| 1. |
- Assimes, Themistocles L., et al.
(författare)
-
Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
- 2010
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 56:19, s. 1552-1563
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
|
|
| 2. |
- Fossati, Andrea, et al.
(författare)
-
PCprophet : a framework for protein complex prediction and differential analysis using proteomic data
- 2021
-
Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 18:5, s. 520-527
-
Tidskriftsartikel (refereegranskat)abstract
- Despite the availability of methods for analyzing protein complexes, systematic analysis of complexes under multiple conditions remains challenging. Approaches based on biochemical fractionation of intact, native complexes and correlation of protein profiles have shown promise. However, most approaches for interpreting cofractionation datasets to yield complex composition and rearrangements between samples depend considerably on protein–protein interaction inference. We introduce PCprophet, a toolkit built on size exclusion chromatography–sequential window acquisition of all theoretical mass spectrometry (SEC-SWATH-MS) data to predict protein complexes and characterize their changes across experimental conditions. We demonstrate improved performance of PCprophet over state-of-the-art approaches and introduce a Bayesian approach to analyze altered protein–protein interactions across conditions. We provide both command-line and graphical interfaces to support the application of PCprophet to any cofractionation MS dataset, independent of separation or quantitative liquid chromatography–MS workflow, for the detection and quantitative tracking of protein complexes and their physiological dynamics.
|
|
| 3. |
- Gowan, Evan J., et al.
(författare)
-
A model of the western Laurentide Ice Sheet, using observations of glacial isostatic adjustment
- 2016
-
Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 139, s. 1-16
-
Forskningsöversikt (refereegranskat)abstract
- We present the results of a new numerical model of the late glacial western Laurentide Ice Sheet, constrained by observations of glacial isostatic adjustment (GIA), including relative sea level indicators, uplift rates from permanent GPS stations, contemporary differential lake level change, and postglacial tilt of glacial lake level indicators. The later two datasets have been underutilized in previous GIA based ice sheet reconstructions. The ice sheet model, called NAICE, is constructed using simple ice physics on the basis of changing margin location and basal shear stress conditions in order to produce ice volumes required to match GIA. The model matches the majority of the observations, while maintaining a relatively realistic ice sheet geometry. Our model has a peak volume at 18,000 yr BP, with a dome located just east of Great Slave Lake with peak thickness of 4000 m, and surface elevation of 3500 m. The modelled ice volume loss between 16,000 and 14,000 yr BP amounts to about 7.5 m of sea level equivalent, which is consistent with the hypothesis that a large portion of Meltwater Pulse 1A was sourced from this part of the ice sheet. The southern part of the ice sheet was thin and had a low elevation profile. This model provides an accurate representation of ice thickness and paleo-topography, and can be used to assess present day uplift and infer past climate.
|
|
| 4. |
- Gowan, Evan J., et al.
(författare)
-
ICESHEET 1.0 : a program to produce paleo-ice sheet reconstructions with minimal assumptions
- 2016
-
Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 9:5, s. 1673-1682
-
Tidskriftsartikel (refereegranskat)abstract
- We describe a program that produces paleo-ice sheet reconstructions using an assumption of steady-state, perfectly plastic ice flow behaviour. It incorporates three input parameters: ice margin, basal shear stress and basal topography. Though it is unlikely that paleo-ice sheets were ever in complete steady-state conditions, this method can produce an ice sheet without relying on complicated and unconstrained parameters such as climate and ice dynamics. This makes it advantageous to use in glacial-isostatic adjustment ice sheet modelling, which are often used as input parameters in global climate modelling simulations. We test this program by applying it to the modern Greenland Ice Sheet and Last Glacial Maximum Barents Sea Ice Sheet and demonstrate the optimal parameters that balance computational time and accuracy.
|
|
| 5. |
- Lambeck, Kurt, et al.
(författare)
-
Constraints on the Late Saalian to early Middle Weichselian ice sheet of Eurasia from field data and rebound modelling
- 2006
-
Ingår i: Boreas. - : Wiley. - 1502-3885 .- 0300-9483. ; 35:3, s. 539-575
-
Tidskriftsartikel (refereegranskat)abstract
- Using glacial rebound models we have inverted observations of crustal rebound and shoreline locations to estimate the ice thickness for the major glaciations over northern Eurasia and to predict the palaeo-topography from late MIS-6 ( the Late Saalian at c. 140 kyr BP) to MIS-4e ( early Middle Weichselian at c. 64 kyr BP). During the Late Saalian, the ice extended across northern Europe and Russia with a broad dome centred from the Kara Sea to Karelia that reached a maximum thickness of c. 4500 m and ice surface elevation of c. 3500 m above sea level. A secondary dome occurred over Finland with ice thickness and surface elevation of 4000 m and 3000 m, respectively. When ice retreat commenced, and before the onset of the warm phase of the early Eemian, extensive marine flooding occurred from the Atlantic to the Urals and, once the ice retreated from the Urals, to the Taymyr Peninsula. The Baltic - White Sea connection is predicted to have closed at about 129 kyr BP, although large areas of arctic Russia remained submerged until the end of the Eemian. During the stadials (MIS-5d, 5b, 4) the maximum ice was centred over the Kara - Barents Seas with a thickness not exceeding c. 1200 m. Ice-dammed lakes and the elevations of sills are predicted for the major glacial phases and used to test the ice models. Large lakes are predicted for west Siberia at the end of the Saalian and during MIS-5d, 5b and 4, with the lake levels, margin locations and outlets depending inter alia on ice thickness and isostatic adjustment. During the Saalian and MIS-5d, 5b these lakes overflowed through the Turgay pass into the Aral Sea, but during MIS-4 the overflow is predicted to have occurred north of the Urals. West of the Urals the palaeo-lake predictions are strongly controlled by whether the Kara Ice Sheet dammed the White Sea. If it did, then the lake levels are controlled by the topography of the Dvina basin with overflow directed into the Kama-Volga river system. Comparisons of predicted with observed MIS-5b lake levels of Komi Lake favour models in which the White Sea was in contact with the Barents Sea.
