| 1. |
- Lissek, T, et al.
(författare)
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Building Bridges through Science
- 2017
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Ingår i: Neuron. - : Elsevier BV. - 1097-4199 .- 0896-6273. ; 96:4, s. 730-735
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Mavaddat, Nasim, et al.
(författare)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 3. |
- McDonald, Karin R., et al.
(författare)
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Pfh1 Is an Accessory Replicative Helicase that Interacts with the Replisome to Facilitate Fork Progression and Preserve Genome Integrity
- 2016
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Ingår i: PLOS Genetics. - : Copernicus GmbH. - 1553-7390 .- 1553-7404. ; 12:9
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Tidskriftsartikel (refereegranskat)abstract
- Replicative DNA helicases expose the two strands of the double helix to the replication apparatus, but accessory helicases are often needed to help forks move past naturally occurring hard-to-replicate sites, such as tightly bound proteins, RNA/DNA hybrids, and DNA secondary structures. Although the Schizosaccharomyces pombe 5'-to-3' DNA helicase Pfh1 is known to promote fork progression, its genomic targets, dynamics, and mechanisms of action are largely unknown. Here we address these questions by integrating genome-wide identification of Pfh1 binding sites, comprehensive analysis of the effects of Pfh1 depletion on replication and DNA damage, and proteomic analysis of Pfh1 interaction partners by immunoaffinity purification mass spectrometry. Of the 621 high confidence Pfh1-binding sites in wild type cells, about 40% were sites of fork slowing (as marked by high DNA polymerase occupancy) and/or DNA damage (as marked by high levels of phosphorylated H2A). The replication and integrity of tRNA and 5S rRNA genes, highly transcribed RNA polymerase II genes, and nucleosome depleted regions were particularly Pfh1-dependent. The association of Pfh1 with genomic integrity at highly transcribed genes was S phase dependent, and thus unlikely to be an artifact of high transcription rates. Although Pfh1 affected replication and suppressed DNA damage at discrete sites throughout the genome, Pfh1 and the replicative DNA polymerase bound to similar extents to both Pfh1-dependent and independent sites, suggesting that Pfh1 is proximal to the replication machinery during S phase. Consistent with this interpretation, Pfh1 co-purified with many key replisome components, including the hexameric MCM helicase, replicative DNA polymerases, RPA, and the processivity clamp PCNA in an S phase dependent manner. Thus, we conclude that Pfh1 is an accessory DNA helicase that interacts with the replisome and promotes replication and suppresses DNA damage at hard-to-replicate sites. These data provide insight into mechanisms by which this evolutionarily conserved helicase helps preserve genome integrity.
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| 4. |
- Perez-Soriano, Alexandra, et al.
(författare)
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PBB3 Imaging in Parkinsonian disorders: Evidence for binding to abnormally aggregated proteins in addition to tau proteins
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 1531-8257 .- 0885-3185. ; 32:Suppl 2, s. 585-587
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Konferensbidrag (refereegranskat)abstract
- Objective: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 ([11C]methylamino pyridin-3-yl buta-1,3-dienyl benzo[d]thiazol-6-ol) in tauopathies, and in conditions not typically associated with tauopathy. Background: Tau imaging is a promising tool to study the link between tau and neurodegeneration. The specificity of tracers in vivo however remains uncertain, and off target binding is frequently present, limiting its use in parkinsonian disorders. Methods: Dynamic PET scans were obtained for 70 min after the bolus injection of [11C]PBB3 (mean dose 518.97MBq) in five PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype,3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 7 healthy controls of similar age. The occipital cortex was used as reference region for the PSP , the DCTN1 mutation and the MSA subjects. The cerebellar white matter was used as a reference region for the SNCA duplication carriers. Tissue reference Logan analysis was applied to each region of interest (ROI) using the appropriate reference region. Results: In PSP subjects, the highest retention of [11C]PBB3 was observed in putamen, midbrain, globus pallidus and substantia nigra. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. The DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and globus pallidus. In SNCA duplication carriers there was a significant increase of [11C] PBB3 binding compared to controls in globus pallidus, putamen, thalamus, ventral striatum, substantia nigra, and pedunculopontine nucleus. The MSA case showed increased binding in comparison to the control group in frontal lobe, globus pallidus, midbrain, parietal lobe, putamen, temporal lobe, substantia nigra, thalamus and ventral striatum. Conclusions: All PSP patients showed increased retention of the tracer in the basal ganglia, as clinically expected. However, binding was also present in asymptomatic SNCA duplication carriers as well as the subject with MSA, which are not typically associated with pathological tau deposition. This suggests the possibility that [11C]PBB3 binds to alpha-synuclein or other proteins involved in neurodegeneration.
