| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Ademuyiwa, Adesoji O., et al.
(författare)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 3. |
- Aebersold, Ruedi, et al.
(författare)
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How many human proteoforms are there?
- 2018
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Ingår i: Nature Chemical Biology. - : NATURE PUBLISHING GROUP. - 1552-4450 .- 1552-4469. ; 14:3, s. 206-214
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Tidskriftsartikel (refereegranskat)abstract
- Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA-and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, "How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.
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| 4. |
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| 5. |
- Tragante, Vinicius, et al.
(författare)
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Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
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Tidskriftsartikel (refereegranskat)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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| 6. |
- Babulal, Ganesh M, et al.
(författare)
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Perspectives on ethnic and racial disparities in Alzheimer's disease and related dementias: Update and areas of immediate need.
- 2019
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:2, s. 292-312
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross-PIA white paper that provides both a concise "state-of-the-science" report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.
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| 7. |
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| 8. |
- Fenstermacher, M.E., et al.
(författare)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 9. |
- Huang, Miller, et al.
(författare)
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Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
- 2019
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Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:3, s. 433-
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Tidskriftsartikel (refereegranskat)abstract
- Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predis- posed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.
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| 10. |
- Martin-Almedina, Silvia, et al.
(författare)
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EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis
- 2016
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 126:8, s. 3080-3088
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Tidskriftsartikel (refereegranskat)abstract
- Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.
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| 11. |
- Nath, Anjali K., et al.
(författare)
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Proteomic-based detection of a protein cluster dysregulated during cardiovascular development identifies biomarkers of congenital heart defects
- 2009
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Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cardiovascular development is vital for embryonic survival and growth. Early gestation embryo loss or malformation has been linked to yolk sac vasculopathy and congenital heart defects (CHDs). However, the molecular pathways that underlie these structural defects in humans remain largely unknown hindering the development of molecular-based diagnostic tools and novel therapies.METHODOLOGY/PRINCIPAL FINDINGS: Murine embryos were exposed to high glucose, a condition known to induce cardiovascular defects in both animal models and humans. We further employed a mass spectrometry-based proteomics approach to identify proteins differentially expressed in embryos with defects from those with normal cardiovascular development. The proteins detected by mass spectrometry (WNT16, ST14, Pcsk1, Jumonji, Morca2a, TRPC5, and others) were validated by Western blotting and immunoflorescent staining of the yolk sac and heart. The proteins within the proteomic dataset clustered to adhesion/migration, differentiation, transport, and insulin signaling pathways. A functional role for several proteins (WNT16, ADAM15 and NOGO-A/B) was demonstrated in an ex vivo model of heart development. Additionally, a successful application of a cluster of protein biomarkers (WNT16, ST14 and Pcsk1) as a prenatal screen for CHDs was confirmed in a study of human amniotic fluid (AF) samples from women carrying normal fetuses and those with CHDs.CONCLUSIONS/SIGNIFICANCE: The novel finding that WNT16, ST14 and Pcsk1 protein levels increase in fetuses with CHDs suggests that these proteins may play a role in the etiology of human CHDs. The information gained through this bed-side to bench translational approach contributes to a more complete understanding of the protein pathways dysregulated during cardiovascular development and provides novel avenues for diagnostic and therapeutic interventions, beneficial to fetuses at risk for CHDs.
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| 12. |
- Snyder, Kristen, 1964-, et al.
(författare)
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Going hybrid on a dime : Lessons from schooling during the pandemic and implications for sustainable quality in education
- 2021
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Ingår i: ICERI2021 Proceedings. - : IATED. - 9788409345496 ; , s. 4503-4512
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Konferensbidrag (refereegranskat)abstract
- It is speculated that the Covid- 19 Pandemic has changed the future of work emphasizing hybrid solutions and networking. Understanding how distance education or hybrid models can be sustainable at the K-12 level is therefore of relevance to better prepare youth for a future world of work and sustainable development. The purpose of this paper is to present findings from phase two of the qualitative case study to examine more in-depth the ways in which a private school adapted it’s educational programming using technology-supported systems to innovate and maintain attractive quality education. Data were gathered from interviews, focus groups and video footage. The Digital Culture model was used as an analytical framework to examine the data from four dimension: pedagogy, communication, organizational systems, and technology.
