| 1. |
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| 2. |
- 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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| 3. |
- Santangelo, James S., et al.
(författare)
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Global urban environmental change drives adaptation in white clover
- 2022
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 375
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Tidskriftsartikel (refereegranskat)abstract
- Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural dines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.
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| 4. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Stanaway, Jeffrey D., et al.
(författare)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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| 6. |
- Feng, Shaohong, et al.
(författare)
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Dense sampling of bird diversity increases power of comparative genomics
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587:7833
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.
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| 7. |
- 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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| 8. |
- Karp, Melissa A., et al.
(författare)
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Increasing the uptake of multispecies models in fisheries management
- 2023
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Ingår i: ICES Journal of Marine Science. - : Oxford University Press (OUP). - 1054-3139 .- 1095-9289. ; 80:2, s. 243-257
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Tidskriftsartikel (refereegranskat)abstract
- Multispecies models have existed in a fisheries context since at least the 1970s, but despite much exploration, advancement, and consideration of multispecies models, there remain limited examples of their operational use in fishery management. Given that species and fleet interactions are inherently multispecies problems and the push towards ecosystem-based fisheries management, the lack of more regular operational use is both surprising and compelling. We identify impediments hampering the regular operational use of multispecies models and provide recommendations to address those impediments. These recommendations are: (1) engage stakeholders and managers early and often; (2) improve messaging and communication about the various uses of multispecies models; (3) move forward with multispecies management under current authorities while exploring more inclusive governance structures and flexible decision-making frameworks for handling tradeoffs; (4) evaluate when a multispecies modelling approach may be more appropriate; (5) tailor the multispecies model to a clearly defined purpose; (6) develop interdisciplinary solutions to promoting multispecies model applications; (7) make guidelines available for multispecies model review and application; and (8) ensure code and models are well documented and reproducible. These recommendations draw from a global assemblage of subject matter experts who participated in a workshop entitled “Multispecies Modeling Applications in Fisheries Management”.
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| 9. |
- Zhang, Mingfeng, et al.
(författare)
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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:41, s. 66328-66343
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10(-15)), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10(-9)) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10(-8)). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10(-8)). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10(-4)-2.0x10(-3)). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
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| 10. |
- Fischer, Debra A., et al.
(författare)
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M2K. II. A Triple-Planet System Orbiting Hip 57274
- 2012
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 745:1, s. 21-
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Tidskriftsartikel (refereegranskat)abstract
- Doppler observations from Keck Observatory have revealed a triple-planet system orbiting the nearby K4V star, HIP 57274. The inner planet, HIP 57274b, is a super-Earth with M sin i = 11.6 M-circle plus (0.036 M-Jup), an orbital period of 8.135 +/- 0.004 days, and slightly eccentric orbit e = 0.19 +/- 0.1. We calculate a transit probability of 6.5% for the inner planet. The second planet has M sin i = 0.4 M-Jup with an orbital period of 32.0 +/- 0.02 days in a nearly circular orbit (e = 0.05 +/- 0.03). The third planet has M sin i = 0.53 M-Jup with an orbital period of 432 +/- 8 days (1.18 years) and an eccentricity e = 0.23 +/- 0.03. This discovery adds to the number of super-Earth mass planets with M sin i < 12 M-circle plus that have been detected with Doppler surveys. We find that 56% +/- 18% of super-Earths are members of multi-planet systems. This is certainly a lower limit because of observational detectability limits, yet significantly higher than the fraction of Jupiter mass exoplanets, 20% +/- 8%, that are members of Doppler-detected, multi-planet systems.
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| 11. |
- Howard, Andrew W., et al.
(författare)
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The California planet survey. I. four new giant exoplanets
- 2010
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 721:2, s. 1467-1481
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Tidskriftsartikel (refereegranskat)abstract
- We present precise Doppler measurements of four stars obtained during the past decade at Keck Observatory by the California Planet Survey (CPS). These stars, namely, HD 34445, HD 126614, HD 13931, and Gl 179, all show evidence for a single planet in Keplerian motion. We also present Doppler measurements from the Hobby-Eberly Telescope (HET) for two of the stars, HD 34445 and Gl 179, that confirm the Keck detections and significantly refine the orbital parameters. These planets add to the statistical properties of giant planets orbiting near or beyond the ice line, and merit follow-up by astrometry, imaging, and space-borne spectroscopy. Their orbital parameters span wide ranges of planetary minimum mass (M sin i = 0.38-1.9 M-Jup), orbital period (P = 2.87-11.5 yr), semimajor axis (a = 2.1-5.2 AU), and eccentricity (e = 0.02-0.41). HD 34445 b (P = 2.87 yr, M sin i = 0.79 MJup, e = 0.27) is a massive planet orbiting an old, G-type star. We announce a planet, HD 126614 Ab, and an M dwarf, HD 126614 B, orbiting the metal-rich star HD 126614 (which we now refer to as HD 126614 A). The planet, HD 126614 Ab, has minimum mass M sin i = 0.38 MJup and orbits the stellar primary with period P = 3.41 yr and orbital separation a = 2.3 AU. The faint M dwarf companion, HD 126614 B, is separated from the stellar primary by 489 mas (33 AU) and was discovered with direct observations using adaptive optics and the PHARO camera at Palomar Observatory. The stellar primary in this new system, HD 126614 A, has the highest measured metallicity ([ Fe/ H] = + 0.56) of any known planet-bearing star. HD 13931 b (P = 11.5 yr, M sin i = 1.88 MJup, e = 0.02) is a Jupiter analog orbiting a near solar twin. Gl 179 b (P = 6.3 yr, M sin i = 0.82 M-Jup, e = 0.21) is a massive planet orbiting a faint M dwarf. The high metallicity of Gl 179 is consistent with the planet-metallicity correlation among M dwarfs, as documented recently by Johnson & Apps.
