| 1. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 2. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 3. |
- Azuaje, Jhonny, et al.
(författare)
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Pyrazin-2(1H)-ones as a novel class of selective A3 adenosine receptor antagonists
- 2015
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Ingår i: Future Medicinal Chemistry. - : Future Science Ltd. - 1756-8919 .- 1756-8927. ; 7:11, s. 1373-1380
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Tidskriftsartikel (refereegranskat)abstract
- Background: A(3)AR antagonists are promising drug candidates as neuroprotective agents as well as for the treatment of inflammation or glaucoma. The most widely known A(3)AR antagonists are derived from polyheteroaromatic scaffolds, which usually show poor pharmacokinetic properties. Accordingly, the identification of structurally simple A(3)AR antagonists by the exploration of novel diversity spaces is a challenging goal. Results: A convergent and efficient Ugi-based multicomponent approach enabled the discovery of pyrazin-2(1H)-ones as a novel class of A(3)AR antagonists. A combined experimental/computational strategy accelerated the establishment of the most salient features of the structure-activity and structure-selectivity relationships in this series. Conclusion: The optimization process provided pyrazin-2(1H)-ones with improved affinity and a plausible hypothesis regarding their binding modes was proposed.
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| 4. |
- Bott, Lukas Thomas, et al.
(författare)
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Coulomb dissociation of O-16 into He-4 and C-12
- 2023
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Ingår i: NUCLEAR PHYSICS IN ASTROPHYSICS - X, NPA-X 2022. - : EDP Sciences. - 2100-014X. ; 279
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Konferensbidrag (refereegranskat)abstract
- We measured the Coulomb dissociation of O-16 into He-4 and C-12 within the FAIR Phase-0 program at GSI Helmholtzzentrum fur Schwerionenforschung Darmstadt, Germany. From this we will extract the photon dissociation cross section O-16(alpha,gamma)C-12, which is the time reversed reaction to C-12(alpha,gamma)O-16. With this indirect method, we aim to improve on the accuracy of the experimental data at lower energies than measured so far. The expected low cross section for the Coulomb dissociation reaction and close magnetic rigidity of beam and fragments demand a high precision measurement. Hence, new detector systems were built and radical changes to the (RB)-B-3 setup were necessary to cope with the high-intensity O-16 beam. All tracking detectors were designed to let the unreacted O-16 ions pass, while detecting the C-12 and He-4.
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| 5. |
- Jimborean, Alexandra, et al.
(författare)
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Dynamic and speculative polyhedral parallelization of loop nests using binary code patterns
- 2013
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Ingår i: ICCS 2013. - : Elsevier BV. ; , s. 2575-2578
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Konferensbidrag (refereegranskat)abstract
- Speculative parallelization is a classic strategy for automatically parallelizing codes that cannot be handled at compile-time due to the use ofdynamic data and control structures. Another motivation of being speculative is to adapt the code to the current execution context, by selecting at run-time an efficient parallel schedule. However, since this parallelization scheme requires on-the-fly semantics verification, it is in general difficult to perform advanced transformations for optimization and parallelism extraction. We propose a framework dedicated tospeculative parallelization of scientific nested loop kernels, able to transform thecode at runtime by re-scheduling the iterations to exhibit parallelism and data locality. The run-time process includes a transformation selection guided by profiling phases on short samples, using an instrumented version of the code. During this phase, the accessed memory addresses are interpolated to build a predictor of the forthcoming accesses. The collected addresses are also used to compute on-the-fly dependence distance vectors by tracking accesses to common addresses. Interpolating functions and distance vectors are then employed in dynamicdependence analysis and in selecting a parallelizing transformation that, if the prediction is correct, does not induce any rollback during execution. In order to ensure that the rollback time overhead stays low, the code is executed in successive slices of the outermost original loop of the nest. Each slice can be either a parallelized version, a sequential original version, or an instrumented version. Moreover, such slicing of the execution provides the opportunity of transforming differently the code to adapt to the observed execution phases. Parallel codegeneration is achieved almost at no cost by using binary code patterns that are generated at compile-time and that are simply patched at run-time to result in the transformed code. The framework has been implemented with extensions of the LLVM compiler and an x86-64 runtime system. Significant speed-ups are shown on a set of benchmarks that could not have been handled efficiently by a compiler.
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| 6. |
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| 7. |
- Jimborean, Alexandra, et al.