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| 13. |
- Snyder, Kristen, 1964-, et al.
(författare)
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“Going hybrid on a dime” : Insights for transformation in education toward sustainable quality development
- 2023
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Ingår i: Seminar.net. - : OsloMet - Oslo Metropolitan University. - 1504-4831. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- This study contributes to research on Quality in Education and examines what possibilities now exist for schools to reinvent and transform using technology-based systems as part of the equation. It is speculated that the pandemic has changed the future of work emphasizing hybrid solutions and networking. The purpose of this article is to present findings from phase two of the qualitative case study to examine what happened to a private school when it went “hybrid on a dime” to maintain attractive quality education.
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| 26. |
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| 27. |
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| 28. |
- Adhikari, Subash, et al.
(författare)
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A high-stringency blueprint of the human proteome
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Forskningsöversikt (refereegranskat)abstract
- The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP’s tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.
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| 29. |
- Alseekh, Saleh, et al.
(författare)
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Mass spectrometry-based metabolomics: a guide for annotation, quantification and best reporting practices
- 2021
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Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 18:7, s. 747-756
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Forskningsöversikt (refereegranskat)abstract
- This Perspective, from a large group of metabolomics experts, provides best practices and simplified reporting guidelines for practitioners of liquid chromatography- and gas chromatography-mass spectrometry-based metabolomics. Mass spectrometry-based metabolomics approaches can enable detection and quantification of many thousands of metabolite features simultaneously. However, compound identification and reliable quantification are greatly complicated owing to the chemical complexity and dynamic range of the metabolome. Simultaneous quantification of many metabolites within complex mixtures can additionally be complicated by ion suppression, fragmentation and the presence of isomers. Here we present guidelines covering sample preparation, replication and randomization, quantification, recovery and recombination, ion suppression and peak misidentification, as a means to enable high-quality reporting of liquid chromatography- and gas chromatography-mass spectrometry-based metabolomics-derived data.
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| 30. |
- Arif, Muhammad, et al.
(författare)
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INetModels 2.0: An interactive visualization and database of multi-omics data
- 2021
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 49:W1, s. W271-W276
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Tidskriftsartikel (refereegranskat)abstract
- It is essential to reveal the associations between various omics data for a comprehensive understanding of the altered biological process in human wellness and disease. To date, very few studies have focused on collecting and exhibiting multi-omics associations in a single database. Here, we present iNetModels, an interactive database and visualization platform of Multi-Omics Biological Networks (MOBNs). This platform describes the associations between the clinical chemistry, anthropometric parameters, plasma proteomics, plasma metabolomics, as well as metagenomics for oral and gut microbiome obtained from the same individuals. Moreover, iNetModels includes tissue- and cancer-specific Gene Co-expression Networks (GCNs) for exploring the connections between the specific genes. This platform allows the user to interactively explore a single feature's association with other omics data and customize its particular context (e.g. male/female specific). The users can also register their data for sharing and visualization of the MOBNs and GCNs. Moreover, iNetModels allows users who do not have a bioinformatics background to facilitate human wellness and disease research. iNetModels can be accessed freely at https://inetmodels.com without any limitation.
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| 31. |
- Bertone, Paul, et al.
(författare)
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Design optimization methods for genomic DNA tiling arrays.