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| 5. |
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| 6. |
- Jafri, Syed M. A. H., et al.
(författare)
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Architecture and Implementation of Dynamic Parallelism, Voltage and Frequency Scaling (PVFS) on CGRAs
- 2015
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Ingår i: ACM Journal on Emerging Technologies in Computing Systems. - : Association for Computing Machinery (ACM). - 1550-4832 .- 1550-4840. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- In the era of platforms hosting multiple applications with arbitrary performance requirements, providing a worst-case platform-wide voltage/frequency operating point is neither optimal nor desirable. As a solution to this problem, designs commonly employ dynamic voltage and frequency scaling (DVFS). DVFS promises significant energy and power reductions by providing each application with the operating point (and hence the performance) tailored to its needs. To further enhance the optimization potential, recent works interleave dynamic parallelism with conventional DVFS. The induced parallelism results in performance gains that allow an application to lower its operating point even further (thereby saving energy and power consumption). However, the existing works employ costly dedicated hardware (for synchronization) and rely solely on greedy algorithms to make parallelism decisions. To efficiently integrate parallelism with DVFS, compared to state-of-the-art, we exploit the reconfiguration (to reduce DVFS synchronization overheads) and enhance the intelligence of the greedy algorithm (to make optimal parallelism decisions). Specifically, our solution relies on dynamically reconfigurable isolation cells and an autonomous parallelism, voltage, and frequency selection algorithm. The dynamically reconfigurable isolation cells reduce the area overheads of DVFS circuitry by configuring the existing resources to provide synchronization. The autonomous parallelism, voltage, and frequency selection algorithm ensures high power efficiency by combining parallelism with DVFS. It selects that parallelism, voltage, and frequency trio which consumes minimum power to meet the deadlines on available resources. Synthesis and simulation results using various applications/algorithms (WLAN, MPEG4, FFT, FIR, matrix multiplication) show that our solution promises significant reduction in area and power consumption (23% and 51%) compared to state-of-the-art.
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| 7. |
- Perez-Soriano, Alexandra, et al.
(författare)
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PBB3 imaging in Parkinsonian disorders : Evidence for binding to tau and other proteins
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:7, s. 1016-1024
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: To study selective regional binding for tau pathology in vivo, using PET with [(11) C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.METHODS: Dynamic PET scans were obtained for 70 minutes after the bolus injection of [(11) C]PBB3 in 5 PSP subjects, 1 subject with DCTN1 mutation and PSP phenotype, 3 asymptomatic SNCA duplication carriers, 1 MSA subject, and 6 healthy controls of similar age. Tissue reference Logan analysis was applied to each region of interest using a cerebellar white matter reference region.RESULTS: In comparison to the control group, PSP subjects showed specific uptake of [(11) C]PBB3 in putamen, midbrain, GP, and SN. Longer disease duration and more advanced clinical severity were generally associated with higher tracer retention. A DCTN1/PSP phenotype case showed increased binding in putamen, parietal lobe, and GP. In SNCA duplication carriers, there was a significant increase of [(11) C] PBB3 binding in GP, putamen, thalamus, ventral striatum, SN, and pedunculopontine nucleus. The MSA case showed increased binding in frontal lobe, GP, midbrain, parietal lobe, putamen, temporal lobe, SN, thalamus, and ventral striatum.CONCLUSIONS: All PSP patients showed increased retention of the tracer in the basal ganglia, as expected. Binding was also present in asymptomatic SNCA duplication carriers and in an MSA case, which are not typically associated with pathological tau deposition. This suggests the possibility that [(11) C]PBB3 binds to alpha-synuclein. © 2017 International Parkinson and Movement Disorder Society.
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