| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Arndt, D. S., et al.
(författare)
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STATE OF THE CLIMATE IN 2017
- 2018
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Ingår i: Bulletin of The American Meteorological Society - (BAMS). - : American Meteorological Society. - 0003-0007 .- 1520-0477. ; 99:8, s. S1-S310
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Forskningsöversikt (refereegranskat)
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| 3. |
- Craddock, Nick, et al.
(författare)
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Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
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Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
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| 4. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Klionsky, Daniel J., et al.
(författare)
-
Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes
- 2008
-
Ingår i: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 4:2, s. 151-175
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Forskningsöversikt (refereegranskat)abstract
- Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.2,3 There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.
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| 6. |
- Newton-Cheh, Christopher, et al.
(författare)
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Genome-wide association study identifies eight loci associated with blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
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| 7. |
- Soranno, Patricia A., et al.
(författare)
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LAGOS-NE : A multi-scaled geospatial and temporal database of lake ecological context and water quality for thousands of U.S. lakes
- 2017
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Ingår i: GigaScience. - : Oxford University Press (OUP). - 2047-217X. ; 6:12, s. 1-22
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the factors that affect water quality and the ecological services provided by freshwater ecosystems is an urgent global environmental issue. Predicting how water quality will respond to global changes not only requires water quality data, but also information about the ecological context of individual water bodies across broad spatial extents. Because lake water quality is usually sampled in limited geographic regions, often for limited time periods, assessing the environmental controls of water quality requires compilation of many data sets across broad regions and across time into an integrated database. LAGOS-NE accomplishes this goal for lakes in the northeastern-most 17 US states. LAGOS-NE contains data for 51101 lakes and reservoirs larger than 4 ha in 17 lake-rich US states. The database includes 3 datamodules for: lake location and physical characteristics for all lakes; ecological context (i.e., the land use, geologic, climatic, and hydrologic setting of lakes) for all lakes; and in situmeasurements of lake water quality for a subset of the lakes fromthe past 3 decades for approximately 2600–12 000 lakes depending on the variable. The database contains approximately 150000 measures of total phosphorus, 200 000 measures of chlorophyll, and 900 000 measures of Secchi depth. The water quality data were compiled from87 lake water quality data sets fromfederal, state, tribal, and non-profit agencies, university researchers, and citizen scientists. This database is one of the largest andmost comprehensive databases of its type because it includes both in situmeasurements and ecological context data. Because ecological context can be used to study a variety of other questions about lakes, streams, and wetlands, this database can also be used as the foundation for other studies of freshwaters at broad spatial and ecological scales
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| 8. |
- Kanai, M, et al.
(författare)
-
- 2023
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swepub:Mat__t
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| 9. |
- Alvarez-Madrazo, Samantha, et al.
(författare)
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Common Polymorphisms in the CYP11B1 and CYP11B2 Genes: Evidence for a Digenic Influence on Hypertension
- 2013
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Ingår i: Hypertension. - 1524-4563. ; 61:1, s. 232-239
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Tidskriftsartikel (refereegranskat)abstract
- The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n = 3340) and confirmation (n = 2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio = 1.16, P = 8.54x10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio = 1.11; P = 7.4x10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio = 0.88, P = 2.2x10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis. (Hypertension. 2013;61:232-239.). center dot Online Data Supplement
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| 10. |
- Hillier, Ladeana W, et al.
(författare)
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Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution
- 2004
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Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 432:7018, s. 695-716
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Tidskriftsartikel (refereegranskat)abstract
- We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.
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| 11. |
- Tiegs, Scott D., et al.
(författare)
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Global patterns and drivers of ecosystem functioning in rivers and riparian zones
- 2019
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Ingår i: Science Advances. - Washington : American Association of Advancement in Science. - 2375-2548. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth's biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented "next-generation biomonitoring" by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.
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| 12. |
- Webster, Christopher R., et al.
(författare)
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Background levels of methane in Mars' atmosphere show strong seasonal variations
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 360:6393, s. 1093-1096
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Tidskriftsartikel (refereegranskat)abstract
- Variable levels of methane in the martian atmosphere have eluded explanation partly because the measurements are not repeatable in time or location. We report in situ measurements at Gale crater made over a 5-year period by the Tunable Laser Spectrometer on the Curiosity rover. The background levels of methane have a mean value 0.41 ± 0.16 parts per billion by volume (ppbv) (95% confidence interval) and exhibit a strong, repeatable seasonal variation (0.24 to 0.65 ppbv). This variation is greater than that predicted from either ultraviolet degradation of impact-delivered organics on the surface or from the annual surface pressure cycle. The large seasonal variation in the background and occurrences of higher temporary spikes (~7 ppbv) are consistent with small localized sources of methane released from martian surface or subsurface reservoirs.
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| 13. |
- Webster, Christopher R., et al.
