| 1. |
- Baumeister, Hannah, et al.
(author)
-
A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
-
In: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
-
Journal article (peer-reviewed)abstract
- Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
|
|
| 2. |
- Thienel, Manuela, et al.
(author)
-
Immobility-associated thromboprotection is conserved across mammalian species from bear to human
- 2023
-
In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6641, s. 178-187
-
Journal article (peer-reviewed)abstract
- Venous thromboembolism (VTE) comprising deep venous thrombosis and pulmonary embolism is a major cause of morbidity and mortality. Short-term immobility-related conditions are a major risk factor for the development of VTE. Paradoxically, long-term immobilized free-ranging hibernating brown bears and paralyzed spinal cord injury (SCI) patients are protected from VTE. We aimed to identify mechanisms of immobility-associated VTE protection in a cross-species approach. Mass spectrometry-based proteomics revealed an antithrombotic signature in platelets of hibernating brown bears with heat shock protein 47 (HSP47) as the most substantially reduced protein. HSP47 down-regulation or ablation attenuated immune cell activation and neutrophil extracellular trap formation, contributing to thromboprotection in bears, SCI patients, and mice. This cross-species conserved platelet signature may give rise to antithrombotic therapeutics and prognostic markers beyond immobility-associated VTE.
|
|
| 3. |
|
|
| 4. |
- Bennaceur, A., et al.
(author)
-
Mechanisms for leveraging models at runtime in self-adaptive software
- 2014
-
In: Lecture Notes in Computer Science: Dagstuhl Seminar 11481 on Models@run.time; ; 27 November 2011 through 2 December 2011. - Cham : Springer. - 9783319089140
-
Conference paper (peer-reviewed)abstract
- Modern software systems are often required to adapt their behavior at runtime in order to maintain or enhance their utility in dynamic environments. Models at runtime research aims to provide suitable abstractions, techniques, and tools to manage the complexity of adapting software systems at runtime. In this chapter, we discuss challenges associated with developing mechanisms that leverage models at runtime to support runtime software adaptation. Specifically, we discuss challenges associated with developing effective mechanisms for supervising running systems, reasoning about and planning adaptations, maintaining consistency among multiple runtime models, and maintaining fidelity of runtime models with respect to the running system and its environment. We discuss related problems and state-of-the-art mechanisms, and identify open research challenges.
|
|
| 5. |
- Brehony, Carina, et al.
(author)
-
Implications of Differential Age Distribution of Disease-Associated Meningococcal Lineages for Vaccine Development
- 2014
-
In: Clinical and Vaccine Immunology. - : American Society for Microbiology. - 1556-6811 .- 1556-679X. ; 21:6, s. 847-853
-
Journal article (peer-reviewed)abstract
- New vaccines targeting meningococci expressing serogroup B polysaccharide have been developed, with some being licensed in Europe. Coverage depends on the distribution of disease-associated genotypes, which may vary by age. It is well established that a small number of hyperinvasive lineages account for most disease, and these lineages are associated with particular antigens, including vaccine candidates. A collection of 4,048 representative meningococcal disease isolates from 18 European countries, collected over a 3-year period, were characterized by multilocus sequence typing (MLST). Age data were available for 3,147 isolates. The proportions of hyperinvasive lineages, identified as particular clonal complexes (ccs) by MLST, differed among age groups. Subjects <1 year of age experienced lower risk of sequence type 11 (ST-11) cc, ST-32 cc, and ST-269 cc disease and higher risk of disease due to unassigned STs, 1- to 4-year-olds experienced lower risk of ST-11 cc and ST-32 cc disease, 5- to 14-year-olds were less likely to experience ST-11 cc and ST-269 cc disease, and >= 25-year-olds were more likely to experience disease due to less common ccs and unassigned STs. Younger and older subjects were vulnerable to a more diverse set of genotypes, indicating the more clonal nature of genotypes affecting adolescents and young adults. Knowledge of temporal and spatial diversity and the dynamics of meningococcal populations is essential for disease control by vaccines, as coverage is lineage specific. The nonrandom age distribution of hyperinvasive lineages has consequences for the design and implementation of vaccines, as different variants, or perhaps targets, may be required for different age groups.
|
|
| 6. |
- Brun, Matthias A, et al.
(author)
-
Semisynthesis of fluorescent metabolite sensors on cell surfaces.
- 2011
-
In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 133:40
-
Journal article (peer-reviewed)abstract
- Progress in understanding signal transduction and metabolic pathways is hampered by a shortage of suitable sensors for tracking metabolites, second messengers, and neurotransmitters in living cells. Here we introduce a class of rationally designed semisynthetic fluorescent sensor proteins, called Snifits, for measuring metabolite concentrations on the cell surface of mammalian cells. Functional Snifits are assembled on living cells through two selective chemical labeling reactions of a genetically encoded protein scaffold. Our best Snifit displayed fluorescence intensity ratio changes on living cells significantly higher than any previously reported cell-surface-targeted fluorescent sensor protein. This work establishes a generally applicable and rational strategy for the generation of cell-surface-targeted fluorescent sensor proteins for metabolites of interest.
|
|
| 7. |
- Gernhardt, Benjamin, et al.
(author)
-
A SEMANTIC REPRESENTATION FOR PROCESS-ORIENTED KNOWLEDGE MANAGEMENT BASED ON FUNCTIONBLOCK DOMAIN MODELS SUPPORTING DISTRIBUTED AND COLLABORATIVE PRODUCTION PLANNING
- 2015
-
In: PROCEEDINGS OF THE ASME 10TH INTERNATIONAL MANUFACTURING SCIENCE AND ENGINEERING CONFERENCE, 2015, VOL 2. - : AMER SOC MECHANICAL ENGINEERS.
