| 1. |
- 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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| 2. |
- Sabouri, Nasim, et al.
(författare)
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The essential Schizosaccharomyces pombe Pfh1 DNA helicase promotes fork movement past G-quadruplex motifs to prevent DNA damage
- 2014
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: G-quadruplexes (G4s) are stable non-canonical DNA secondary structures consisting of stacked arrays of four guanines, each held together by Hoogsteen hydrogen bonds. Sequences with the ability to form these structures in vitro, G4 motifs, are found throughout bacterial and eukaryotic genomes. The budding yeast Pif1 DNA helicase, as well as several bacterial Pif1 family helicases, unwind G4 structures robustly in vitro and suppress G4-induced DNA damage in S. cerevisiae in vivo.Results: We determined the genomic distribution and evolutionary conservation of G4 motifs in four fission yeast species and investigated the relationship between G4 motifs and Pfh1, the sole S. pombe Pif1 family helicase. Using chromatin immunoprecipitation combined with deep sequencing, we found that many G4 motifs in the S. pombe genome were associated with Pfh1. Cells depleted of Pfh1 had increased fork pausing and DNA damage near G4 motifs, as indicated by high DNA polymerase occupancy and phosphorylated histone H2A, respectively. In general, G4 motifs were underrepresented in genes. However, Pfh1-associated G4 motifs were located on the transcribed strand of highly transcribed genes significantly more often than expected, suggesting that Pfh1 has a function in replication or transcription at these sites.Conclusions: In the absence of functional Pfh1, unresolved G4 structures cause fork pausing and DNA damage of the sort associated with human tumors.
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| 3. |
- Bochman, Matthew L, et al.
(författare)
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Unwinding the functions of the Pif1 family helicases
- 2010
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Ingår i: DNA Repair. - : Elsevier BV. - 1568-7864 .- 1568-7856. ; 9:3, s. 237-249
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Tidskriftsartikel (refereegranskat)abstract
- Helicases are ubiquitous enzymes found in all organisms that are necessary for all (or virtually all) aspects of nucleic acid metabolism. The Pif1 helicase family is a group of 5'-->3' directed, ATP-dependent, super family IB helicases found in nearly all eukaryotes. Here, we review the discovery, evolution, and what is currently known about these enzymes in Saccharomyces cerevisiae (ScPif1 and ScRrm3), Schizosaccharomyces pombe (SpPfh1), Trypanosoma brucei (TbPIF1, 2, 5, and 8), mice (mPif1), and humans (hPif1). Pif1 helicases variously affect telomeric, ribosomal, and mitochondrial DNA replication, as well as Okazaki fragment maturation, and in at least some cases affect these processes by using their helicase activity to disrupt stable nucleoprotein complexes. While the functions of these enzymes vary within and between organisms, it is evident that Pif1 family helicases are crucial for both nuclear and mitochondrial genome maintenance.
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| 4. |
- Farahini, Nasim, et al.
(författare)
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Parallel distributed scalable runtime address generation scheme for a coarse grain reconfigurable computation and storage fabric
- 2014
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Ingår i: Microprocessors and microsystems. - : Elsevier BV. - 0141-9331 .- 1872-9436. ; 38:8, s. 788-802
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a hardware based solution for a scalable runtime address generation scheme for DSP applications mapped to a parallel distributed coarse grain reconfigurable computation and storage fabric. The scheme can also deal with non-affine functions of multiple variables that typically correspond to multiple nested loops. The key innovation is the judicious use of two categories of address generation resources. The first category of resource is the low cost AGU that generates addresses for given address bounds for affine functions of up to two variables. Such low cost AGUs are distributed and associated with every read/write port in the distributed memory architecture. The second category of resource is relatively more complex but is also distributed but shared among a few storage units and is capable of handling more complex address generation requirements like dynamic computation of address bounds that are then used to configure the AGUs, transformation of non-affine functions to affine function by computing the affine factor outside the loop, etc. The runtime computation of the address constraints results in negligibly small overhead in latency, area and energy while it provides substantial reduction in program storage, reconfiguration agility and energy compared to the prevalent pre-computation of address constraints. The efficacy of the proposed method has been validated against the prevalent address generation schemes for a set of six realistic DSP functions. Compared to the pre-computation method, the proposed solution achieved 75% average code compaction and compared to the centralized runtime address generation scheme, the proposed solution achieved 32.7% average performance improvement.
