| 1. |
- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Livingstone, Katherine M., et al.
(författare)
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FTO genotype and weight loss : systematic review and meta-analysis of 9563 individual participant data from eight randomised controlled trials
- 2016
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Ingår i: BMJ: British Medical Journal. - : BMJ. - 1756-1833. ; 354
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess the effect of the FTO genotype on weight loss after dietary, physical activity, or drug based interventions in randomised controlled trials.DESIGN: Systematic review and random effects meta-analysis of individual participant data from randomised controlled trials.DATA SOURCES: Ovid Medline, Scopus, Embase, and Cochrane from inception to November 2015.ELIGIBILITY CRITERIA FOR STUDY SELECTION: Randomised controlled trials in overweight or obese adults reporting reduction in body mass index, body weight, or waist circumference by FTO genotype (rs9939609 or a proxy) after dietary, physical activity, or drug based interventions. Gene by treatment interaction models were fitted to individual participant data from all studies included in this review, using allele dose coding for genetic effects and a common set of covariates. Study level interactions were combined using random effect models. Metaregression and subgroup analysis were used to assess sources of study heterogeneity.RESULTS: We identified eight eligible randomised controlled trials for the systematic review and meta-analysis (n=9563). Overall, differential changes in body mass index, body weight, and waist circumference in response to weight loss intervention were not significantly different between FTO genotypes. Sensitivity analyses indicated that differential changes in body mass index, body weight, and waist circumference by FTO genotype did not differ by intervention type, intervention length, ethnicity, sample size, sex, and baseline body mass index and age category.CONCLUSIONS: We have observed that carriage of the FTO minor allele was not associated with differential change in adiposity after weight loss interventions. These findings show that individuals carrying the minor allele respond equally well to dietary, physical activity, or drug based weight loss interventions and thus genetic predisposition to obesity associated with the FTO minor allele can be at least partly counteracted through such interventions.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015015969.
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| 3. |
- Wang, Harris H., et al.
(författare)
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Multiplexed in Vivo His-Tagging of Enzyme Pathways for in Vitro Single-Pot Multienzyme Catalysis
- 2012
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Ingår i: ACS Synthetic Biology. - : American Chemical Society (ACS). - 2161-5063. ; 1:2, s. 43-52
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Tidskriftsartikel (refereegranskat)abstract
- Protein pathways are dynamic and highly coordinated spatially and temporally, capable of performing a diverse range of complex chemistries and enzymatic reactions with precision and at high efficiency. Biotechnology aims to harvest these natural systems to construct more advanced in vitro reactions, capable of new chemistries and operating at high yield. Here, we present an efficient Multiplex Automated Genome Engineering (MAGE) strategy to simultaneously modify and co-purify large protein complexes and pathways from the model organism Escherichia coli to reconstitute functional synthetic proteomes in vitro. By application of over 110 MAGE cycles, we successfully inserted hexa-histidine sequences into 38 essential genes in vivo that encode for the entire translation machinery. Streamlined co-purification and reconstitution of the translation, protein complex enabled protein synthesis in vitro. Our approach can be applied to a growing area of applications in in vitro one-pot multienzyme catalysis (MEC) to manipulate or enhance in vitro pathways such as natural product or carbohydrate biosynthesis.
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| 4. |
- Angelou, George C., et al.