- 2006
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 16:2, s. 271-281
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Tidskriftsartikel (refereegranskat)abstract
- A recent development in microarray research entails the unbiased coverage, or tiling, of genomic DNA for the large-scale identification of transcribed sequences and regulatory elements. A central issue in designing tiling arrays is that of arriving at a single-copy tile path, as significant sequence cross-hybridization can result from the presence of non-unique probes on the array. Due to the fragmentation of genomic DNA caused by the widespread distribution of repetitive elements, the problem of obtaining adequate sequence coverage increases with the sizes of subsequence tiles that are to be included in the design. This becomes increasingly problematic when considering complex eukaryotic genomes that contain many thousands of interspersed repeats. The general problem of sequence tiling can be framed as finding an optimal partitioning of non-repetitive subsequences over a prescribed range of tile sizes, on a DNA sequence comprising repetitive and non-repetitive regions. Exact solutions to the tiling problem become computationally infeasible when applied to large genomes, but successive optimizations are developed that allow their practical implementation. These include an efficient method for determining the degree of similarity of many oligonucleotide sequences over large genomes, and two algorithms for finding an optimal tile path composed of longer sequence tiles. The first algorithm, a dynamic programming approach, finds an optimal tiling in linear time and space; the second applies a heuristic search to reduce the space complexity to a constant requirement. A Web resource has also been developed, accessible at http://tiling.gersteinlab.org, to generate optimal tile paths from user-provided DNA sequences.
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| 32. |
- Bray, Molly S, et al.
(författare)
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NIH working group report-using genomic information to guide weight management: From universal to precision treatment.
- 2016
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Ingår i: Obesity. - : Wiley. - 1930-739X .- 1930-7381. ; 24:1, s. 14-22
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine utilizes genomic and other data to optimize and personalize treatment. Although more than 2,500 genetic tests are currently available, largely for extreme and/or rare phenotypes, the question remains whether this approach can be used for the treatment of common, complex conditions like obesity, inflammation, and insulin resistance, which underlie a host of metabolic diseases.
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| 33. |
- Czeszumski, Artur, et al.
(författare)
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#EEGManyLabs: Investigating the Replicability of Influential EEG Experiments
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- There is growing awareness across the neuroscience community that the replicability of findings on the relationship between brain activity and cognitive phenomena can be improved by conducting studies with high statistical power that adhere to well-defined and standardized analysis pipelines. Inspired by efforts from the psychological sciences, and with the desire to examine some of the foundational findings using electroencephalography (EEG), we have launched #EEGManyLabs, a large-scale international collaborative replication effort. Since its discovery in the early 20th century, EEG has had a profound influence on our understanding of human cognition, but there is limited evidence on the replicability of some of the most highly cited discoveries. After a systematic search and selection process, we have identified 27 of the most influential and continually cited studies in the field. We plan to directly test the replicability of key findings from 20 of these studies in teams of at least three independent laboratories. The design and protocol of each replication effort will be submitted as a Registered Report and peer-reviewed prior to data collection. Prediction markets, open to all EEG researchers, will be used as a forecasting tool to examine which findings the community expects to replicate. This project will update our confidence in some of the most influential EEG findings and generate a large open access database that can be used to inform future research practices. Finally, through this international effort, we hope to create a cultural shift towards inclusive, high-powered multi-laboratory collaborations.
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| 34. |
- DeFilipp, Zachariah, et al.
(författare)
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Maintenance Tyrosine Kinase Inhibitors Following Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia : A Center for International Blood and Marrow Transplant Research Study
- 2020
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier. - 1083-8791 .- 1523-6536. ; 26:3, s. 472-479
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Tidskriftsartikel (refereegranskat)abstract
- It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined.
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| 35. |
- Emanuelsson, Olof, et al.
(författare)
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Assessing the performance of different high-density tiling microarray strategies for mapping transcribed regions of the human genome.