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| 12. |
- Howard, Andrew W., et al.
(författare)
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The NASA-UC Eia-earth program. II. a planet orbiting HD 156668 with a minimum mass of four earth masses
- 2011
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 726:2, s. 73-
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of HD 156668 b, an extrasolar planet with a minimum mass of M-P sin i = 4.15 M-circle plus. This planet was discovered through Keplerian modeling of precise radial velocities from Keck-HIRES and is the second super-Earth to emerge from the NASA-UC Eta-Earth Survey. The best-fit orbit is consistent with circular and has a period of P = 4.6455 days. The Doppler semi-amplitude of this planet, K = 1.89 m s(-1), is among the lowest ever detected, on par with the detection of GJ 581 e using HARPS. A longer period (P approximate to 2.3 years), low-amplitude signal of unknown origin was also detected in the radial velocities and was filtered out of the data while fitting the short-period planet. Additional data are required to determine if the long-period signal is due to a second planet, stellar activity, or another source. Photometric observations using the Automated Photometric Telescopes at Fairborn Observatory show that HD 156668 (an old, quiet K3 dwarf) is photometrically constant over the radial velocity period to 0.1 mmag, supporting the existence of the planet. No transits were detected down to a photometric limit of similar to 3 mmag, ruling out transiting planets dominated by extremely bloated atmospheres, but not precluding a transiting solid/liquid planet with a modest atmosphere.
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| 13. |
- Howard, Andrew W., et al.
(författare)
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THE NASA-UC ETA-EARTH PROGRAM : I. A SUPER-EARTH ORBITING HD 7924
- 2009
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 696:1, s. 75-83
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of the first low-mass planet to emerge from the NASA-UC Eta-Earth Program, a super-Earth orbiting the K0 dwarf HD 7924. Keplerian modeling of precise Doppler radial velocities reveals a planet with minimum mass M-P sin i = 9.26M(circle plus) in a P = 5.398 d orbit. Based on Keck-HIRES measurements from 2001 to 2008, the planet is robustly detected with an estimated false alarm probability of less than 0.001. Photometric observations using the Automated Photometric Telescopes at Fairborn Observatory show that HD 7924 is photometrically constant over the radial velocity period to 0.19 mmag, supporting the existence of the planetary companion. No transits were detected down to a photometric limit of similar to 0.5 mmag, eliminating transiting planets with a variety of compositions. HD 7924b is one of only eight planets detected by the radial velocity technique with M-P sini < 10 M-circle plus and as such is a member of an emerging family of low-mass planets that together constrain theories of planet formation.
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| 14. |
- Howard, Andrew W., et al.
(författare)
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THE NASA-UC ETA-EARTH PROGRAM. III. A SUPER-EARTH ORBITING HD 97658 AND A NEPTUNE-MASS PLANET ORBITING G1 785
- 2011
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 730:1, s. 10-
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of planets orbiting two bright, nearby early K dwarf stars, HD 97658 and G1 785. These planets were detected by Keplerian modeling of radial velocities measured with Keck-HIRES for the NASA-UC Eta-Earth Survey. HD 97658 b is a close-in super-Earth with minimum mass M sin i = 8.2 +/- 1.2 M-circle plus, orbital period P = 9.494 +/- 0.005 days, and an orbit that is consistent with circular. G1 785 b is a Neptune-mass planet with M sin i = 21.6 +/- 2.0 M-circle plus, P = 74.39 +/- 0.12 days, and orbital eccentricity e = 0.30 +/- 0.09. Photometric observations with the T12 0.8 m automatic photometric telescope at Fairborn Observatory show that HD 97658 is photometrically constant at the radial velocity period to 0.09 mmag, supporting the existence of the planet.
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| 15. |
- Jarvis, Erich D., et al.
