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. |
- Clark, Andrew G., et al.
(författare)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Tidskriftsartikel (refereegranskat)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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3. |
- Blunden, Jessica, et al.
(författare)
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State of the Climate in 2012
- 2013
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - 0003-0007 .- 1520-0477. ; 94:8, s. S1-S258
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Tidskriftsartikel (refereegranskat)abstract
- For the first time in serveral years, the El Nino-Southern Oscillation did not dominate regional climate conditions around the globe. A weak La Ni a dissipated to ENSOneutral conditions by spring, and while El Nino appeared to be emerging during summer, this phase never fully developed as sea surface temperatures in the eastern conditions. Nevertheless, other large-scale climate patterns and extreme weather events impacted various regions during the year. A negative phase of the Arctic Oscillation from mid-January to early February contributed to frigid conditions in parts of northern Africa, eastern Europe, and western Asia. A lack of rain during the 2012 wet season led to the worst drought in at least the past three decades for northeastern Brazil. Central North America also experienced one of its most severe droughts on record. The Caribbean observed a very wet dry season and it was the Sahel's wettest rainy season in 50 years. Overall, the 2012 average temperature across global land and ocean surfaces ranked among the 10 warmest years on record. The global land surface temperature alone was also among the 10 warmest on record. In the upper atmosphere, the average stratospheric temperature was record or near-record cold, depending on the dataset. After a 30-year warming trend from 1970 to 1999 for global sea surface temperatures, the period 2000-12 had little further trend. This may be linked to the prevalence of La Ni a-like conditions during the 21st century. Heat content in the upper 700 m of the ocean remained near record high levels in 2012. Net increases from 2011 to 2012 were observed at 700-m to 2000-m depth and even in the abyssal ocean below. Following sharp decreases in to the effects of La Ni a, sea levels rebounded to reach records highs in 2012. The increased hydrological cycle seen in recent years continued, with more evaporation in drier locations and more precipitation in rainy areas. In a pattern that has held since 2004, salty areas of the ocean surfaces and subsurfaces were anomalously salty on average, while fresher areas were anomalously fresh. Global tropical cyclone activity during 2012 was near average, with a total of 84 storms compared with the 1981-2010 average of 89. Similar to 2010 and 2011, the North Atlantic was the only hurricane basin that experienced above-normal activity. In this basin, Sandy brought devastation to Cuba and parts of the eastern North American seaboard. All other basins experienced either near-or below-normal tropical cyclone activity. Only three tropical cyclones reached Category 5 intensity-all in Bopha became the only storm in the historical record to produce winds greater than 130 kt south of 7 N. It was also the costliest storm to affect the Philippines and killed more than 1000 residents. Minimum Arctic sea ice extent in September and Northern Hemisphere snow cover extent in June both reached new record lows. June snow cover extent is now declining at a faster rate (-17.6% per decade) than September sea ice extent (-13.0% per decade). Permafrost temperatures reached record high values in northernmost Alaska. A new melt extent record occurred on 11-12 July on the Greenland ice sheet; 97% of the ice sheet showed some form of melt, four times greater than the average melt for this time of year. The climate in Antarctica was relatively stable overall. The largest maximum sea ice extent since records begain in 1978 was observed in September 2012. In the stratosphere, warm air led to the second smallest ozone hole in the past two decades. Even so, the springtime ozone layer above Antarctica likely will not return to its early 1980s state until about 2060. Following a slight decline associated with the global 2 emissions from fossil fuel combustion and cement production reached a record 9.5 +/- 0.5 Pg C in 2011 and a new record of 9.7 +/- 0.5 Pg C is estimated for 2012. Atmospheric CO2 concentrations increased by 2.1 ppm in 2012, to 392.6 ppm. In spring 2012, 2 concentration exceeded 400 ppm at 7 of the 13 Arctic observation sites. Globally, other greenhouse gases including methane and nitrous oxide also continued to rise in concentration and the combined effect now represents a 32% increase in radiative forcing over a 1990 baseline. Concentrations of most ozone depleting substances continued to fall.
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4. |
- Björkman, Anne, 1981, et al.