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 886-897
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Tidskriftsartikel (refereegranskat)abstract
- Genomic tiling microarrays have become a popular tool for interrogating the transcriptional activity of large regions of the genome in an unbiased fashion. There are several key parameters associated with each tiling experiment (e.g., experimental protocols and genomic tiling density). Here, we assess the role of these parameters as they are manifest in different tiling-array platforms used for transcription mapping. First, we analyze how a number of published tiling-array experiments agree with established gene annotation on human chromosome 22. We observe that the transcription detected from high-density arrays correlates substantially better with annotation than that from other array types. Next, we analyze the transcription-mapping performance of the two main high-density oligonucleotide array platforms in the ENCODE regions of the human genome. We hybridize identical biological samples and develop several ways of scoring the arrays and segmenting the genome into transcribed and nontranscribed regions, with the aim of making the platforms most comparable to each other. Finally, we develop a platform comparison approach based on agreement with known annotation. Overall, we find that the performance improves with more data points per locus, coupled with statistical scoring approaches that properly take advantage of this, where this larger number of data points arises from higher genomic tiling density and the use of replicate arrays and mismatches. While we do find significant differences in the performance of the two high-density platforms, we also find that they complement each other to some extent. Finally, our experiments reveal a significant amount of novel transcription outside of known genes, and an appreciable sample of this was validated by independent experiments.
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| 36. |
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| 37. |
- Euskirchen, Ghia M, et al.
(författare)
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Mapping of transcription factor binding regions in mammalian cells by ChIP : comparison of array- and sequencing-based technologies.
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 898-909
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Tidskriftsartikel (refereegranskat)abstract
- Recent progress in mapping transcription factor (TF) binding regions can largely be credited to chromatin immunoprecipitation (ChIP) technologies. We compared strategies for mapping TF binding regions in mammalian cells using two different ChIP schemes: ChIP with DNA microarray analysis (ChIP-chip) and ChIP with DNA sequencing (ChIP-PET). We first investigated parameters central to obtaining robust ChIP-chip data sets by analyzing STAT1 targets in the ENCODE regions of the human genome, and then compared ChIP-chip to ChIP-PET. We devised methods for scoring and comparing results among various tiling arrays and examined parameters such as DNA microarray format, oligonucleotide length, hybridization conditions, and the use of competitor Cot-1 DNA. The best performance was achieved with high-density oligonucleotide arrays, oligonucleotides >/=50 bases (b), the presence of competitor Cot-1 DNA and hybridizations conducted in microfluidics stations. When target identification was evaluated as a function of array number, 80%-86% of targets were identified with three or more arrays. Comparison of ChIP-chip with ChIP-PET revealed strong agreement for the highest ranked targets with less overlap for the low ranked targets. With advantages and disadvantages unique to each approach, we found that ChIP-chip and ChIP-PET are frequently complementary in their relative abilities to detect STAT1 targets for the lower ranked targets; each method detected validated targets that were missed by the other method. The most comprehensive list of STAT1 binding regions is obtained by merging results from ChIP-chip and ChIP-sequencing. Overall, this study provides information for robust identification, scoring, and validation of TF targets using ChIP-based technologies.
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| 38. |
- Gerstein, Mark B, et al.
(författare)
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What is a gene, post-ENCODE? : History and updated definition
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 669-681
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Tidskriftsartikel (refereegranskat)abstract
- While sequencing of the human genome surprised us with how many protein-coding genes there are, it did not fundamentally change our perspective on what a gene is. In contrast, the complex patterns of dispersed regulation and pervasive transcription uncovered by the ENCODE project, together with non-genic conservation and the abundance of noncoding RNA genes, have challenged the notion of the gene. To illustrate this, we review the evolution of operational definitions of a gene over the past century--from the abstract elements of heredity of Mendel and Morgan to the present-day ORFs enumerated in the sequence databanks. We then summarize the current ENCODE findings and provide a computational metaphor for the complexity. Finally, we propose a tentative update to the definition of a gene: A gene is a union of genomic sequences encoding a coherent set of potentially overlapping functional products. Our definition side-steps the complexities of regulation and transcription by removing the former altogether from the definition and arguing that final, functional gene products (rather than intermediate transcripts) should be used to group together entities associated with a single gene. It also manifests how integral the concept of biological function is in defining genes.
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| 39. |
- Glinos, Dafni A., et al.