(författare)
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Mars methane detection and variability at Gale crater
- 2015
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 347:6220, s. 415-417
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Tidskriftsartikel (refereegranskat)abstract
- Reports of plumes or patches of methane in the Martian atmosphere that vary over monthly timescales have defied explanation to date. From in situ measurements made over a 20-month period by the Tunable Laser Spectrometer (TLS) of the Sample Analysis at Mars (SAM) instrument suite on Curiosity at Gale Crater, we report detection of background levels of atmospheric methane of mean value 0.69 ± 0.25 ppbv at the 95% confidence interval (CI). This abundance is lower than model estimates of ultraviolet (UV) degradation of accreted interplanetary dust particles (IDP’s) or carbonaceous chondrite material. Additionally, in four sequential measurements spanning a 60-sol period, we observed elevated levels of methane of 7.2 ± 2.1 (95% CI) ppbv implying that Mars is episodically producing methane from an additional unknown source.
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| 14. |
- Costello, David M., et al.
(författare)
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Global patterns and controls of nutrient immobilization on decomposing cellulose in riverine ecosystems
- 2022
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Ingår i: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 36:3
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Tidskriftsartikel (refereegranskat)abstract
- Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature. Collectively, we demonstrated that exogenous nutrient supply and immobilization are critical control points for decomposition of organic matter.
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| 15. |
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| 16. |
- El Zowalaty, Mohamed E., et al.
(författare)
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Molecular detection of influenza A viruses and H5 subtype among migratory Amur falcons (Falco amurensis) and captive birds of prey
- 2022
-
Ingår i: Transboundary and Emerging Diseases. - : John Wiley & Sons. - 1865-1674 .- 1865-1682. ; 69:2, s. 369-377
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Tidskriftsartikel (refereegranskat)abstract
- Influenza A viruses (IAVs) and Newcastle disease viruses (NDVs) are major human and animal health threats with geographic differences in prevalence, characteristics and host populations. Currently, there is sparse information on IAVs and NDVs in avian species in South Africa. Because raptors feed on live wild birds which are the reservoir hosts of IAVs and NDVs, we considered them a good sentinel for surveillance. Therefore, in addition to other resident birds of prey, migratory Amur falcons (Falco amurensis) were screened for IAVs and NDVs. Oropharyngeal and cloacal samples were collected from raptor species at three sampling sites in KwaZulu-Natal Province and samples were screened for IAVs and NDVs using molecular and virus isolation methods. IAV-positive samples were further screened for the presence of H5, H7 and H9 viruses. A total of 14 samples from 11 birds (45.8% of all sampled birds) were IAV positive with C-t lower than 36 in duplicate tests. Five out of 24 birds (20.8%) were positive for IAV RNA in duplicate testing, albeit at low concentrations. Among raptor samples, three out of 24 birds (12.5%) were positive for IAVs with viral RNA detected in both cloacal and oropharyngeal swabs. One IAV-positive sample was also positive for H5 subtype (4.1%); all other samples were H5, H7 and H9 negative. Besides, all samples were NDV negative. Overall, our results support the development of more intensive and expanded influenza and other emerging virus studies in raptor species.
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| 17. |
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| 18. |
- Friedman, James S., et al.
(författare)
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Mutations in a BTB-Kelch Protein, KLHL7, Cause Autosomal-Dominant Retinitis Pigmentosa
- 2009
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 84:6, s. 792-800
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Tidskriftsartikel (refereegranskat)abstract
- Retinitis pigmentosa (RP) refers to a genetically heterogeneous group of progressive neurodegenerative diseases that result in dysfunction and/or death of rod and cone photoreceptors in the retina. So far, 18 genes have been identified for autosomal-dominant (ad) RP. Here, we describe an adRP locus (RP42) at chromosome 7p15 through linkage analysis in a six-generation Scandinavian family and identify a disease-causing mutation, c.449G -> A (p.S150N), in exon 6 of the KLHL7 gene. Mutation screening of KLHL7 in 502 retinopathy probands has revealed three different missense mutations in six independent families. KLHL7 is widely expressed, including expression in rod photoreceptors, and encodes a 75 kDa protein of the BTB-Kelch Subfamily within the BTB superfamily. BTB-Kelch proteins have been implicated in ubiquitination through Cullin E3 ligases. Notably, all three putative disease-causing KLHL7 mutations are within a conserved BACK domain; homology modeling suggests that mutant amino acid side chains can potentially fill the cleft between two helices, thereby affecting the ubiquitination complexes. Mutations in an identical region of another BTB-Kelch protein, gigaxonin, have previously been associated with giant axonal neuropathy. Our studies suggest an additional role of the ubiquitin-proteasome protein-degradation pathway in maintaining neuronal health and in disease.
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| 19. |
- Friedman, James S., et al.