|
|
| 6. |
- Lambeck, Kurt, et al.
(författare)
-
The Scandinavian Ice Sheet: from MIS 4 to the end of the Last Glacial Maximum
- 2010
-
Ingår i: Boreas. - : Wiley. - 1502-3885 .- 0300-9483. ; 39:2, s. 410-435
-
Forskningsöversikt (refereegranskat)abstract
- Glacial rebound modelling, to establish constraints on past ice sheets from the observational evidence of palaeo-shoreline elevations, is well established for the post- Last Glacial Maximum (post-LGM) period, for which the observational evidence is relatively abundant and well distributed spatially and in time. This is particularly the case for Scandinavia. For the earlier part of the glacial cycle this evidence becomes increasingly sparse and uncertain such that, with the exception of the Eemian period, there are very few, if any, direct sea-level indicators that constrain any part of the Scandinavian Ice Sheet evolution before the LGM. Instead, we assume that ice-sheet basal conditions during Marine Isotope Stage 3 (MIS 3) are the same as those for the LGM, focus on establishing these conditions from the rebound analysis for the LGM and Lateglacial period, and then extrapolate to the earlier period using observationally constrained locations of the ice margins. The glacial rebound modelling and inversion follow previously established formulations, with the exception that the effects of water loading from proglacial lakes that form within the Baltic Basin and elsewhere have been included. The data set for the inversion of the sea- and lake-level data has been extended to include marine-limit data in order to extend the observational record further back in time. The result is a sequence of time slices for the Scandinavian Ice Sheet from the time of MIS 4 to the Lateglacial that are characterized by frozen basal conditions until late in the LGM interval when rapid thinning occurred in the eastern and southern sectors of the ice sheet. The primary function of these models is as an interpolator between the fragmentary observational constraints and to produce quantitative models for the glaciation history with predictive capabilities, for example regarding the evolution of the Baltic Basin.
|
|
| 7. |
- Lango Allen, Hana, et al.
(författare)
-
Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
-
Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
|
|
| 8. |
- Lozano, Rafael, et al.
(författare)
-
Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017
- 2018
-
Ingår i: The Lancet. - : Elsevier. - 1474-547X .- 0140-6736. ; 392:10159, s. 2091-2138
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030.
|
|
| 9. |
- Reeves, Jessica M., et al.
(författare)
-
Palaeoenvironmental change in tropical Australasia over the last 30,000 years - a synthesis by the OZ-INTIMATE group
- 2013
-
Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 74, s. 97-114
-
Tidskriftsartikel (refereegranskat)abstract
- The tropics are the major source of heat and moisture for the Australasian region. Determining the tropics' response over time to changes in climate forcing mechanisms, such as summer insolation, and the effects of relative sea level on exposed continental shelves during the Last Glacial period, is an ongoing process of re-evaluation. We present a synthesis of climate proxy data from tropical Australasia spanning the last 30,000 years that incorporates deep sea core, coral, speleothem, pollen, charcoal and terrestrial sedimentary records. Today, seasonal variability is governed largely by the annual migration of the inter-tropical convergence zone (ITCZ), influencing this region most strongly during the austral summer. However, the position of the ITCZ has varied through time. Towards the end of Marine Isotope Stage (MIS) 3, conditions were far wetter throughout the region, becoming drier first in the south. Universally cooler land and sea-surface temperature (SST) were characteristic of the Last Glacial Maximum, with drier conditions than previously, although episodic wet periods are noted in the fluvial records of northern Australia. The deglacial period saw warming first in the Coral Sea and then the Indonesian seas, with a pause in this trend around the time of the Antarctic Cold Reversal (c. 14.5 ka), coincident with the flooding of the Sunda Shelf. Wetter conditions occurred first in Indonesia around 17 ka and northern Australia after 14 ka. The early Holocene saw a peak in marine SST to the northwest and northeast of Australia. Modern vegetation was first established on Indonesia, then progressively south and eastward to NE Australia. Flores and the Atherton Tablelands show a dry period around 11.6 ka, steadily becoming wetter through the early Holocene. The mid-late Holocene was punctuated by millennial-scale variability, associated with the El Nino-Southern Oscillation; this is evident in the marine, coral, speleothem and pollen records of the region.
|
|
| 10. |
- Speliotes, Elizabeth K., et al.
(författare)
-
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
|
|
