| 1. |
- Brandão, Lenisa, et al.
(författare)
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Discourse intervention strategies in Alzheimer's disease : eye-tracking and the effect of visual cues in conversation
- 2014
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Ingår i: Dementia & Neuropsychologia. - 1980-5764. ; 8:3, s. 278-284
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The goal of this study was to investigate whether on-topic visual cues can serve as aids for the maintenance of discourse coherence and informativeness in autobiographical narratives of persons with Alzheimer's disease (AD). METHODS: The experiment consisted of three randomized conversation conditions: one without prompts, showing a blank computer screen; an on-topic condition, showing a picture and a sentence about the conversation; and an off-topic condition, showing a picture and a sentence which were unrelated to the conversation. Speech was recorded while visual attention was examined using eye tracking to measure how long participants looked at cues and the face of the listener. RESULTS: Results suggest that interventions using visual cues in the form of images and written information are useful to improve discourse informativeness in AD. CONCLUSION: This study demonstrated the potential of using images and short written messages as means of compensating for the cognitive deficits which underlie uninformative discourse in AD. Future studies should further investigate the efficacy of language interventions based in the use of these compensation strategies for AD patients and their family members and friends.
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| 2. |
- Brandão, Rita D., et al.
(författare)
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Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes
- 2019
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:2, s. 401-414
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Tidskriftsartikel (refereegranskat)abstract
- A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep-sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA-seq approach was used to analyse the naturally-occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non-BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non-targeted RNA-seq approach. We also compared splicing events from lymphoblastoid cell-lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA-seq to detect pathogenic changes in RNA-splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted-RNA-seq can be very useful to classify variants based on their putative pathogenic impact on splicing.
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| 3. |
- 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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| 4. |
- Eberle, Sebastian, et al.
(författare)
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Additive manufacturing of an AlSi40 mirror coated with electroless nickel for cryogenic space applications
- 2018
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Ingår i: International Conference on Space Optics—ICSO 2018. - : SPIE - International Society for Optical Engineering.
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Konferensbidrag (refereegranskat)abstract
- Advanced Manufacturing (AM) has the potential to improve existing technologies and applications in terms of performance, light-weighting and costs. In the context of the SME4ALM initiative, launched by DLR and ESA, the company Kampf Telescope Optics GmbH (KTO) in cooperation with the Fraunhofer Institute for Material and Beam Technology (IWS) have assessed the feasibility of AM to build a high-performance optical mirror for space applications. For the assessment of the AM potentials, a mirror design concept for cryogenic instruments for observations in the IR and NIR range was baselined. In a second step, Nickel-Phosphorus (NiP) was selected as optical coating. The combination of coating and mirror material is a primary design driver for optical performance. Both materials must have a very similar CTE as well as be compliant to modern optical manufacturing (diamond turning, polishing). As a promising candidate for NiP coating the AlSi40 was selected for the mirror structure. The potential advantages of AM for optical mirrors in terms of mechanical performance, cost, and manufacturing time were exploited. The achievement of those objectives was / will be demonstrated by:1. verifying AM material properties and manufacturability of AM mirrors by material sample tests and subcomponent tests2. designing AM mirror demonstrator by structural, thermal, and optical performance analysis3. applying and elaborating AM specific design methods (topology optimization, sandwich structures with internal microstructures, monolithic design, etc.)4. manufacturing, assembling, and testing AM mirror demonstrator to verify manufacturability and optical performance5. comparing optical and mechanical performance of the AM mirror demonstrator to a conventional mirror by numerical analysis to exploit potential advantages of AM
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| 5. |
- Leonardo, Diego A., et al.
(författare)
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Orientational Ambiguity in Septin Coiled Coils and its Structural Basis
- 2021
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 0022-2836. ; 433:9
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Tidskriftsartikel (refereegranskat)abstract
- Septins are an example of subtle molecular recognition whereby different paralogues must correctly assemble into functional filaments important for essential cellular events such as cytokinesis. Most possess C-terminal domains capable of forming coiled coils which are believed to be involved in filament formation and bundling. Here, we report an integrated structural approach which aims to unravel their architectural diversity and in so doing provide direct structural information for the coiled-coil regions of five human septins. Unexpectedly, we encounter dimeric structures presenting both parallel and antiparallel arrangements which are in consonance with molecular modelling suggesting that both are energetically accessible. These sequences therefore code for two metastable states of different orientations which employ different but overlapping interfaces. The antiparallel structures present a mixed coiled-coil interface, one side of which is dominated by a continuous chain of core hydrophilic residues. This unusual type of coiled coil could be used to expand the toolkit currently available to the protein engineer for the design of previously unforeseen coiled-coil based assemblies. Within a physiological context, our data provide the first atomic details related to the assumption that the parallel orientation is likely formed between septin monomers from the same filament whilst antiparallelism may participate in the widely described interfilament cross bridges necessary for higher order structures and thereby septin function.
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| 6. |
- Mueller, Michael, et al.
