focusing on the minimum population sizes that are viable for the individual species.In Papers III and IV the focus changes somewhat, from models of ecological systems to models of how infectious livestock disease spread between farms in spatially explicit contexts. For this kind of model, information about the spatial distribution of the hosts is of course crucial, but not always readily available. In the USA, the only available information about livestock premises demography is aggregated at the county scale, meaning that the spatial distribution of the premises within each county is unknown. However, a method exists to simulate realistic stochastic spatial configurations of premises using a set of predictor variables, such as topology, climate and roads. An alternative approach that have been used previously is to assume a uniformly random spatial distribution of premises within each county. But to what extent does the choice between these two methods affect the model’s evaluation of the risk of disease outbreaks? In Paper III, this is analyzed specifically for foot and mouth disease. Through simulated outbreaks and by looking at the reproductive ratio of the disease, the outbreak dynamics within the two different spatial configurations of premises are compared. The results show that there is a clear difference in the risk of outbreaks between them, with the non-uniform distributions showing a general pattern of higher outbreak risk. However this difference is dependent on the size and geographic location of the county that the outbreak start in with larger counties in the west of the US showing a stronger effect.When running numerical simulations with large scale models such as the one used in Paper III, a considerable amount of replication is usually necessary in order to account for the high degree of stochasticity inherent to the problem. Even further replication is required when performing sensitivity analyses of model parameters or when exploring different scenarios, for instance when trying to determine the optimal control strategy for a disease. For this reason, the amount and quality of results that can be produced by such studies can quickly become limited by the availability of computational resources. Finding ways to optimize the computations involved with regard to simulation time is therefore of great value as it can be directly related to the robustness of the results. In Paper IV, an efficient optimization method for the kind of kernel-based local disease spread model used in paper III is presented. The method revolves around constructing a grid structure that is overlaid on top of the farm landscape and dividing the infection process into two steps, first evaluating if any farms within one of the grid squares can become infected given an over-estimation of the probability of infection, and then only if so, evaluate actual infection of a subset of the farms within the receiving square. The method is compared to similar published methods and is shown to be more efficient in most cases, while also being easy to implement and understand. Furthermore, while other methods often involve approximations of the transmission process in order to improve computational speed, the method of Paper IV is shown to be exact. This is a major advantage, since with an approximative method the extent to which the results are affected by the simplification is unknown unless the effect of the approximation is explicitly quantified. In most cases, such quantification would require extensive simulations with the unsimplified approach, something which of course may not be feasible.
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