(författare)
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Tundra Trait Team: A database of plant traits spanning the tundra biome
- 2018
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Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 27:12, s. 1402-1411
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Tidskriftsartikel (refereegranskat)abstract
- © 2018 The Authors Global Ecology and Biogeography Published by John Wiley & Sons Ltd Motivation: The Tundra Trait Team (TTT) database includes field-based measurements of key traits related to plant form and function at multiple sites across the tundra biome. This dataset can be used to address theoretical questions about plant strategy and trade-offs, trait–environment relationships and environmental filtering, and trait variation across spatial scales, to validate satellite data, and to inform Earth system model parameters. Main types of variable contained: The database contains 91,970 measurements of 18 plant traits. The most frequently measured traits (>1,000 observations each) include plant height, leaf area, specific leaf area, leaf fresh and dry mass, leaf dry matter content, leaf nitrogen, carbon and phosphorus content, leaf C:N and N:P, seed mass, and stem specific density. Spatial location and grain: Measurements were collected in tundra habitats in both the Northern and Southern Hemispheres, including Arctic sites in Alaska, Canada, Greenland, Fennoscandia and Siberia, alpine sites in the European Alps, Colorado Rockies, Caucasus, Ural Mountains, Pyrenees, Australian Alps, and Central Otago Mountains (New Zealand), and sub-Antarctic Marion Island. More than 99% of observations are georeferenced. Time period and grain: All data were collected between 1964 and 2018. A small number of sites have repeated trait measurements at two or more time periods. Major taxa and level of measurement: Trait measurements were made on 978 terrestrial vascular plant species growing in tundra habitats. Most observations are on individuals (86%), while the remainder represent plot or site means or maximums per species. Software format: csv file and GitHub repository with data cleaning scripts in R; contribution to TRY plant trait database (www.try-db.org) to be included in the next version release.
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5. |
- Ding, Li, et al.
(författare)
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Somatic mutations affect key pathways in lung adenocarcinoma
- 2008
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 455:7216, s. 1069-1075
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Tidskriftsartikel (refereegranskat)abstract
- Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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6. |
- Ahmad, Amais, et al.
(författare)
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IMI – Oral biopharmaceutics tools project – Evaluation of bottom-up PBPK prediction success part 4 : Prediction accuracy and software comparisons with improved data and modelling strategies
- 2020
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 156, s. 50-63
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Tidskriftsartikel (refereegranskat)abstract
- Oral drug absorption is a complex process depending on many factors, including the physicochemical properties of the drug, formulation characteristics and their interplay with gastrointestinal physiology and biology. Physiological-based pharmacokinetic (PBPK) models integrate all available information on gastro-intestinal system with drug and formulation data to predict oral drug absorption. The latter together with in vitro-in vivo extrapolation and other preclinical data on drug disposition can be used to predict plasma concentration-time profiles in silico. Despite recent successes of PBPK in many areas of drug development, an improvement in their utility for evaluating oral absorption is much needed. Current status of predictive performance, within the confinement of commonly available in vitro data on drugs and formulations alongside systems information, were tested using 3 PBPK software packages (GI-Sim (ver.4.1), Simcyp® Simulator (ver.15.0.86.0), and GastroPlusTM (ver.9.0.00xx)). This was part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project.Fifty eight active pharmaceutical ingredients (APIs) were qualified from the OrBiTo database to be part of the investigation based on a priori set criteria on availability of minimum necessary information to allow modelling exercise. The set entailed over 200 human clinical studies with over 700 study arms. These were simulated using input parameters which had been harmonised by a panel of experts across different software packages prior to conduct of any simulation. Overall prediction performance and software packages comparison were evaluated based on performance indicators (Fold error (FE), Average fold error (AFE) and absolute average fold error (AAFE)) of pharmacokinetic (PK) parameters.On average, PK parameters (Area Under the Concentration-time curve (AUC0-tlast), Maximal concentration (Cmax), half-life (t1/2)) were predicted with AFE values between 1.11 and 1.97. Variability in FEs of these PK parameters was relatively high with AAFE values ranging from 2.08 to 2.74. Around half of the simulations were within the 2-fold error for AUC0-tlast and around 90% of the simulations were within 10-fold error for AUC0-tlast. Oral bioavailability (Foral) predictions, which were limited to 19 APIs having intravenous (i.v.) human data, showed AFE and AAFE of values 1.37 and 1.75 respectively. Across different APIs, AFE of AUC0-tlast predictions were between 0.22 and 22.76 with 70% of the APIs showing an AFE > 1. When compared across different formulations and routes of administration, AUC0-tlast for oral controlled release and i.v. administration were better predicted than that for oral immediate release formulations. Average predictive performance did not clearly differ between software packages but some APIs showed a high level of variability in predictive performance across different software packages. This variability could be related to several factors such as compound specific properties, the quality and availability of information, and errors in scaling from in vitro and preclinical in vivo data to human in vivo behaviour which will be explored further. Results were compared with previous similar exercise when the input data selection was carried by the modeller rather than a panel of experts on each in vitro test. Overall, average predictive performance was increased as reflected in smaller AAFE value of 2.8 as compared to AAFE value of 3.8 in case of previous exercise.