(författare)
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Premature truncation of a novel protein, RD3, exhibiting subnuclear localization is associated with retinal degeneration
- 2006
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Ingår i: American Journal of Human Genetics. - 0002-9297. ; 79:6, s. 1059-1070
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Tidskriftsartikel (refereegranskat)abstract
- The rd3 mouse is one of the oldest identified models of early-onset retinal degeneration. Using the positional candidate approach, we have identified a C -> T substitution in a novel gene, Rd3, that encodes an evolutionarily conserved protein of 195 amino acids. The rd3 mutation results in a predicted stop codon after residue 106. This change is observed in four rd3 lines derived from the original collected mice but not in the nine wild-type mouse strains that were examined. Rd3 is preferentially expressed in the retina and exhibits increasing expression through early postnatal development. In transiently transfected COS-1 cells, the RD3-fusion protein shows subnuclear localization adjacent to promyelocytic leukemia-gene-product bodies. The truncated mutant RD3 protein is detectable in COS-1 cells but appears to get degraded rapidly. To explore potential association of the human RD3 gene at chromosome 1q32 with retinopathies, we performed a mutation screen of 881 probands from North America, India, and Europe. In addition to several alterations of uncertain significance, we identified a homozygous alteration in the invariant G nucleotide of the RD3 exon 2 donor splice site in two siblings with Leber congenital amaurosis. This mutation is predicted to result in premature truncation of the RD3 protein, segregates with the disease, and is not detected in 121 ethnically matched control individuals. We suggest that the retinopathy-associated RD3 protein is part of subnuclear protein complexes involved in diverse processes, such as transcription and splicing.
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| 20. |
- Gladding, Patrick, et al.
(författare)
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The Antiplatelet Effect of Higher Loading and Maintenance Dose Regimens of Clopidogrel The PRINC (Plavix Response in Coronary Intervention) Trial
- 2008
-
Ingår i: JACC. Cardiovascular interventions. - : Elsevier BV. - 1936-8798. ; 1:6, s. 612-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study evaluated the antiplatelet effect of a higher loading and maintenance dose regimen of clopidogrel and a possible drug interaction with verapamil. BACKGROUND: Clopidogrel loading doses above 600 mg have not resulted in more rapid or complete platelet inhibition. Higher maintenance dosages may be more effective than 75 mg/day. METHODS: A double-blind, randomized, placebo-controlled trial was undertaken in 60 patients undergoing percutaneous coronary intervention. All patients received clopidogrel 600 mg at the start of the procedure. Using a 2 x 2 design, patients were allocated to clopidogrel 600 mg given 2 h later or matching placebo, and to verapamil 5 mg intra-arterial or placebo. Platelet function was measured using the VerifyNow P2Y12 analyzer (Accumetrics Ltd., San Diego, California) at 2, 4, and 7 h. Patients were further randomized to receive a clopidogrel 75 or 150 mg once daily, with platelet function assessed after 1 week. RESULTS: Two hours after the second dose of clopidogrel or placebo, platelet inhibition was 42 +/- 27% with clopidogrel, compared with 24 +/- 22% with placebo (p = 0.0006). By 5 h after the second dose, platelet inhibition was 49 +/- 30% with clopidogrel, compared with 29 +/- 22% with placebo (p = 0.01). No drug interaction was seen with verapamil. A clopidogrel maintenance dosage of 150 mg daily for 1 week resulted in greater platelet inhibition than 75 mg daily (50 +/- 28% vs. 29 +/- 19%, p = 0.01). CONCLUSIONS: In an unselected population undergoing percutaneous coronary intervention a clopidogrel 1,200-mg loading dose, given as two 600-mg doses 2 h apart, results in more rapid and complete platelet inhibition than a single 600-mg dose. A maintenance dosage of 150 mg daily produces greater platelet inhibition than 75 mg daily. (The PRINC trial; ACTRN12606000129583).
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| 21. |
- Gladding, Patrick, et al.
(författare)
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The Pharmacogenetics and Pharmacodynamics of Clopidogrel Response : An Analysis From the PRINC (Plavix Response in Coronary Intervention) Trial
- 2008
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Ingår i: JACC. Cardiovascular interventions. - : Elsevier BV. - 1936-8798. ; 1:6, s. 620-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: This study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel. BACKGROUND: Variability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate-receptor P2Y12). METHODS: Sixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction-based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes. RESULTS: CYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers (9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042). CONCLUSIONS: Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583).
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| 22. |
- Greenwood, John, et al.
(författare)
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Current research into brain barriers and the delivery of therapeutics for neurological diseases : a report on CNS barrier congress London, UK, 2017
- 2017
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Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14
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Forskningsöversikt (refereegranskat)abstract
- This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.
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| 23. |
- Grüning, Björn, et al.
(författare)
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Bioconda: A sustainable and comprehensive software distribution for the life sciences
- 2017
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We present Bioconda (https://bioconda.github.io), a distribution of bioinformatics software for the lightweight, multi-platform and language-agnostic package manager Conda. Currently, Bioconda offers a collection of over 3000 software packages, which is continuously maintained, updated, and extended by a growing global community of more than 200 contributors. Bioconda improves analysis reproducibility by allowing users to define isolated environments with defined software versions, all of which are easily installed and managed without administrative privileges.
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| 24. |
- Kariippanon, Katharina E., et al.
