| 21. |
- Gomes, Leonardo Augusto de Vasconcelos, et al.
(författare)
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Playing chess or playing poker? : Assessment of uncertainty propagation in open innovation projects
- 2021
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Ingår i: International Journal of Project Management. - : Elsevier. - 0263-7863 .- 1873-4634. ; 39:2, s. 154-169
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Tidskriftsartikel (refereegranskat)abstract
- Consider an interorganizational open innovation project, in which different organizations cooperate to generate value for clients or to solve a technological problem. In this setting, both the focal firm and the partners face uncertainties over time (e.g., technological uncertainties, market uncertainties) and, therefore, the performance of the focal firm and the overall interorganizational project depend on that firm's ability to assess potential uncertainties. The process of diffusion of a particular uncertainty throughout an inter-organizational project can be defined as uncertainty propagation. Assessment of uncertainty propagation can be employed to mitigate its detrimental impact. This paper connects previous studies of open innovation, uncertainty management and project management by providing a comprehensive, but structured, framework to assess uncertainty propagation. First, we propose the underlying causes of uncertainty propagation. Then, we present the three different approaches to its assessment, based on causes, effects and protection.
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| 22. |
- Law, Philip J., et al.
(författare)
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Association analyses identify 31 new risk loci for colorectal cancer susceptibility
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
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| 23. |
- Matejcic, Marco, et al.
(författare)
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Germline variation at 8q24 and prostate cancer risk in men of European ancestry
- 2018
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p < 4.28 x 10(-15)), including three risk variants that have yet to be reported. From a polygenic risk score (PRS) model, derived to assess the cumulative effect of risk variants at 8q24, men in the top 1% of the PRS have a 4-fold (95% CI = 3.62-4.40) greater risk compared to the population average. These 12 variants account for similar to 25% of what can be currently explained of the familial risk of prostate cancer by known genetic risk factors. These findings highlight the overwhelming contribution of germline variation at 8q24 on prostate cancer risk which has implications for population risk stratification.
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| 24. |
- Michel, M., et al.
(författare)
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Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function
- 2022
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Ingår i: Science. - Stockholm : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 376:6600, s. 1471-1476
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Tidskriftsartikel (refereegranskat)abstract
- Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works
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| 25. |
- Serrano, Inmaculada, et al.
(författare)
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C4BP(β-)-mediated immunomodulation attenuates inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients
- 2023
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Ingår i: Pharmacological Research. - 1043-6618. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(β-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(β-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(β-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(β-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(β-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to “reprogram” myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.
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| 26. |
- Serrano, Inmaculada, et al.
(författare)
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The Hidden Side of Complement Regulator C4BP : Dissection and Evaluation of Its Immunomodulatory Activity
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- C4b-binding protein (C4BP) is a well-known regulator of the complement system that holds additional and important activities unrelated to complement inhibition. Recently, we have described a novel immunomodulatory activity in the minor C4BP(β-) isoform directly acting over inflammatory phagocytes. Here we show that incorporation of the β-chain to the C4BP α-chain oligomer interferes with this immunomodulatory activity of C4BP. Moreover, an oligomeric form including only the complement control protein 6 (CCP6) domain of the C4BP α-chain (PRP6-HO7) is sufficient to “reprogram” monocyte-derived DCs (Mo-DCs) from a pro-inflammatory and immunogenic phenotype to an anti-inflammatory and tolerogenic state. PRP6-HO7 lacks complement regulatory activity but retains full immunomodulatory activity over inflammatory Mo-DCs induced by TLRs, characterized by downregulation of relevant surface markers such as CD83, HLA-DR, co-stimulatory molecules such as CD86, CD80 and CD40, and pro-inflammatory cytokines such as IL-12 and TNF-α. Furthermore, PRP6-HO7-treated Mo-DCs shows increased endocytosis, significantly reduced CCR7 expression and CCL21-mediated chemotaxis, and prevents T cell alloproliferation. Finally, PRP6-HO7 shows also full immunomodulatory activity over Mo-DCs isolated from lupus nephritis patients with active disease, even without further pro-inflammatory stimulation. Therefore PRP6-HO7, retaining the immunomodulatory activity of C4BP(β-) and lacking its complement regulatory activity, might represent a promising and novel alternative to treat autoimmune diseases.
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| 27. |
- 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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| 28. |
- Turmo Vidal, Laia, et al.
(författare)
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Body Sensations as Design Material : An Approach to Design Sensory Technology for Altering Body Perception
- 2024
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Ingår i: Proceedings of the 2024 ACM Designing Interactive Systems Conference, DIS 2024. - : Association for Computing Machinery (ACM). ; , s. 2545-2561
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Konferensbidrag (refereegranskat)abstract
- Sensory technologies alter how we perceive our body, which can have profound implications for multiple domains. Prior work has contributed a myriad of artefacts and evaluative studies, but we still lack design knowledge to design meaningful body perception alterations facilitated by sensory technologies. To address this gap, we draw from soma design to propose a methodological approach centered on body sensations as design material. We articulate our approach based on a project on co-designing wearables to alter body perception together with professional dancers. Our approach involves engaging participants in articulating and sharing body sensations to others, and exploring somatically sensory stimuli to co-design concepts for future technologies. We contribute experiential facets of body sensations, movement and sensory potentials to alter sensations, methods and design strategies, and a collection of ideas. Our work can be relevant to design communities interested in sensory technologies, perceptual alterations and body sensations as material.
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| 29. |
- van Delden, Robby, et al.
(författare)
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Technology, Movement, and Play Is Hampering and Boosting Interactive Play
- 2023
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Ingår i: CHI PLAY Companion '23: Companion Proceedings of the Annual Symposium on Computer-Human Interaction in Play. - : Association for Computing Machinery (ACM). - 9798400700293 ; , s. 231-234
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Konferensbidrag (refereegranskat)abstract
- In this paper, we highlight how including technology, movement or play can boost a design process but with unbalanced amounts can also hamper the process. We provide a set of examples where we miscalculated the amount of technology, movement, or play that was needed in a design activity in such a way that it became counterproductive and for each example mention possible adaptations. Finally, we highlight three existing approaches that can balance the overabundance of technology, movement, and play in design processes: activity-centered design, somaesthetic design, and perspective-changing movement-based design.
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| 30. |
- Vega-Cebrián, José Manuel, et al.
(författare)
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Design Resources in Movement-based Design Methods : A Practice-based Characterization
- 2023
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Ingår i: Proceedings of the 2023 ACM Designing Interactive Systems Conference. - : Association for Computing Machinery (ACM). ; , s. 871-888
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Konferensbidrag (refereegranskat)abstract
- Movement-based design methods are increasingly adopted to help design rich embodied experiences. While there are well-known methods in the feld, there is no systematic overview to help designers choose among them, adapt them, or create their own. We collected 41 methods used by movement design researchers and employed a practice-based, bottom-up approach to analyze and characterize their properties. We found 17 categories and arranged them into five main groups: Design Resources, Activities, Delivery, Framing, and Context. In this paper, we describe these groups in general and then focus on Design Resources containing the categories of Movement, Space, and Objects. We ground the characterization with examples from empirical material provided by the design researchers and references to previous work. Additionally, we share recommendations and action points to bring these into practice. This work can help novice and seasoned design researchers who want to employ movement-based design methods in their practice.
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