(författare)
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Online dynamic dependence analysis for speculative polyhedral parallelization
- 2013
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Ingår i: Euro-Par 2013 Parallel Processing. - Berlin, Heidelberg : Springer Berlin/Heidelberg. - 9783642400469 ; , s. 191-202
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Konferensbidrag (refereegranskat)abstract
- We present a dynamic dependence analyzer whose goal is to compute dependencies from instrumented execution samples of loop nests. The resulting information serves as a prediction of the execution behavior during the remaining iterations and can be used to select and apply a speculatively optimizing and parallelizing polyhedral transformation of the target sequential loop nest. Thus, a parallel lock-free version can be generated which should not induce any rollback if the prediction is correct. The dependence analyzer computes distance vectors and linear functions interpolating the memory addresses accessed by each memory instruction, and the values of some scalars. Phases showing a changing memory behavior are detected thanks to a dynamic adjustment of the instrumentation frequency.The dependence analyzer takes part of a whole framework dedicated to speculative parallelization of loop nests which has been implemented with extensions of the LLVM compiler and an x86-64 runtime system.
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| 8. |
- Majellaro, María, et al.
(författare)
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3,4-Dihydropyrimidin-2(1H)-ones as Antagonists of the Human A2B Adenosine Receptor : Optimization, Structure–Activity Relationship Studies, and Enantiospecific Recognition
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:1, s. 458-480
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Tidskriftsartikel (refereegranskat)abstract
- We present and thoroughly characterize a large collection of 3,4-dihydropyrimidin-2(1H)-ones as A2BAR antagonists, an emerging strategy in cancer (immuno) therapy. Most compounds selectively bind A2BAR, with a number of potent and selective antagonists further confirmed by functional cyclic adenosine monophosphate experiments. The series was analyzed with one of the most exhaustive free energy perturbation studies on a GPCR, obtaining an accurate model of the structure–activity relationship of this chemotype. The stereospecific binding modeled for this scaffold was confirmed by resolving the two most potent ligands [(±)-47, and (±)-38Ki = 10.20 and 23.6 nM, respectively] into their two enantiomers, isolating the affinity on the corresponding (S)-eutomers (Ki = 6.30 and 11.10 nM, respectively). The assessment of the effect in representative cytochromes (CYP3A4 and CYP2D6) demonstrated insignificant inhibitory activity, while in vitro experiments in three prostate cancer cells demonstrated that this pair of compounds exhibits a pronounced antimetastatic effect.
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| 9. |
- Sukumaran-Rajam, Aravind, et al.
(författare)
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Speculative program parallelization with scalable and decentralized runtime verification
- 2014
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Ingår i: Runtime Verification. - Cham : Springer Berlin/Heidelberg. - 9783319111636 ; , s. 124-139
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Konferensbidrag (refereegranskat)abstract
- Thread Level Speculation (TLS) is a dynamic code parallelization technique proposed to keep the software in pace with the advances in hardware,in particular, to automatically parallelize programs to take advantage of the multi-core processors. Being speculative, frameworks of this type unavoidably rely on verification systems that are similar to software transactional memory, and that require voluminous inter-thread communications or centralized registering of the performed memory accesses. The high degree of communication is against the basic principles of high performance parallel computing, does not scale with an increasing number of processor cores, and yields weak performance. Moreover, TLS systems often apply one unique parallelization strategy consisting in slicing a loop into several parallel speculative threads. Such a strategy is also against the basic principles since loops in the original serial code are not necessarily parallel and also, it is well-known that the parallel schedule must promote data locality which is crucial in obtaining good performance. This situation appeals to scalable and decentralized verification systems and new strategies to dynamically generate efficient parallel code resulting from advanced optimizing parallelizing transformations. Such transformations require a more complex verification system that allows intra-thread iterations to be reordered. In this paper, we propose a verification system of this kind, based on a model built at runtime and predicting a linear memory behavior. This strategy is part of the Apollo speculative code parallelizer which is based on an adaptation for dynamic usage of the polyhedral model.
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| 10. |
- Taiebi, Julien, et al.
(författare)
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Studies on Fission with Aladin
- 2018
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Ingår i: FISSION AND PROPERTIES OF NEUTRON-RICH NUCLEI. - 9789813229426 ; , s. 339-340
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Konferensbidrag (refereegranskat)
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