(författare)
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Levels and Correlates of Objectively Measured Sedentary Behavior in Young Children : SUNRISE Study Results from 19 Countries
- 2022
-
Ingår i: Medicine & Science in Sports & Exercise. - : Lippincott, Williams & Wilkins. - 0195-9131 .- 1530-0315. ; 54:7, s. 1123-1130
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Tidskriftsartikel (refereegranskat)abstract
- Purpose There is a paucity of global data on sedentary behavior during early childhood. The purpose of this study was to examine how device-measured sedentary behavior in young children differed across geographically, economically, and sociodemographically diverse populations, in an international sample. Methods This multinational, cross-sectional study included data from 1071 children 3-5 yr old from 19 countries, collected between 2018 and 2020 (pre-COVID). Sedentary behavior was measured for three consecutive days using activPAL accelerometers. Sedentary time, sedentary fragmentation, and seated transport duration were calculated. Linear mixed models were used to examine the differences in sedentary behavior variables between sex, country-level income groups, urban/rural settings, and population density. Results Children spent 56% (7.4 h) of their waking time sedentary. The longest average bout duration was 81.1 +/- 45.4 min, and an average of 61.1 +/- 50.1 min center dot d(-1) was spent in seated transport. Children from upper-middle-income and high-income countries spent a greater proportion of the day sedentary, accrued more sedentary bouts, had shorter breaks between sedentary bouts, and spent significantly more time in seated transport, compared with children from low-income and lower-middle-income countries. Sex and urban/rural residential setting were not associated with any outcomes. Higher population density was associated with several higher sedentary behavior measures. Conclusions These data advance our understanding of young childrens sedentary behavior patterns globally. Country income levels and population density appear to be stronger drivers of the observed differences, than sex or rural/urban residential setting.
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| 25. |
- Lagou, Vasiliki, et al.
(författare)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
-
Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 26. |
- Leisawitz, David, et al.
(författare)
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Origins Space Telescope: Baseline mission concept
- 2021
-
Ingår i: Journal of Astronomical Telescopes, Instruments, and Systems. - 2329-4221 .- 2329-4124. ; 7:1
-
Tidskriftsartikel (refereegranskat)abstract
- The Origins Space Telescope will trace the history of our origins from the time dust and heavy elements permanently altered the cosmic landscape to present-day life. How did galaxies evolve from the earliest galactic systems to those found in the Universe today? How do habitable planets form? How common are life-bearing worlds? To answer these alluring questions, Origins will operate at mid-and far-infrared (IR) wavelengths and offer powerful spectroscopic instruments and sensitivity three orders of magnitude better than that of the Herschel Space Observatory, the largest telescope flown in space to date. We describe the baseline concept for Origins recommended to the 2020 US Decadal Survey in Astronomy and Astrophysics. The baseline design includes a 5.9-m diameter telescope cryocooled to 4.5 K and equipped with three scientific instruments. A mid-infrared instrument (Mid-Infrared Spectrometer and Camera Transit spectrometer) will measure the spectra of transiting exoplanets in the 2.8 to 20 μm wavelength range and offer unprecedented spectrophotometric precision, enabling definitive exoplanet biosignature detections. The far-IR imager polarimeter will be able to survey thousands of square degrees with broadband imaging at 50 and 250 μm. The Origins Survey Spectrometer will cover wavelengths from 25 to 588 μm, making wide-area and deep spectroscopic surveys with spectral resolving power R ∼ 300, and pointed observations at R ∼ 40,000 and 300,000 with selectable instrument modes. Origins was designed to minimize complexity. The architecture is similar to that of the Spitzer Space Telescope and requires very few deployments after launch, while the cryothermal system design leverages James Webb Space Telescope technology and experience. A combination of current-state-of-the-art cryocoolers and next-generation detector technology will enable Origins' natural background-limited sensitivity.
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| 27. |
- Ma, Jianhui, et al.
(författare)
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Inhibition of Nuclear PTEN Tyrosine Phosphorylation Enhances Glioma Radiation Sensitivity through Attenuated DNA Repair
- 2019
-
Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 35:3, s. 504-518.e7
-
Tidskriftsartikel (refereegranskat)abstract
- Ionizing radiation (IR) and chemotherapy are standard-of-care treatments for glioblastoma (GBM) patients and both result in DNA damage, however, the clinical efficacy is limited due to therapeutic resistance. We identified a mechanism of such resistance mediated by phosphorylation of PTEN on tyrosine 240 (pY240-PTEN) by FGFR2. pY240-PTEN is rapidly elevated and bound to chromatin through interaction with Ki-67 in response to IR treatment and facilitates the recruitment of RAD51 to promote DNA repair. Blocking Y240 phosphorylation confers radiation sensitivity to tumors and extends survival in GBM preclinical models. Y240F-Pten knockin mice showed radiation sensitivity. These results suggest that FGFR-mediated pY240-PTEN is a key mechanism of radiation resistance and is an actionable target for improving radiotherapy efficacy.
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| 28. |
- Mackay, Donna S, et al.