(författare)
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Whole-genome analyses resolve early branches in the tree of life of modern birds
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1320-1331
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Tidskriftsartikel (refereegranskat)abstract
- To better determine the history of modern birds, we performed a genome-scale phylogenetic analysis of 48 species representing all orders of Neoaves using phylogenomic methods created to handle genome-scale data. We recovered a highly resolved tree that confirms previously controversial sister or close relationships. We identified the first divergence in Neoaves, two groups we named Passerea and Columbea, representing independent lineages of diverse and convergently evolved land and water bird species. Among Passerea, we infer the common ancestor of core landbirds to have been an apex predator and confirm independent gains of vocal learning. Among Columbea, we identify pigeons and flamingoes as belonging to sister clades. Even with whole genomes, some of the earliest branches in Neoaves proved challenging to resolve, which was best explained by massive protein-coding sequence convergence and high levels of incomplete lineage sorting that occurred during a rapid radiation after the Cretaceous-Paleogene mass extinction event about 66 million years ago.
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| 16. |
- Klein, Alison P., et al.
(författare)
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Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
- 2018
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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| 17. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 18. |
- Thorek, Daniel L J, et al.
(författare)
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Internalization of secreted antigen-targeted antibodies by the neonatal Fc receptor for precision imaging of the androgen receptor axis
- 2016
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 8:367
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Tidskriftsartikel (refereegranskat)abstract
- Targeting the androgen receptor (AR) pathway prolongs survival in patients with prostate cancer, but resistance rapidly develops. Understanding this resistance is confounded by a lack of noninvasive means to assess AR activity in vivo. We report intracellular accumulation of a secreted antigen-targeted antibody (SATA) that can be used to characterize disease, guide therapy, and monitor response. AR-regulated human kallikrein-related peptidase 2 (free hK2) is a prostate tissue-specific antigen produced in prostate cancer and androgen-stimulated breast cancer cells. Fluorescent and radio conjugates of 11B6, an antibody targeting free hK2, are internalized and noninvasively report AR pathway activity in metastatic and genetically engineered models of cancer development and treatment. Uptake is mediated by a mechanism involving the neonatal Fc receptor. Humanized 11B6, which has undergone toxicological tests in nonhuman primates, has the potential to improve patient management in these cancers. Furthermore, cellspecific SATA uptake may have a broader use for molecularly guided diagnosis and therapy in other cancers.
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| 19. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 20. |
- Buchhave, Lars A., et al.
(författare)
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An abundance of small exoplanets around stars with a wide range of metallicities
- 2012
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 486:7403, s. 375-377
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Tidskriftsartikel (refereegranskat)abstract
- The abundance of heavy elements (metallicity) in the photospheres of stars similar to the Sun provides a 'fossil' record of the chemical composition of the initial protoplanetary disk. Metal-rich stars are much more likely to harbour gas giant planets(1-4), supporting the model that planets form by accumulation of dust and ice particles(5). Recent ground-based surveys suggest that this correlation is weakened for Neptunian-sized planets(4,6-9). However, how the relationship between size and metallicity extends into the regime of terrestrial-sized exoplanets is unknown. Here we report spectroscopic metallicities of the host stars of 226 small exoplanet candidates discovered by NASA's Kepler mission(10), including objects that are comparable in size to the terrestrial planets in the Solar System. We find that planets with radii less than four Earth radii form around host stars with a wide range of metallicities (but on average a metallicity close to that of the Sun), whereas large planets preferentially form around stars with higher metallicities. This observation suggests that terrestrial planets may be widespread in the disk of the Galaxy, with no special requirement of enhanced metallicity for their formation.
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| 21. |
- Green, Richard E., et al.
(författare)
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Three crocodilian genomes reveal ancestral patterns of evolution among archosaurs
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6215, s. 1335-
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Tidskriftsartikel (refereegranskat)abstract
- To provide context for the diversification of archosaurs-the group that includes crocodilians, dinosaurs, and birds-we generated draft genomes of three crocodilians: Alligator mississippiensis (the American alligator), Crocodylus porosus (the saltwater crocodile), and Gavialis gangeticus (the Indian gharial). We observed an exceptionally slow rate of genome evolution within crocodilians at all levels, including nucleotide substitutions, indels, transposable element content and movement, gene family evolution, and chromosomal synteny. When placed within the context of related taxa including birds and turtles, this suggests that the common ancestor of all of these taxa also exhibited slow genome evolution and that the comparatively rapid evolution is derived in birds. The data also provided the opportunity to analyze heterozygosity in crocodilians, which indicates a likely reduction in population size for all three taxa through the Pleistocene. Finally, these data combined with newly published bird genomes allowed us to reconstruct the partial genome of the common ancestor of archosaurs, thereby providing a tool to investigate the genetic starting material of crocodilians, birds, and dinosaurs.
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| 22. |
- Jarvis, Erich D., et al.