(författare)
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Transcriptome variation in human tissues revealed by long-read sequencing
- 2022
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 608:7922, s. 353-359
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Tidskriftsartikel (refereegranskat)abstract
- Regulation of transcript structure generates transcript diversity and plays an important role in human disease(1-7). The advent oflong-read sequencing technologies offers the opportunity to study the role of genetic variation in transcript structure(8-)(16). In this Article, we present a large human long-read RNA-seq dataset using the Oxford Nanopore Technologies platform from 88 samples from Genotype-Tissue Expression (GTEx) tissues and cell lines, complementing the GTEx resource. We identified just over 70,000 novel transcripts for annotated genes, and validated the protein expression of 10% of novel transcripts. We developed a new computational package, LORALS, to analyse the genetic effects of rare and common variants on the transcriptome by allele-specific analysis of long reads. We characterized allele-specific expression and transcript structure events, providing new insights into the specific transcript alterations caused by common and rare genetic variants and highlighting the resolution gained from long-read data. We were able to perturb the transcript structure upon knockdown of PTBP1, an RNA binding protein that mediates splicing, thereby finding genetic regulatory effects that are modified by the cellular environment. Finally, we used this dataset to enhance variant interpretation and study rare variants leading to aberrant splicing patterns.
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| 40. |
- Groopman, Emily E., et al.
(författare)
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Diagnostic Utility of Exome Sequencing for Kidney Disease
- 2019
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 380:2, s. 142-151
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally.METHODS We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings.RESULTS In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management.CONCLUSIONS Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases.
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| 41. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 42. |
- Johnson, Michael, et al.
(författare)
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Responsiveness to Change : How can the concept of Attractive Quality Enhance School Sustainability?
- 2022
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Ingår i: Proceedings M2D2022: 9th International Conference on mechanics and materials in design. - 9789895475636 ; , s. 997-1014
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Konferensbidrag (refereegranskat)abstract
- The global COVID 19 pandemic created a challenge for organizations and schools worldwide that raised fundamental questions about the degree to which they are sustainable. Some schools struggled to adapt quickly to the needs of their stakeholders while others saw opportunity in the moment to create and innovate to generate new value for their customers and increase attractive quality. Sustainability can be defined as the responsiveness of a living system to change in its environment (Snyder and Snyder, 2021) and responsiveness as the quality of reacting quickly and positively. When faced with the pandemic, schools and organizations around the world were put to the test on how responsive they could be to changes in their complex environments and this turbulent time in history has forced educational leaders to ask how schools can create more sustainable practices. This paper presents a phenomenological study which examined what school leaders did to sustain attractive quality during the pandemic, specifically by evaluating responsiveness as a core capability. Findings were explored to better understand responsiveness and ask what lessons can be learned that will help inform a framework for developing sustainable quality in education.
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| 43. |
- Kry, Stephen F., et al.
(författare)
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APM Task Group 329 : Reference dose specification for dose calculations: Dose-to-water or dose-to-muscle?
- 2020
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Ingår i: Medical Physics. - : Wiley. - 0094-2405 .- 2473-4209. ; 47:3, s. 52-64
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Tidskriftsartikel (refereegranskat)abstract
- Linac calibration is done in water, but patients are comprised primarily of soft tissue. Conceptually, and specified in NRG/RTOG trials, dose should be reported as dose-to-muscle to describe the dose to the patient. Historically, the dose-to-water of the linac calibration was often converted to dose-to-muscle for patient calculations through manual application of a 0.99 dose-to-water to dose-to-muscle correction factor, applied during the linac clinical reference calibration. However, many current treatment planning system (TPS) dose calculation algorithms approximately provide dose-to-muscle (tissue), making application of a manual scaling unnecessary. There is little guidance on when application of a scaling factor is appropriate, resulting in highly inconsistent application of this scaling by the community. In this report we provide guidance on the steps necessary to go from the linac absorbed dose-to-water calibration to dose-to-muscle in patient, for various commercial TPS algorithms. If the TPS does not account for the difference between dose-to-water and dose-to-muscle, then TPS reference dose scaling is warranted. We have tabulated the major vendors' TPS in terms of whether they approximate dose-to-muscle or calculate dose-to-water and recommend the correction factor required to report dose-to-muscle directly from the TPS algorithm. Physicists should use this report to determine the applicable correction required for specifying the reference dose in their TPS to achieve this goal and should remain attentive to possible changes to their dose calculation algorithm in the future.