(författare)
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Screening of a Large Cohort of Leber Congenital Amaurosis and Retinitis Pigmentosa Patients Identifies Novel LCA5 Mutations and New Genotype-Phenotype Correlations
- 2013
-
Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 34:11, s. 1537-1546
-
Tidskriftsartikel (refereegranskat)abstract
- This study was undertaken to investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early-onset retinal dystrophy (EORD), and autosomal recessive retinitis pigmentosa (arRP); to delineate the ocular phenotypes; and to provide an overview of all published LCA5 variants in an online database. Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autofluorescence imaging were possible. DNA samples from 797 unrelated patients with LCA and 211 with the various types of retinitis pigmentosa (RP) were screened by Sanger sequence analysis of all LCA5 exons and intron/exon junctions. Some LCA patients were prescreened by APEX technology or selected based on homozygosity mapping. In silico analyses were performed to assess the pathogenicity of the variants. Segregation analysis was performed where possible. Published and novel LCA5 variants were collected, amended for their correct nomenclature, and listed in a Leiden Open Variation Database (LOVD). Sequence analysis identified 18 new probands with 19 different LCA5 variants. Seventeen of the 19 LCA5 variants were novel. Except for two missense variants and one splice site variant, all variants were protein-truncating mutations. Most patients expressed a severe phenotype, typical of LCA. However, some LCA subjects had better vision and intact inner segment/outer segment (IS/OS) junctions on OCT imaging. In two families with LCA5 variants, the phenotype was more compatible with EORD with affected individuals displaying preserved islands of retinal pigment epithelium. One of the families with a milder phenotype harbored a homozygous splice site mutation; a second family was found to have a combination of a stop mutation and a missense mutation. This is the largest LCA5 study to date. We sequenced 1,008 patients (797 with LCA, 211 with arRP) and identified 18 probands with LCA5 mutations. Mutations in LCA5 are a rare cause of childhood retinal dystrophy accounting for ∼2% of disease in this cohort, and the majority of LCA5 mutations are likely null. The LCA5 protein truncating mutations are predominantly associated with LCA. However, in two families with the milder EORD, the LCA5 gene analysis revealed a homozygous splice site mutation in one and a stop mutation in combination with a missense mutation in a second family, suggesting that this milder phenotype is due to residual function of lebercilin and expanding the currently known phenotypic spectrum to include the milder early onset RP. Some patients have remaining foveal cone structures (intact IS/OS junctions on OCT imaging) and remaining visual acuities, which may bode well for upcoming treatment trials.
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| 29. |
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| 30. |
- Medrano-Gracia, Pau, et al.
(författare)
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A computational atlas of normal coronary artery anatomy
- 2016
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Ingår i: EuroIntervention. - : EUROPA EDITION. - 1774-024X .- 1969-6213. ; 12:7, s. 845-854
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: The aim of this study was to define the shape variations, including diameters and angles, of the major coronary artery bifurcations. Methods and results: Computed tomographic angiograms from 300 adults with a zero calcium score and no stenoses were segmented for centreline and luminal models. A computational atlas was constructed enabling automatic quantification of 3D angles, diameters and lengths of the coronary tree. The diameter (mean +/- SD) of the left main coronary was 3.5 +/- 0.8 mm and the length 10.5 +/- 5.3 mm. The left main bifurcation angle (distal angle or angle B) was 89 +/- 21 degrees for cases with, and 75 +/- 23 degrees for those without an intermediate artery (p<0.001). Analogous measurements of diameter and angle were tabulated for the other major bifurcations (left anterior descending/diagonal, circumflex/obtuse marginal and right coronary crux). Novel 3D angle definitions are proposed and analysed. Conclusions: A computational atlas of normal coronary artery anatomy provides distributions of diameter, lengths and bifurcation angles as well as more complex shape analysis. These data define normal anatomical variation, facilitating stent design, selection and optimal treatment strategy. These population models are necessary for accurate computational flow dynamics, can be 3D printed for bench testing bifurcation stents and deployment strategies, and can aid in the discussion of different approaches to the treatment of coronary bifurcations.
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| 31. |
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| 32. |
- Medrano-Gracia, Pau, et al.
(författare)
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A Study of Coronary Bifurcation Shape in a Normal Population
- 2017
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Ingår i: Journal of Cardiovascular Translational Research. - : SPRINGER. - 1937-5387 .- 1937-5395. ; 10:1, s. 82-90
-
Tidskriftsartikel (refereegranskat)abstract
- During percutaneous coronary intervention, stents are placed in narrowings of the arteries to restore normal blood flow. Despite improvements in stent design, deployment techniques and drug-eluting coatings, restenosis and stent thrombosis remain a significant problem. Population stent design based on statistical shape analysis may improve clinical outcomes. Computed tomographic (CT) coronary angiography scans from 211 patients with a zero calcium score, no stenoses and no intermediate artery, were used to create statistical shape models of 446 major coronary artery bifurcations (left main, first diagonal and obtuse marginal and right coronary crux). Coherent point drift was used for registration. Principal component analysis shape scores were tested against clinical risk factors, quantifying the importance of recognised shape features in intervention including size, angles and curvature. Significant differences were found in (1) vessel size and bifurcation angle between the left main and other bifurcations; (2) inlet and curvature angle between the right coronary crux and other bifurcations; and (3) size and bifurcation angle by sex. Hypertension, smoking history and diabetes did not appear to have an association with shape. Physiological diameter laws were compared, with the Huo-Kassab model having the best fit. Bifurcation coronary anatomy can be partitioned into clinically meaningful modes of variation showing significant shape differences. A computational atlas of normal coronary bifurcation shape, where disease is common, may aid in the design of new stents and deployment techniques, by providing data for bench-top testing and computational modelling of blood flow and vessel wall mechanics.
