| 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. |
- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 3. |
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| 4. |
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| 5. |
- Paul, Jan, et al.
(författare)
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Ab initio calculations of electron distributions in heme-CO models
- 1983
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier BV. - 0005-2728 .- 1879-2650. ; 722:1, s. 209-213
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Tidskriftsartikel (refereegranskat)abstract
- We have, by the use of ab initio calculations, found a back-bonding state of π symmetry close to the Fermi level for CO bound to FeN5C14. We thus find it likely that small shifts of the redox potential ¦EF - Ev¦ will cause relatively large changes of the CO vibrational frequency. The separation of Fe 3d orbitals in our heme model is found to agree with what is predicted by ligand field theory for Oh symmetry. This paper presents nonrelativistic Hartree-Fock-Slater calculations of the 5σ bonding and 2π back-bonding between CO and Fe. The effects of up to 19 additional atoms are discussed for models of heme (COFe to COFeN5C14). The filled back-bonding state is found to be strongly influenced by second nearest neighbor atoms. By use of symmetry orbitals we have resolved the Fe 3d orbitals into the T2g and Eg representations of the Oh point group and find the former states to be occupied whereas the latter are unoccupied. The difference in occupancy is reduced when the CO ligand is removed which also causes an increased density of states at the Fermi level, i.e., the highest occupied and lowest unoccupied orbitals. Possible correlations between our data and experimental results are discussed for heme proteins as well as for metal surfaces.
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| 6. |
- Paul, Jan, et al.
(författare)
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Fast heme release from inactive proteins
- 1991
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Ingår i: Biochimica et Biophysica Acta - Protein Structure and Molecular Enzymology. - 0167-4838 .- 1879-2588. ; 1079:3, s. 330-334
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Tidskriftsartikel (refereegranskat)abstract
- Kinetics for the release of the prosthetic group from hemoproteins is presented. Heme-protein separation is a biphasic reaction, where an initial phase is significantly faster than the dominant, slow phase. A previous communication concluded that the slow phase represents the active protein. This communication presents data for porphyrin release which shows that the initial fast phase represents an inactive form of the protein. Moreover, we suggest that the fast to slow phase ratio is a sensitive monitor of sample quality for many hemoproteins and that an extrapolation of the slow phase absorbance leads to new estimates for the true physical parameters of unperturbed proteins.
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| 7. |
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| 8. |
- Paul, Jan, et al.
(författare)
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The vibrational bands of carbon monoxide bound to hemes or metal surfaces
- 1985
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Ingår i: Biochimica et Biophysica Acta - Protein Structure and Molecular Enzymology. - : Elsevier BV. - 0167-4838 .- 1879-2588. ; 832:3, s. 257-264
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Tidskriftsartikel (refereegranskat)abstract
- Infrared spectra of imidazole carbonyl complexes of 2,4-substituted hemes are presented. An increased CO stretch frequency is accompanied by a lowered FeC vibrational energy. Hartree-Fock-Slater electron structure calculations discern π and σ contributions to the observed shifts of vibrational energies. We conclude that an enhanced electron availability manifests itself as (i) a lowered ferric/ferrous reduction potential, (ii) increased filling of the 2π orbital of liganded CO which in turn reduces νCO and increases νFec, and (iii) increased basicity of the liganded CO. Analogies between CO liganded to heme and CO adsorbed onto metal surfaces are discussed.
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| 9. |
- Singh, Amit K, et al.
(författare)
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Bovine Carbonyl Lactoperoxidase Structure at 2.0Å Resolution and Infrared Spectra as a Function of pH.
- 2012
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Ingår i: The protein journal. - : Springer Science and Business Media LLC. - 1875-8355 .- 1572-3887. ; 31:7, s. 598-608
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Tidskriftsartikel (refereegranskat)abstract
- Lactoperoxidase (LPO) is a hemeprotein catalyzing the oxidation of thiocyanate and I(-) into antimicrobials and small aromatic organics after being itself oxidized by H(2)O(2). LPO is excreted by the lungs, mammary glands, found in saliva and tears and protects mammals against bacterial, fungal and viral invasion. The Fe(II) form binds CO which inactivates LPO like many other hemeproteins. We present the 3-dimensional structure of CO-LPO at 2.0Å resolution and infrared (IR) spectra of the iron-bound CO stretch from pH 3 to 8.8 at 1 cm(-1) resolution. The observed Fe-C-O bond angle of 132° is more acute than the electronically related Fe(III), CN-LPO with a Fe-C-N angle of 161°. The orientations of the two ligands are different with the oxygen of CO pointing towards the imidazole of distal His109 while the nitrogen of CN points away, the Fe(II) moves towards His109 while the Fe(III) moves away; both movements are consistent with a hydrogen bond between the distal His109 and CO, but not to the nitrogen of CN-LPO. The IR spectra of CO-LPO exhibit two major CO absorbances with pH dependent relative intensities. Both crystallographic and IR data suggest proton donation to the CO oxygen by His109 with a pK ≈ 4; close to the pH of greatest enzyme turnover. The IR absorbance maxima are consistent with a first order correlation between frequency and Fe(III)/Fe(II) reduction potential at pH 7; both band widths at half-height correlate with electron density donation from Fe(II) to CO as gauged by the reduction potential.
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