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7. |
- Haraldsson, Klas Tommy, et al.
(författare)
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3D Polymeric Microfluidic Device Fabrication via Contact Liquid Photolithographic Polymerization (CLiPP)
- 2006
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Ingår i: Sensors and actuators. B, Chemical. - : Elsevier BV. - 0925-4005 .- 1873-3077. ; 113:1, s. 454-460
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Tidskriftsartikel (refereegranskat)abstract
- In this contribution, a new method for the fabrication of complex polymeric microfluidic devices is presented. The technology, contact liquid photolithographic polymerization (CLIPP). overcomes many of the draw backs associated kith other rapid prototyping schemes, such as limited materials choices and time-consuming microassembly protocols. CUPP shares many traits with other photolithographic methods, but three distinct features: (i) liquid photoresists in contact with the photomask. (ii) readily removed sacrificial Materials. and (iii) living radical processes, enable multiple polymeric chemistries and mechanical properties while simultaneously enabling facile fabrication of 3D geometries and surface chemistry control. This contribution details fabrication techniques and methods for the fabrication of high aspect ratio posts covalently bonded to a polymeric substrate, an array of independently stacked bars on top of perpendicular bars, multiple undercut structures fabricated simultaneously, and a complex 3D geometry with intertwined channels.
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8. |
- Ho, Joshua W. K., et al.
(författare)
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Comparative analysis of metazoan chromatin organization
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 512:7515, s. 449-U507
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Tidskriftsartikel (refereegranskat)abstract
- Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms(1-3). Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths(4,5). To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.
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9. |
- Hutchison, J., et al.
(författare)
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Robust Polymer Microfluidic Device Fabrication via Contact Liquid Photolitographic Polymerization (CLiPP)
- 2004
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Ingår i: Lab on a Chip. - : Royal Society of Chemistry (RSC). - 1473-0197 .- 1473-0189. ; 4:6, s. 658-662
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Tidskriftsartikel (refereegranskat)abstract
- Microfluidic devices are commonly fabricated in silicon or glass using micromachining technology or elastomers using soft lithography methods; however, invariable bulk material properties, limited surface modification methods and difficulty in fabricating high aspect ratio devices prevent these materials from being utilized in numerous applications and/or lead to high fabrication costs. Contact Liquid Photolithographic Polymerization (CLiPP) was developed as an alternative microfabrication approach that uniquely exploits living radical photopolymerization chemistry to facilitate surface modification of device components, fabrication of high aspect ratio structures from many different materials with numerous covalently-adhered layers and facile construction of three-dimensional devices. This contribution describes CLiPP and demonstrates unique advantages of this new technology for microfabrication of polymeric microdevices. Specifically, the procedure for fabricating devices with CLiPP is presented, the living radical photopolymerization chemistry which enables this technology is described, and examples of devices made using CLiPP are shown.
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11. |
- Roy, Sushmita, et al.
(författare)
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Identification of functional elements and regulatory circuits by Drosophila modENCODE.
- 2010
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6012, s. 1787-1797
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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12. |
- Wilkinson, John L., et al.
(författare)
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Pharmaceutical pollution of the world's rivers
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:8
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposure to active pharmaceutical ingredients (APIs) can have negative effects on the health of ecosystems and humans. While numerous studies have monitored APIs in rivers, these employ different analytical methods, measure different APIs, and have ignored many of the countries of the world. This makes it difficult to quantify the scale of the problem from a global perspective. Furthermore, comparison of the existing data, generated for different studies/regions/continents, is challenging due to the vast differences between the analytical methodologies employed. Here, we present a global-scale study of API pollution in 258 of the world's rivers, representing the environmental influence of 471.4 million people across 137 geographic regions. Samples were obtained from 1,052 locations in 104 countries (representing all continents and 36 countries not previously studied for API contamination) and analyzed for 61 APIs. Highest cumulative API concentrations were observed in sub-Saharan Africa, south Asia, and South America. The most contaminated sites were in low- to middle-income countries and were associated with areas with poor wastewater and waste management infrastructure and pharmaceutical manufacturing. The most frequently detected APIs were carbamazepine, metformin, and caffeine (a compound also arising from lifestyle use), which were detected at over half of the sites monitored. Concentrations of at least one API at 25.7% of the sampling sites were greater than concentrations considered safe for aquatic organisms, or which are of concern in terms of selection for antimicrobial resistance. Therefore, pharmaceutical pollution poses a global threat to environmental and human health, as well as to delivery of the United Nations Sustainable Development Goals.
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