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| 33. |
- Medrano-Gracia, Pau, et al.
(författare)
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Construction of a coronary artery atlas from CT angiography
- 2014
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Ingår i: Medical Image Computing and Computer-Assisted Intervention – MICCAI 2014. - Cham : Springer. ; , s. 513-520
-
Konferensbidrag (refereegranskat)abstract
- Describing the detailed statistical anatomy of the coronary artery tree is important for determining the ætiology of heart disease. A number of studies have investigated geometrical features and have found that these correlate with clinical outcomes, e.g. bifurcation angle with major adverse cardiac events. These methodologies were mainly two-dimensional, manual and prone to inter-observer variability, and the data commonly relates to cases already with pathology. We propose a hybrid atlasing methodology to build a population of computational models of the coronary arteries to comprehensively and accurately assess anatomy including 3D size, geometry and shape descriptors. A random sample of 122 cardiac CT scans with a calcium score of zero was segmented and analysed using a standardised protocol. The resulting atlas includes, but is not limited to, the distributions of the coronary tree in terms of angles, diameters, centrelines, principal component shape analysis and cross-sectional contours. This novel resource will facilitate the improvement of stent design and provide a reference for hemodynamic simulations, and provides a basis for large normal and pathological databases.
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| 34. |
- Odom, Karan J., et al.
(författare)
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Sex role similarity and sexual selection predict male and female song elaboration and dimorphism in fairy-wrens
- 2021
-
Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 11:24, s. 17901-17919
-
Tidskriftsartikel (refereegranskat)abstract
- Historically, bird song complexity was thought to evolve primarily through sexual selection on males; yet, in many species, both sexes sing and selection pressure on both sexes may be broader. Previous research suggests competition for mates and resources during short, synchronous breeding seasons leads to more elaborate male songs at high, temperate latitudes. Furthermore, we expect male-female song structure and elaboration to be more similar at lower, tropical latitudes, where longer breeding seasons and year-round territoriality yield similar social selection pressures in both sexes. However, studies seldom take both types of selective pressures and sexes into account. We examined song in both sexes in 15 populations of nine-fairy-wren species (Maluridae), a Southern Hemisphere clade with female song. We compared song elaboration (in both sexes) and sexual song dimorphism to latitude and life-history variables tied to sexual and social selection pressures and sex roles. Our results suggest that song elaboration evolved in part due to sexual competition in males: male songs were longer than female songs in populations with low male survival and less male provisioning. Also, female songs evolved independently of male songs: female songs were slower paced than male songs, although only in less synchronously breeding populations. We also found male and female songs were more similar when parental care was more equal and when male survival was high, which provides strong evidence that sex role similarity correlates with male-female song similarity. Contrary to Northern Hemisphere latitudinal patterns, male and female songs were more similar at higher, temperate latitudes. These results suggest that selection on song can be sex specific, with male song elaboration favored in contexts with stronger sexual selection. At the same time, selection pressures associated with sex role similarity appear to favor sex role similarity in song structure.
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| 35. |
- Okely, Anthony D., et al.
(författare)
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Cross-sectional examination of 24-hour movement behaviours among 3-and 4-year-old children in urban and rural settings in low-income, middle-income and high-income countries : the SUNRISE study protocol
- 2021
-
Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 11:10
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction 24-hour movement behaviours (physical activity, sedentary behaviour and sleep) during the early years are associated with health and developmental outcomes, prompting the WHO to develop Global guidelines for physical activity, sedentary behaviour and sleep for children under 5 years of age. Prevalence data on 24-hour movement behaviours is lacking, particularly in low-income and middle-income countries (LMICs). This paper describes the development of the SUNRISE International Study of Movement Behaviours in the Early Years protocol, designed to address this gap. Methods and analysis SUNRISE is the first international cross-sectional study that aims to determine the proportion of 3- and 4-year-old children who meet the WHO Global guidelines. The study will assess if proportions differ by gender, urban/rural location and/or socioeconomic status. Executive function, motor skills and adiposity will be assessed and potential correlates of 24-hour movement behaviours examined. Pilot research from 24 countries (14 LMICs) informed the study design and protocol. Data are collected locally by research staff from partnering institutions who are trained throughout the research process. Piloting of all measures to determine protocol acceptability and feasibility was interrupted by COVID-19 but is nearing completion. At the time of publication 41 countries are participating in the SUNRISE study. Ethics and dissemination The SUNRISE protocol has received ethics approved from the University of Wollongong, Australia, and in each country by the applicable ethics committees. Approval is also sought from any relevant government departments or organisations. The results will inform global efforts to prevent childhood obesity and ensure young children reach their health and developmental potential. Findings on the correlates of movement behaviours can guide future interventions to improve the movement behaviours in culturally specific ways. Study findings will be disseminated via publications, conference presentations and may contribute to the development of local guidelines and public health interventions.