(författare)
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Diagnostics of stellar modelling from spectroscopy and photometry of globular clusters
- 2015
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 1365-2966 .- 0035-8711. ; 450:3, s. 2423-2440
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Tidskriftsartikel (refereegranskat)abstract
- We conduct a series of comparisons between spectroscopic and photometric observations of globular clusters and stellar models to examine their predictive power. Data from medium-to-high resolution spectroscopic surveys of lithium allow us to investigate first dredge-up and extra mixing in two clusters well separated in metallicity. Abundances at first dredge-up are satisfactorily reproduced but there is preliminary evidence to suggest that the models overestimate the luminosity at which the surface composition first changes in the lowest metallicity system. Our models also begin extra mixing at luminosities that are too high, demonstrating a significant discrepancy with observations at low metallicity. We model the abundance changes during extra mixing as a thermohaline process and determine that the usual diffusive form of this mechanism cannot simultaneously reproduce both the carbon and lithium observations. Hubble Space Telescope photometry provides turn-off and bump magnitudes in a large number of globular clusters and offers the opportunity to better test stellar modelling as function of metallicity. We directly compare the predicted main-sequence turn-off and bump magnitudes as well as the distance-independent parameter $\Delta M_V \,<^>{\rm {MSTO}}_{\rm {bump}}$. We require 15 Gyr isochrones to match the main-sequence turn-off magnitude in some clusters and cannot match the bump in low-metallicity systems. Changes to the distance modulus, metallicity scale and bolometric corrections may impact on the direct comparisons but $\Delta M_V \,<^>{\rm {MSTO}}_{\rm {bump}}$, which is also underestimated from the models, can only be improved through changes to the input physics. Overshooting at the base of the convective envelope with an efficiency that is metallicity dependent is required to reproduce the empirically determined value of $\Delta M_V \,<^>{\rm {MSTO}}_{\rm {bump}}$.
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| 5. |
- Angelou, George C., et al.
(författare)
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The Role of Thermohaline Mixing in Intermediate- and Low-Metallicity Globular Clusters
- 2012
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Ingår i: Astrophysical Journal. - 0004-637X. ; 749:2
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Tidskriftsartikel (refereegranskat)abstract
- It is now widely accepted that globular cluster red giant branch (RGB) stars owe their strange abundance patterns to a combination of pollution from progenitor stars and in situ extra mixing. In this hybrid theory a first generation of stars imprints abundance patterns into the gas from which a second generation forms. The hybrid theory suggests that extra mixing is operating in both populations and we use the variation of [C/Fe] with luminosity to examine how efficient this mixing is. We investigate the observed RGBs ofM3, M13, M92, M15, and NGC 5466 as a means to test a theory of thermohaline mixing. The second parameter pair M3 and M13 are of intermediate metallicity and our models are able to account for the evolution of carbon along the RGB in both clusters, although in order to fit the most carbon-depleted main-sequence stars in M13 we require a model whose initial [C/Fe] abundance leads to a carbon abundance lower than is observed. Furthermore, our results suggest that stars in M13 formed with some primary nitrogen (higher C+N+O than stars in M3). In the metal-poor regime only NGC 5466 can be tentatively explained by thermohaline mixing operating in multiple populations. We find thermohaline mixing unable to model the depletion of [C/Fe] with magnitude in M92 and M15. It appears as if extra mixing is occurring before the luminosity function bump in these clusters. To reconcile the data with the models would require first dredge-up to be deeper than found in extant models.
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| 6. |
- Angelou, George C., et al.
(författare)
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Thermohaline Mixing And Its Role In The Evolution Of Carbon And Nitrogen Abundances In Globular Cluster Red Giants: The Test Case Of Messier 3
- 2011
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Ingår i: Astrophysical Journal. - 0004-637X. ; 728:2
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Tidskriftsartikel (refereegranskat)abstract
- We review the observational evidence for extra mixing in stars on the red giant branch (RGB) and discuss why thermohaline mixing is a strong candidate mechanism. We recall the simple phenomenological description of thermohaline mixing and aspects of mixing in stars in general. We use observations of M3 to constrain the form of the thermohaline diffusion coefficient and any associated free parameters. This is done by matching [C/Fe] and [N/Fe] along the RGB of M3. After taking into account a presumed initial primordial bimodality of [C/Fe] in the CN-weak and CN-strong stars, our thermohaline mixing models can explain the full spread of [C/Fe]. Thermohaline mixing can produce a significant change in [N/Fe] as a function of absolute magnitude on the RGB for initially CN-weak stars, but not for initially CN-strong stars, which have so much nitrogen to begin with that any extra mixing does not significantly affect the surface nitrogen composition.
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| 7. |
- Angelou, George C., et al.
(författare)
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Thermohaline mixing and the variation of [C/Fe] with magnitude in M3
- 2010
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Ingår i: 11th Symposium on Nuclei in the Cosmos, NIC 2010; Heidelberg; Germany; 19 July 2010 through 23 July 2010.