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| 5. |
- Jafri, Syed. M. A. H., et al.
(författare)
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Energy-Aware Coarse-Grained Reconfigurable Architectures using Dynamically Reconfigurable Isolation Cells
- 2013
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Ingår i: Proceedings Of The Fourteenth International Symposium On Quality Electronic Design (ISQED 2013). - 9781467349529 ; , s. 104-111
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Konferensbidrag (refereegranskat)abstract
- This paper presents a self adaptive architecture to enhance the energy efficiency of coarse-grained reconfigurable architectures (CGRAs). Today, platforms host multiple applications, with arbitrary inter-application communication and concurrency patterns. Each application itself can have multiple versions (implementations with different degree of parallelism) and the optimal version can only be determined at runtime. For such scenarios, traditional worst case designs and compile time mapping decisions are neither optimal nor desirable. Existing solutions to this problem employ costly dedicated hardware to configure the operating point at runtime (using DVFS). As an alternative to dedicated hardware, we propose exploiting the reconfiguration features of modern CGRAs. Our solution relies on dynamically reconfigurable isolation cells (DRICs) and autonomous parallelism, voltage, and frequency selection algorithm (APVFS). The DRICs reduce the overheads of DVFS circuitry by configuring the existing resources as isolation cells. APVFS ensures high efficiency by dynamically selecting the parallelism, voltage and frequency trio, which consumes minimum power to meet the deadlines on available resources. Simulation results using representative applications (Matrix multiplication, FIR, and FFT) showed up to 23% and 51% reduction in power and energy, respectively, compared to traditional DVFS designs. Synthesis results have confirmed significant reduction in area overheads compared to state of the art DVFS methods.
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| 6. |
- McDonald, Karin R, et al.
(författare)
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The Pif1 family helicase Pfh1 facilitates telomere replication and has an RPA-dependent role during telomere lengthening
- 2014
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Ingår i: DNA Repair. - : Elsevier BV. - 1568-7864 .- 1568-7856. ; 24, s. 80-86
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Tidskriftsartikel (refereegranskat)abstract
- Pif1 family helicases are evolutionary conserved 5'-3' DNA helicases. Pfh1, the sole Schizosaccharomyces pombe Pif1 family DNA helicase, is essential for maintenance of both nuclear and mitochondrial DNAs. Here we show that its nuclear functions include roles in telomere replication and telomerase action. Pfh1 promoted semi-conservative replication through telomeric DNA, as replication forks moved more slowly through telomeres when Pfh1 levels were reduced. Unlike other organisms, S. pombe cells overexpressing Pfh1 displayed markedly longer telomeres. Because this lengthening occurred in the absence of homologous recombination but not in a replication protein A mutant (rad11-D223Y) that has defects in telomerase function, it is probably telomerase-mediated. The effects of Pfh1 on telomere replication and telomere length are likely direct as Pfh1 exhibited high telomere binding in cells expressing endogenous levels of Pfh1. These findings argue that Pfh1 is a positive regulator of telomere length and telomere replication.
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| 7. |
- Sabouri, Nasim, et al.
(författare)
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DNA replication through hard-to-replicate sites, including both highly transcribed RNA Pol II and Pol III genes, requires the S. pombe Pfh1 helicase
- 2012
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 26:6, s. 581-593
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Tidskriftsartikel (refereegranskat)abstract
- Replication forks encounter impediments as they move through the genome, including natural barriers due to stable protein complexes and highly transcribed genes. Unlike lesions generated by exogenous damage, natural barriers are encountered in every S phase. Like humans, Schizosaccharomyces pombe encodes a single Pif1 family DNA helicase, Pfh1. Here, we show that Pfh1 is required for efficient fork movement in the ribosomal DNA, the mating type locus, tRNA, 5S ribosomal RNA genes, and genes that are highly transcribed by RNA polymerase II. In addition, converged replication forks accumulated at all of these sites in the absence of Pfh1. The effects of Pfh1 on DNA replication are likely direct, as it had high binding to sites whose replication was impaired in its absence. Replication in the absence of Pfh1 resulted in DNA damage specifically at those sites that bound high levels of Pfh1 in wild-type cells and whose replication was slowed in its absence. Cells depleted of Pfh1 were inviable if they also lacked the human TIMELESS homolog Swi1, a replisome component that stabilizes stalled forks. Thus, Pfh1 promotes DNA replication and separation of converged replication forks and suppresses DNA damage at hard-to-replicate sites.
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