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| 36. |
- Qviller, Atle Jorstad, et al.
(författare)
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Hydrogen Concentration in Photovoltaic a-Si:H Annealed at Different Temperatures Measured by Neutron Reflectometry
- 2018
-
Ingår i: IEEE Journal of Photovoltaics. - : IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC. - 2156-3381 .- 2156-3403. ; 8:4, s. 1098-1101
-
Tidskriftsartikel (refereegranskat)abstract
- Amorphous hydrogenated silicon (a-Si:H) is an important material for surface defect passivation of photovoltaic silicon (Si) wafers in order to reduce their recombination losses. The material is, however, unstable with regard to hydrogen (H) desorption at elevated temperatures, which can be an issue during processing and device manufacturing. In this work, we determine the temperature stability of a-Si:H by structural characterization of a-Si:H/Si bilayers with neutron reflectometry and X-ray reflectometry combined with photoconductance measurements, yielding the minority carrier lifetime. The neutrons are sensitive to light elements such as H, while the X-rays, which are insensitive to the H concentration, provide an independent constraint on the layer structure. It is shown that H desorption takes place at a temperature of approximately T = 425 degrees C, and that the H content and minority carrier lifetimes have a strongly correlated linear relationship, which can be interpreted as one H atom passivating one defect.
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| 37. |
- Ryder, Edward, et al.
(författare)
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The DrosDel collection : a set of P-element insertions for generating custom chromosomal aberrations in Drosophila melanogaster.
- 2004
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Ingår i: Genetics. - 0016-6731. ; 167:2, s. 797-813
-
Tidskriftsartikel (refereegranskat)abstract
- We describe a collection of P-element insertions that have considerable utility for generating custom chromosomal aberrations in Drosophila melanogaster. We have mobilized a pair of engineered P elements, p[RS3] and p[RS5], to collect 3243 lines unambiguously mapped to the Drosophila genome sequence. The collection contains, on average, an element every 35 kb. We demonstrate the utility of the collection for generating custom chromosomal deletions that have their end points mapped, with base-pair resolution, to the genome sequence. The collection was generated in an isogenic strain, thus affording a uniform background for screens where sensitivity to genetic background is high. The entire collection, along with a computational and genetic toolbox for designing and generating custom deletions, is publicly available. Using the collection it is theoretically possible to generate >12,000 deletions between 1 bp and 1 Mb in size by simple eye color selection. In addition, a further 37,000 deletions, selectable by molecular screening, may be generated. We are now using the collection to generate a second-generation deficiency kit that is precisely mapped to the genome sequence.
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| 38. |
- Ryder, Edward, et al.
(författare)
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The DrosDel deletion collection : A Drosophila genomewide chromosomal deficiency resource
- 2007
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Ingår i: Genetics. - Austin, Tex. : Genetics Society of America. - 0016-6731 .- 1943-2631. ; 177:1, s. 615-629
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Tidskriftsartikel (refereegranskat)abstract
- We describe a second-generation deficiency kit for Drosophila melanogaster composed of molecularly mapped deletions on an isogenic background, covering 77% of the Release 5.1 genome. Using a previously reported collection of FRT-bearing P-element insertions, we have generated 655 new deletions and verified a set of 209 deletion-bearing fly stocks. In addition to deletions, we demonstrate how the P elements may also be used to generate a set of custom inversions and duplications, particularly useful for balancing difficult regions of the genome carrying haplo-insufficient loci. We describe a simple computational resource that facilitatesselection of appropriate elements for generating custom deletions. Finally, we provide a computational resource that facilitates selection of other mapped FRT-bearing elements that, when combined with the DrosDel collection, can theoretically generate over half a million precisely mapped deletions.
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| 39. |
- Sedlar, Joseph, et al.
(författare)
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Confronting Arctic Troposphere, Clouds, and Surface Energy Budget Representations in Regional Climate Models With Observations
- 2020
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Ingår i: Journal of Geophysical Research - Atmospheres. - 2169-897X .- 2169-8996. ; 125:6
-
Tidskriftsartikel (refereegranskat)abstract
- A coordinated regional climate model (RCM) evaluation and intercomparison project based on observations from a July-October 2014 trans-Arctic Ocean field experiment (ACSE-Arctic Clouds during Summer Experiment) is presented. Six state-of-the-art RCMs were constrained with common reanalysis lateral boundary forcing and upper troposphere nudging techniques to explore how the RCMs represented the evolution of the surface energy budget (SEB) components and their relation to cloud properties. We find that the main reasons for the modeled differences in the SEB components are a direct consequence of the RCM treatment of cloud and cloud-radiative interactions. The RCMs could be separated into groups by their overestimation or underestimation of cloud liquid. While radiative and turbulent heat flux errors were relatively large, they often invoke compensating errors. In addition, having the surface sea-ice concentrations constrained by the reanalysis or satellite observations limited how errors in the modeled radiative fluxes could affect the SEB and ultimately the surface evolution and its coupling with lower tropospheric mixing and cloud properties. Many of these results are consistent with RCM biases reported in studies over a decade ago. One of the six models was a fully coupled ocean-ice-atmosphere model. Despite the biases in overestimating cloud liquid, and associated SEB errors due to too optically thick clouds, its simulations were useful in understanding how the fully coupled system is forced by, and responds to, the SEB evolution. Moving forward, we suggest that development of RCM studies need to consider the fully coupled climate system.