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Konferensbidrag (refereegranskat)abstract
- We use observations of M3 to constrain thermohaline mixing. This is done by matching [C/Fe] and [N/Fe] along the RGB of M3. We find our models can explain observations if it is assumed there is a spread of ∼ 0.3 - 0.4 dex in [C/Fe] in the stars in M3 from their birth. We reproduce the full spread in [C/Fe] at the tip of the RGB. Thermohaline mixing can produce a significant change in [N/Fe] as a function of absolute magnitude on the RGB for initially CN-weak stars, but not for initially CN-strong stars, which have so much nitrogen to begin with that any deep mixing does not significantly affect the surface nitrogen composition.
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| 8. |
- Brewington, Seth, et al.
(författare)
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Islands of change vs. islands of disaster : Managing pigs and birds in the Anthropocene of the North Atlantic
- 2015
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Ingår i: The Holocene. - : Sage Publications. - 0959-6836 .- 1477-0911. ; 25:10, s. 1676-1684
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Tidskriftsartikel (refereegranskat)abstract
- The offshore islands of the North Atlantic were among some of the last settled places on earth, with humans reaching the Faroes and Iceland in the late Iron Age and Viking period. While older accounts emphasizing deforestation and soil erosion have presented this story of island colonization as yet another social–ecological disaster, recent archaeological and paleoenvironmental research combined with environmental history, environmental humanities, and bioscience is providing a more complex understanding of long-term human ecodynamics in these northern islands. An ongoing interdisciplinary investigation of the management of domestic pigs and wild bird populations in Faroes and Iceland is presented as an example of sustained resource management using local and traditional knowledge to create structures for successful wild fowl management on the millennial scale.
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| 9. |
- Church, Ross, et al.
(författare)
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Which physics determines the location of the mean molecular weight minimum in red giants?
- 2014
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 1365-2966 .- 0035-8711. ; 443:2, s. 977-984
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Tidskriftsartikel (refereegranskat)abstract
- Stars ascending the red giant branch develop an inversion in mean molecular weight (mu) owing to the burning of He-3 in the region immediately above their hydrogen-burning shells. This inversion may drive thermohaline mixing and thereby be responsible for the extra mixing which is observationally indicated on the red giant branch. In this paper, we investigate the physical influences that determine the mass and temperature at which the inversion in mu develops. We find that it depends most strongly on the thermal structure of the envelope - the profiles of density and temperature in the region of the star immediately above the shell - and is otherwise relatively insensitive to abundances and nuclear reaction rates. The changes in the effects of thermohaline mixing as stars proceed up the giant branch can mostly be understood in terms of their changing thermal structure, driven by their increasing core mass.
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| 10. |
- Conrad, Chris, et al.
(författare)
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Single molecule profiling of tau gene expression in Alzheimer's disease
- 2007
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Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 103:3, s. 1228-1236
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Tidskriftsartikel (refereegranskat)abstract
- Tau is a microtubule-associated protein that is important for establishing and maintaining neuronal morphology. In addition to its role in normal cells, tau protein is involved in many neurodegenerative diseases, e.g. Alzheimer's disease (AD) and frontotemporal dementia, as the main component of intraneuronal aggregates. Alternative splicing of tau gene in the brain can give rise to at least six protein variants. A causative role of skewed tau exon 10 inclusion has been defined in frontotemporal dementia; however, no link was established between the aberrant splicing of tau and AD. Here, we applied a single-molecule-based technology, polymerase colony or polony, to simultaneously monitor tau splicing variant and haplotype profile in sporadic AD and normal brains. We found that the coordinated expression of tau exons 2 and 10 is altered in AD. Additional investigations of cis and trans mechanisms of this observation revealed a decreased protein expression of a known tau splicing factor, htra2-beta-1 in AD, thereby implicating a trans mechanism. Our results demonstrate that dysregulation of combinatorial splicing might serve as a signature for aging-related diseases, and the polony assay could be widely adapted for the study of other tauopathies. Furthermore, splicing-based therapeutics is an emerging area of drug development, and a well-defined and quantitative assay for monitoring single-gene transcriptome will be relevant for such development.
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