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| 44. |
- Landegren, Nils, 1986-, et al.
(författare)
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Comment on 'AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies'
- 2019
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Ingår i: eLife. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The AIRE gene plays a key role in the development of central immune tolerance by promoting thymic presentation of tissue-specific molecules. Patients with AIRE-deficiency develop multiple autoimmune manifestations and display autoantibodies against the affected tissues. In 2016 it was reported that: i) the spectrum of autoantibodies in patients with AIRE-deficiency is much broader than previously appreciated; ii) neutralizing autoantibodies to type I interferons (IFNs) could provide protection against type 1 diabetes in these patients (Meyer et al., 2016). We attempted to replicate these new findings using a similar experimental approach in an independent patient cohort, and found no evidence for either conclusion.
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| 45. |
- Landegren, Nils, et al.
(författare)
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Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1
- 2016
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1) is a monogenic disorder that features multiple autoimmune disease manifestations. It is caused by mutations in the Autoimmune regulator (AIRE) gene, which promote thymic display of thousands of peripheral tissue antigens in a process critical for establishing central immune tolerance. We here used proteome arrays to perform a comprehensive study of autoimmune targets in APS1. Interrogation of established autoantigens revealed highly reliable detection of autoantibodies, and by exploring the full panel of more than 9000 proteins we further identified MAGEB2 and PDILT as novel major autoantigens in APS1. Our proteome-wide assessment revealed a marked enrichment for tissue-specific immune targets, mirroring AIRE's selectiveness for this category of genes. Our findings also suggest that only a very limited portion of the proteome becomes targeted by the immune system in APS1, which contrasts the broad defect of thymic presentation associated with AIRE-deficiency and raises novel questions what other factors are needed for break of tolerance.
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| 46. |
- Landegren, Nils, et al.
(författare)
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Transglutaminase 4 as a prostate autoantigen in male subfertility
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 7:292
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.
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| 47. |
- Legrain, Pierre, et al.
(författare)
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The Human Proteome Project : Current State and Future Direction
- 2011
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- After the successful completion of the Human Genome Project, the Human Proteome Organization has recently officially launched a global Human Proteome Project (HPP), which is designed to map the entire human protein set. Given the lack of protein-level evidence for about 30% of the estimated 20,300 protein-coding genes, a systematic global effort will be necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP research groups will use the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge bases. The HPP participants will take advantage of the output and cross-analyses from the ongoing Human Proteome Organization initiatives and a chromosome-centric protein mapping strategy, termed C-HPP, with which many national teams are currently engaged. In addition, numerous biologically driven and disease-oriented projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents, and tools for protein studies and analyses, and a stronger basis for personalized medicine. The Human Proteome Organization urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.
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| 48. |
- Lichtenberg, Elinor M., et al.
(författare)
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A global synthesis of the effects of diversified farming systems on arthropod diversity within fields and across agricultural landscapes
- 2017
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 23:11, s. 4946-4957
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Tidskriftsartikel (refereegranskat)abstract
- Agricultural intensification is a leading cause of global biodiversity loss, which can reduce the provisioning of ecosystem services in managed ecosystems. Organic farming and plant diversification are farm management schemes that may mitigate potential ecological harm by increasing species richness and boosting related ecosystem services to agroecosystems. What remains unclear is the extent to which farm management schemes affect biodiversity components other than species richness, and whether impacts differ across spatial scales and landscape contexts. Using a global metadataset, we quantified the effects of organic farming and plant diversification on abundance, local diversity (communities within fields), and regional diversity (communities across fields) of arthropod pollinators, predators, herbivores, and detritivores. Both organic farming and higher in-field plant diversity enhanced arthropod abundance, particularly for rare taxa. This resulted in increased richness but decreased evenness. While these responses were stronger at local relative to regional scales, richness and abundance increased at both scales, and richness on farms embedded in complex relative to simple landscapes. Overall, both organic farming and in-field plant diversification exerted the strongest effects on pollinators and predators, suggesting these management schemes can facilitate ecosystem service providers without augmenting herbivore (pest) populations. Our results suggest that organic farming and plant diversification promote diverse arthropod metacommunities that may provide temporal and spatial stability of ecosystem service provisioning. Conserving diverse plant and arthropod communities in farming systems therefore requires sustainable practices that operate both within fields and across landscapes.