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| 40. |
- Shimwell, T. W., et al.
(författare)
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The LOFAR Two-metre Sky Survey: II. First data release
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 622
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Forskningsöversikt (refereegranskat)abstract
- The LOFAR Two-metre Sky Survey (LoTSS) is an ongoing sensitive, high-resolution 120-168 MHz survey of the entire northern sky for which observations are now 20% complete. We present our first full-quality public data release. For this data release 424 square degrees, or 2% of the eventual coverage, in the region of the HETDEX Spring Field (right ascension 10h45m00s to 15h30m00s and declination 45°00′00″ to 57°00′00″) were mapped using a fully automated direction-dependent calibration and imaging pipeline that we developed. A total of 325 694 sources are detected with a signal of at least five times the noise, and the source density is a factor of ∼10 higher than the most sensitive existing very wide-area radio-continuum surveys. The median sensitivity is S144 MHz = 71 μJy beam -1 and the point-source completeness is 90% at an integrated flux density of 0.45 mJy. The resolution of the images is 6″ and the positional accuracy is within 0.2″. This data release consists of a catalogue containing location, flux, and shape estimates together with 58 mosaic images that cover the catalogued area. In this paper we provide an overview of the data release with a focus on the processing of the LOFAR data and the characteristics of the resulting images. In two accompanying papers we provide the radio source associations and deblending and, where possible, the optical identifications of the radio sources together with the photometric redshifts and properties of the host galaxies. These data release papers are published together with a further ∼20 articles that highlight the scientific potential of LoTSS.
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| 41. |
- Tait, Brian D, et al.
(författare)
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Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation.
- 2013
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Ingår i: Transplantation. - 1534-6080. ; 95:1, s. 19-47
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS: With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS: A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS: A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.
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| 42. |
- Turro, Ernest, et al.
(författare)
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Whole-genome sequencing of patients with rare diseases in a national health system.
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 583:7814, s. 96-102
-
Tidskriftsartikel (refereegranskat)abstract
- Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065extensively phenotypedparticipants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data ofUK Biobankparticipants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.
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| 43. |
- Webster, Mary, et al.
(författare)
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Effectiveness of intergenerational exchange programs between adolescents and older adults : a systematic review
- 2023
-
Ingår i: Journal of Intergenerational Relationships. - : Routledge. - 1535-0770 .- 1535-0932.
-
Tidskriftsartikel (refereegranskat)abstract
- Communities are aging and becoming more segregated, leading to fractured relationships between generations. Intergenerational exchange has improved cohesion, particularly when different generations engage as equal partners. This paper presents a systematic review of intergenerational studies between adolescents and older adults. Thirteen papers were reviewed using PRISMA guidelines, and outcomes, methodological quality, facilitators, and barriers identified, to better understand effectiveness and inform recommendations for future practice. The framework informed quality assessment, and the papers were rated moderate or high quality. Unfortunately, heterogeneity across studies rendered comparison challenging. Further attention is required to elucidate guidelines for implementing and reporting intergenerational studies.Contribution to the Field This review demonstrated how non-familial intergenerational programs involving adolescents and older adults provided benefits to both. Benefits for older adults included improved wellbeing, cognitive, and social engagement.Benefits for adolescents were identity formation and skill development. Shared outcomes for both generations were improved attitudes and stereotypes, reduced generational gap, and solidarity.High variability in program design, methodology, and sample size was evident across studies. However, it highlighted the suitability of IG engagement across differing contexts.Future recommendations included facilitator training, diverse samples, and longitudinal methodological designs.
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| 44. |
- Webster, Matthew T, et al.
(författare)
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Analysis of variation in the human beta-globin gene cluster using a novel DHPLC technique.
- 2002
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Ingår i: Mutation research. - 0027-5107 .- 1873-135X. ; 501:1-2, s. 99-103
-
Tidskriftsartikel (refereegranskat)abstract
- We have implemented a technique combining allele-specific PCR (AS-PCR) and denaturing high-performance liquid chromatography (DHPLC) to identify new polymorphic variants within an intergenic region in the beta-globin cluster. This technique is applicable to the detection of new variants in genomic regions where variation is apportioned into distinct classes of haplotype. Duplexes for DHPLC analysis were created by denaturation and re-annealing of a mixture of two AS-PCR products of known and unknown sequence from the same haplotypic class, permitting detection of new haplotypes in each class. A 454bp fragment 3.5kb 5' to the human delta-globin gene, which may have a gene regulatory function, was analysed in 840 chromosomes from a global sampling of human populations using this method. Two divergent haplotypes were found to predominate in all populations studied, possibly as a result of balancing selection.
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