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- El Omari, Kamel, et al.
(författare)
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Experimental phasing opportunities for macromolecular crystallography at very long wavelengths
- 2023
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Ingår i: Communications Chemistry. - : Nature Publishing Group. - 2399-3669. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite recent advances in cryo-electron microscopy and artificial intelligence-based model predictions, a significant fraction of structure determinations by macromolecular crystallography still requires experimental phasing, usually by means of single-wavelength anomalous diffraction (SAD) techniques. Most synchrotron beamlines provide highly brilliant beams of X-rays of between 0.7 and 2 Å wavelength. Use of longer wavelengths to access the absorption edges of biologically important lighter atoms such as calcium, potassium, chlorine, sulfur and phosphorus for native-SAD phasing is attractive but technically highly challenging. The long-wavelength beamline I23 at Diamond Light Source overcomes these limitations and extends the accessible wavelength range to λ = 5.9 Å. Here we report 22 macromolecular structures solved in this extended wavelength range, using anomalous scattering from a range of elements which demonstrate the routine feasibility of lighter atom phasing. We suggest that, in light of its advantages, long-wavelength crystallography is a compelling option for experimental phasing.
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| 2. |
- Inagaki-Kawata, Y, et al.
(författare)
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Genetic and clinical landscape of breast cancers with germline BRCA1/2 variants
- 2020
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1, s. 578-
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Tidskriftsartikel (refereegranskat)abstract
- The genetic and clinical characteristics of breast tumors with germline variants, including their association with biallelic inactivation through loss-of-heterozygosity (LOH) and second somatic mutations, remain elusive. We analyzed germline variants of 11 breast cancer susceptibility genes for 1,995 Japanese breast cancer patients, and identified 101 (5.1%) pathogenic variants, including 62 BRCA2 and 15 BRCA1 mutations. Genetic analysis of 64 BRCA1/2-mutated tumors including TCGA dataset tumors, revealed an association of biallelic inactivation with more extensive deletions, copy neutral LOH, gain with LOH and younger onset. Strikingly, TP53 and RB1 mutations were frequently observed in BRCA1- (94%) and BRCA2- (9.7%) mutated tumors with biallelic inactivation. Inactivation of TP53 and RB1 together with BRCA1 and BRCA2, respectively, involved LOH of chromosomes 17 and 13. Notably, BRCA1/2 tumors without biallelic inactivation were indistinguishable from those without germline variants. Our study highlights the heterogeneity and unique clonal selection pattern in breast cancers with germline variants.
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| 13. |
- Niimi, Yoshiki, et al.
(författare)
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Combining plasma Aβ and p-tau217 improves detection of brain amyloid in non-demented elderly
- 2024
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Ingår i: Alzheimer's Research and Therapy. - 1758-9193. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer’s disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-β (Aβ)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aβ-positron emission tomography (PET) in the preclinical and prodromal AD. Methods: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aβ and p-tau217 assessments, and Aβ-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aβ(1-42) (Aβ42) and Aβ(1-40) (Aβ40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). Results: Aβ-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aβ42/Aβ40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aβ-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aβ42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aβ42/Aβ40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aβ42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aβ42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aβ42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). Conclusions: Combination of plasma Aβ-related biomarkers and p-tau217 exhibits high performance when predicting Aβ-PET positivity. Adding basic clinical information (i.e., age, sex, APOE ε genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aβ-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.
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| 14. |
- Oseen-Senda, K. M., et al.
(författare)
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Cooling of PEMFC with pentane boiling in minichannels : A study of flow instabilities using neutron radiography visualization
- 2006
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Ingår i: 16th World Hydrogen Energy Conference 2006. - 9781622765409 ; , s. 2885-2894
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Konferensbidrag (refereegranskat)abstract
- Compared to other heat transfer systems, Polymer Electrolyte Fuel Cells are characterized by very low heat flux. In order to analyse two-phase pentane cooling of bipolar plates, high speed neutron visualizations have been performed in a circular steel tube (Di=1.1 mm, Do=2 mm) at the Institut Laue-Langevin in Grenoble, France. The flow pattern is clearly visible and can be synchronized with time resolved temperature measurements. At low mass flow rates, the pipe wall is high above the saturation temperature and the pipe filled with vapour and liquid slugs. At higher flow rates, the wall is superheated when filled with liquid and at saturation temperature when exposed to a liquid-vapour mixture. An irregular switching between these two states was observed. Superheated liquid exists in both stable and time dependent states. The ?-radiation produced by the neutrons is shown to have an important effect on the boiling process. Simplified steady and time dependent models are proposed to explain the measured wall temperature instabilities and superheat.
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| 15. |
- Oseen-Senda, K. M., et al.
(författare)
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The cooling of PEFC with pentane boiling in minichannels : A study of flow instabilities using neutron radiography visualization
- 2007
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Ingår i: Heat Transfer Engineering. - : Informa UK Limited. - 0145-7632 .- 1521-0537. ; 28:1, s. 49-57
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Tidskriftsartikel (refereegranskat)abstract
- Polymer electrolyte fuel cells (PEFC) operate best at a steady temperature of about 80 degrees C and have a very low heat flux compared to other heat transfer applications. Two-phase pentane cooling of bipolar plates is studied in order to optimize fuel cell cooling in transport applications. High-speed visualizations of boiling pentane in a circular steel tube (D-i = 1.1 mm, D-o = 2 mm) have been performed in a Neutrograph instrument at the Institut Laue-Langevin in Grenoble, France. The heat and mass flux were both very low and appropriate for cooling of PEFC. The spatial resolution of the images is approximately 0.15 mm and the maximum frequency is 154 Hz. In the images, the liquid-vapor differentiation is clearly visible. Time resolved measurements of the outer pipe wall temperature, synchronized with the images, show that at low mass flow rates, the pipe wall is high above the saturation temperature and the pipe filled with vapor and liquid slugs. At higher flow rates, the wall is superheated when filled with liquid, and at saturation temperature during boiling when exposed to a liquid-vapor mixture. An irregular switch between these two states was observed. The superheated wall is shown to be consistent with the superheated liquid in the pipe in both stable and time-dependent states. Unfortunately, the strong gamma-radiation produced by the neutrons has a substantial effect on the onset of boiling, which is why comparisons with non-irradiated systems might be difficult. Simplified steady and time-dependent models are proposed to explain the measured wall temperature instabilities and superheat.
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