(författare)
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Phylogenomic analyses data of the avian phylogenomics project
- 2015
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Ingår i: GigaScience. - : Oxford University Press (OUP). - 2047-217X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Determining the evolutionary relationships among the major lineages of extant birds has been one of the biggest challenges in systematic biology. To address this challenge, we assembled or collected the genomes of 48 avian species spanning most orders of birds, including all Neognathae and two of the five Palaeognathae orders. We used these genomes to construct a genome-scale avian phylogenetic tree and perform comparative genomic analyses. Findings: Here we present the datasets associated with the phylogenomic analyses, which include sequence alignment files consisting of nucleotides, amino acids, indels, and transposable elements, as well as tree files containing gene trees and species trees. Inferring an accurate phylogeny required generating: 1) A well annotated data set across species based on genome synteny; 2) Alignments with unaligned or incorrectly overaligned sequences filtered out; and 3) Diverse data sets, including genes and their inferred trees, indels, and transposable elements. Our total evidence nucleotide tree (TENT) data set (consisting of exons, introns, and UCEs) gave what we consider our most reliable species tree when using the concatenation-based ExaML algorithm or when using statistical binning with the coalescence-based MP-EST algorithm (which we refer to as MP-EST*). Other data sets, such as the coding sequence of some exons, revealed other properties of genome evolution, namely convergence. Conclusions: The Avian Phylogenomics Project is the largest vertebrate phylogenomics project to date that we are aware of. The sequence, alignment, and tree data are expected to accelerate analyses in phylogenomics and other related areas.
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| 23. |
- L. B. Almeida, Bilena, et al.
(författare)
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The transcription factor network of E. coli steers global responses to shifts in RNAP concentration
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press. - 0305-1048 .- 1362-4962. ; 50:12, s. 6801-6819
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Tidskriftsartikel (refereegranskat)abstract
- The robustness and sensitivity of gene networks to environmental changes is critical for cell survival. How gene networks produce specific, chronologically ordered responses to genome-wide perturbations, while robustly maintaining homeostasis, remains an open question. We analysed if short- and mid-term genome-wide responses to shifts in RNA polymerase (RNAP) concentration are influenced by the known topology and logic of the transcription factor network (TFN) of Escherichia coli. We found that, at the gene cohort level, the magnitude of the single-gene, mid-term transcriptional responses to changes in RNAP concentration can be explained by the absolute difference between the gene's numbers of activating and repressing input transcription factors (TFs). Interestingly, this difference is strongly positively correlated with the number of input TFs of the gene. Meanwhile, short-term responses showed only weak influence from the TFN. Our results suggest that the global topological traits of the TFN of E. coli shape which gene cohorts respond to genome-wide stresses.
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| 24. |
- Lai, Heidi T. M., et al.
(författare)
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Trans Fatty Acid Biomarkers and Incident Type 2 Diabetes : Pooled Analysis of 12 Prospective Cohort Studies in the Fatty Acids and Outcomes Research Consortium (FORCE)
- 2022
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 45:4, s. 854-863
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Trans fatty acids (TFAs) have harmful biologic effects that could increase the risk of type 2 diabetes (T2D), but evidence remains uncertain. We aimed to investigate the prospective associations of TFA biomarkers and T2D by conducting an individual participant-level pooled analysis.RESEARCH DESIGN AND METHODS: We included data from an international consortium of 12 prospective cohorts and nested case-control studies from six nations. TFA biomarkers were measured in blood collected between 1990 and 2008 from 25,126 participants aged >= 18 years without prevalent diabetes. Each cohort conducted de novo harmonized analyses using a prespecified protocol, and findings were pooled using inverse-variance weighted meta-analysis. Heterogeneity was explored by prespecified between-study and within-study characteristics.RESULTS: During a mean follow-up of 13.5 years, 2,843 cases of incident T2D were identified. In multivariable-adjusted pooled analyses, no significant associations with T2D were identified for trans/trans-18:2, relative risk (RR) 1.09 (95% CI 0.94-1.25); cis/trans-18:2, 0.89 (0.73-1.07); and trans/cis-18:2, 0.87 (0.73-1.03). Trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated with T2D (RR 0.81 [95% CI 0.67-0.99], 0.86 [0.75-0.99], and 0.84 [0.74-0.96], respectively). Findings were not significantly different according to prespecified sources of potential heterogeneity (each P >= 0.1).CONCLUSIONS: Circulating individual trans-18:2 TFA biomarkers were not associated with risk of T2D, while trans-16:1n-9, total trans-18:1, and total trans-18:2 were inversely associated. Findings may reflect the influence of mixed TFA sources (industrial vs. natural ruminant), a general decline in TFA exposure due to policy changes during this period, or the relatively limited range of TFA levels.
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| 25. |
- McDevitt, Michael R., et al.
(författare)
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Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.
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