(författare)
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Microstructural, mechanical, and thermo-physical characterization of hypereutectic AlSi40 fabricated by selective laser melting
- 2019
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Ingår i: Journal of laser applications. - : Laser Institute of America. - 1042-346X .- 1938-1387. ; 31:2
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Tidskriftsartikel (refereegranskat)abstract
- The powder bed additive manufacturing process selective laser melting (SLM) enables designers and engineers to overcome restrictions of conventional manufacturing technologies. The potential of fabricating complex lightweight structures and processing advanced materials is a key feature for enhancing further development of high performance components for space applications. Due to a high specific stiffness and a thermal expansion coefficient very close to electroless nickel, which is an advantageous optical coating material, the hypereutectic aluminum-silicon alloy AlSi40 shows great potential for the manufacturing of optical mirrors for space applications. In prior investigations, Hilpert et al.showed the feasibility to process AlSi40 by SLM [E. Hilpert and S. Risse, Materials Science & Technology Conference and Exhibition MS&T'15, Columbus, Ohio, 4–8 October 2015(Association for Iron & Steel Technology, Warrendale, PA, 2015) and E. Hilpert, “Struktur und Eigenschaften von additiv gefertigten hypereutektischen Aluminum-Siliciumlegierungen,” in Werkstoffwoche 2017, Dresden, Germany, 28 September 2017 (Deutsche Gesellschaft für Materialkunde e.V., Berlin, 2017)]. Nevertheless, in order to qualify this material for space applications, the manufacturing process and fabricated samples need to be thoroughly investigated in terms of microstructural, mechanical, as well as thermo-physical characterization. The authors present results of the SLM process development for manufacturing dense AlSi40 samples with a relative density above 99.50%. The effect of various process parameters, such as hatch distance, preheating, and scanning strategy, on the formation of defects was investigated by destructive [e.g., optical microscopy (OM)] and nondestructive (e.g., computed tomography) testing. In addition, the effect of several thermal post-treatments on the AlSi40 microstructure was profoundly analyzed by multiple methods such as OM, scanning electron microscopy, and energy dispersive x-ray spectroscopy analysis. Moreover, mechanical and thermo-physical testing of manufactured specimens was conducted to provide material characteristics for component design. In conclusion, the determined material properties of AlSi40 samples fabricated by SLM were compared to bulk material properties. The gained knowledge and testing data were evaluated in order to identify correlations and dependencies.
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| 7. |
- Shen, Ruidan, et al.
(författare)
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Insights into the importance of WPD-loop sequence for activity and structure in protein tyrosine phosphatases
- 2022
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Ingår i: Chemical Science. - : Royal Society of Chemistry. - 2041-6520 .- 2041-6539. ; 13:45, s. 13524-13540
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Tidskriftsartikel (refereegranskat)abstract
- Protein tyrosine phosphatases (PTPs) possess a conserved mobile catalytic loop, the WPD-loop, which brings an aspartic acid into the active site where it acts as an acid/base catalyst. Prior experimental and computational studies, focused on the human enzyme PTP1B and the PTP from Yersinia pestis, YopH, suggested that loop conformational dynamics are important in regulating both catalysis and evolvability. We have generated a chimeric protein in which the WPD-loop of YopH is transposed into PTP1B, and eight chimeras that systematically restored the loop sequence back to native PTP1B. Of these, four chimeras were soluble and were subjected to detailed biochemical and structural characterization, and a computational analysis of their WPD-loop dynamics. The chimeras maintain backbone structural integrity, with somewhat slower rates than either wild-type parent, and show differences in the pH dependency of catalysis, and changes in the effect of Mg2+. The chimeric proteins' WPD-loops differ significantly in their relative stability and rigidity. The time required for interconversion, coupled with electrostatic effects revealed by simulations, likely accounts for the activity differences between chimeras, and relative to the native enzymes. Our results further the understanding of connections between enzyme activity and the dynamics of catalytically important groups, particularly the effects of non-catalytic residues on key conformational equilibria.
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| 8. |
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| 9. |
- Thomassen, Mads, et al.
(författare)
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Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants : Application of a points-based ACMG/AMP approach
- 2022
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 43:12, s. 1921-1944
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Tidskriftsartikel (refereegranskat)abstract
- Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength.
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| 10. |
- 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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| 11. |
- Willner, Robin, et al.
(författare)
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Potential and challenges of additive manufacturing for topology optimized spacecraft structures
- 2020
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Ingår i: Journal of laser applications. - : American Institute of Physics (AIP). - 1042-346X .- 1938-1387. ; 32:3
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Tidskriftsartikel (refereegranskat)abstract
- This study focused on the potential of topology optimization (TO) for metallic tertiary structures of spacecrafts produced by the additive manufacturing (AM) technique laser powder bed fusion. First, a screening of existing conventionally manufactured products was carried out to evaluate the benefits of a redesign concerning product performance and the associated economic impact. As a result of the study, the most suitable demonstrator was selected. This reference structure was redesigned by TO taking into consideration the AM process constraints. Another major aim of this work was to evaluate the possibilities and challenges of AM (accuracies, surface quality, process parameters, postmachining, and mechanical properties) in addition to the redesign process. A comprehensive approach was implemented including detailed analysis of the powder, mechanical properties, in-process parameters, and nondestructive inspection (NDI). All measured values were used for a back loop to the design process, thereby providing a final robust redesign. Finally, the fine-tuned demonstrator was built up in an iterative process. The parts were tested under representative conditions for the application to verify the performance. The demonstrator qualification test campaign contained thermal cycling, vibration testing, static load testing, and NDI. Thus, an improvement in technology readiness level up to "near flight qualified" was reached.
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