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| 49. |
- Liu, Suli, et al.
(författare)
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A Chromosome-centric Human Proteome Project (C-HPP) to Characterize the Sets of Proteins Encoded in Chromosome 17
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:1, s. 49-61
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Tidskriftsartikel (refereegranskat)abstract
- We report progress assembling the parts list for chromosome 17 and illustrate the various processes that we have developed to integrate available data from diverse genomic and proteomic knowledge bases. As primary resources, we have used GPMDB, neXtProt, PeptideAtlas, Human Protein Atlas (HPA), and GeneCards. All sites share the common resource of Ensembl for the genome modeling information. We have defined the chromosome 17 parts list with the following information: 1169 protein-coding genes, the numbers of proteins confidently identified by various experimental approaches as documented in GPMDB, neXtProt, PeptideAtlas, and HPA, examples of typical data sets obtained by RNASeq and proteomic studies of epithelial derived tumor cell lines (disease proteome) and a normal proteome (peripheral mononuclear cells), reported evidence of post-translational modifications, and examples of alternative splice variants (ASVs). We have constructed a list of the 59 "missing" proteins as well as 201 proteins that have inconclusive mass spectrometric (MS) identifications. In this report we have defined a process to establish a baseline for the incorporation of new evidence on protein identification and characterization as well as related information from transcriptome analyses. This initial list of "missing" proteins that will guide the selection of appropriate samples for discovery studies as well as antibody reagents. Also we have illustrated the significant diversity of protein variants (including post-translational modifications, PTMs) using regions on chromosome 17 that contain important oncogenes. We emphasize the need for mandated deposition of proteomics data in public databases, the further development of improved PTM, ASV, and single nucleotide variant (SNV) databases, and the construction of Web sites that can integrate and regularly update such information. In addition, we describe the distribution of both clustered and scattered sets of protein families on the chromosome. Since chromosome 17 is rich in cancer-associated genes, we have focused the clustering of cancer-associated genes in such genomic regions and have used the ERBB2 amplicon as an example of the value of a proteogenomic approach in which one integrates transcriptomic with proteomic information and captures evidence of coexpression through coordinated regulation.
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| 50. |
- Mazei-Robison, Michelle S., et al.
(författare)
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Role for mTOR Signaling and Neuronal Activity in Morphine-Induced Adaptations in Ventral Tegmental Area Dopamine Neurons
- 2011
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 72:6, s. 977-990
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Tidskriftsartikel (refereegranskat)abstract
- While the abuse of opiate drugs continues to rise, the neuroadaptations that occur with long-term drug exposure remain poorly understood. We describe here a series of chronic morphine-induced adaptations in ventral tegmental area (VTA) dopamine neurons, which are mediated via downregulation of AKT-mTORC2 (mammalian target of rapamycin complex-2). Chronic opiates decrease the size of VTA dopamine neurons in rodents, an effect seen in humans as well, and concomitantly increase the excitability of the cells but decrease dopamine output to target regions. Chronic morphine decreases mTORC2 activity, and overexpression of Rictor, a component of mTORC2, prevents morphine-induced changes in cell morphology and activity. Further, local knockout of Rictor in VTA decreases DA soma size and reduces rewarding responses to morphine, consistent with the hypothesis that these adaptations represent a mechanism of reward tolerance. Together, these findings demonstrate a novel role for AKT-mTORC2 signaling in mediating neuroadaptations to opiate drugs of abuse.
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