-
Conference paper (peer-reviewed)abstract
- Semantic knowledge representation, management, sharing, access, and re-use approaches can support collaborative production planning in a flexible and efficient as well as an effective way. Therefore, semantic-technology based representations of Collaborative Production Process Planning (CAPP) knowledge integrated into a machine readable process formalization is a key enabling factor for sharing such knowledge in cloud-based semantic-enabled knowledge repositories supporting CAPP scenarios as required in the CAPP4SMES project [1]. Beyond that, Small and Medium Enterprises (SMEs) as represented in CAPP4SMES request for a standardized CAPP-oriented product-knowledge- and production-feature representation that can be achieved by applying function-block based knowledge representation models. Semantic Web- and at the same time Cloud-based technologies, tool suites and application solutions which are based on process-oriented semantic knowledge representation methodologies such as Process-oriented Knowledge-based Innovation Management (German: Wissens-basiertes Prozesess-orientiertes Innovationsmanagement, WPIM) [2] can satisfy these needs, supporting the semantic integration, management, access and re-use in a machine readable and integrated representation of distributed CAPP knowledge that is shared within a cloud-based centralized semantic-enabled knowledge repository. Furthermore semantic knowledge representation and querying add value to knowledge-based and computer-aided re-use of such knowledge within CAPP activities and, finally, pave the way towards further automating planning, simulation and optimization support in a semantic web for CAPP.
|
|
| 8. |
- Gernhardt, Benjamin, et al.
(author)
-
A Semantic Representation for Process-Oriented Knowledge Management to Support Production Planning based on Function Block Domain Models and a Three-level Mediator Architecture
- 2015
-
Conference paper (peer-reviewed)abstract
- Semantic knowledge representation, management, sharing, access, and re-use approaches can support collaborative production planning in a flexible and efficient as well as an effective way. Therefore, semantic-technology based representations of Collaborative Production Process Planning (CAPP) knowledge integrated into a machine readable process formalization is a key enabling factor for sharing such knowledge in cloud-based semantic-enabled knowledge repositories supporting CAPP scenarios as required in the CAPP4SMES project [1]. Beyond that, Small and Medium Enterprises (SMEs) as represented in CAPP4SMES request for a standardized CAPP-oriented product-knowledge- and production-feature representation that can be achieved by applying function-block based knowledge representation models. Semantic Web- and at the same time Cloud-based technologies, tool suites and application solutions which are based on process-oriented semantic knowledge representation methodologies such as Process-oriented Knowledge-based Innovation Management (German: Wissens-basiertes Prozesess-orientiertes Innovationsmanagement, WPIM) [2] can satisfy these needs, supporting the semantic integration, management, access and re-use in a machine readable and integrated representation of distributed CAPP knowledge that is shared within a cloud-based centralized semantic-enabled knowledge repository. Furthermore semantic knowledge representation and querying add value to knowledge-based and computer-aided re-use of such knowledge within CAPP activities and, finally, pave the way towards further automating planning, simulation and optimization support in a semantic web for CAPP.
|
|
| 9. |
- Gernhardt, Benjamin, et al.
(author)
-
IMPLEMENTATION OF A KNOWLEDGE-BASED PRODUCTION PLANNING INCLUDING A DIRECT MANIPULATIVE PROCESS EDITOR AND A MEDIATOR ARCHITECTURE
- 2017
-
In: PROCEEDINGS OF THE ASME 12TH INTERNATIONAL MANUFACTURING SCIENCE AND ENGINEERING CONFERENCE - 2017, VOL 3. - : AMER SOC MECHANICAL ENGINEERS.
-
Conference paper (peer-reviewed)abstract
- Today, in the era of modern Intelligent Production Environments (IPE) and Industry 4.0, the manufacturing of a product takes place in various partial steps and these mostly in different locations, potentially distributed all over the world. The producing companies must assert in the global market and always find new ways to cut costs by saving tax, changing to the best providers, and by using the most efficient and fastest production processes. Furthermore, they must be inevitably based on a cloud-based repository and distributed architectures to make data and information accessible everywhere as well as development processes and knowledge available for a worldwide cooperation. A so called Collaborative Adaptive (Production) Process Planning (CAPP) can be supported by semantic approaches for knowledge representation and management as well as knowledge sharing, access, and re-use in a flexible and efficient way. In this way, to support CAPP scenarios, semantic representations of such knowledge integrated into a machine-readable process formalization is a key enabling factor for sharing in cloud-based knowledge repositories. This is especially required for, e.g., Small and Medium Enterprises (SMEs). When SMEs work together on a production planning for a joint product, they exchange component production and manufacturing change information between different planning subsystems. These exchanges are mostly based on the already well-established Standard for the Exchange of Product model data (STEP), not least to obtain a computer-interpretable representation. Moreover, so-called Function Block (FB) Domain Models could support these planning process. FBs serve as a high-level planning-process knowledge-resource template and to the representation of knowledge. Furthermore, methodologies are required, which based on process-oriented semantic knowledge-representation, such as Process-oriented Knowledge-based Innovation Management (German: Wissens-basiertes Prozess-orientiertes Innovations Management, WPIM). WPIM is already a web and cloud-based tool suites and can represent such planning processes and their knowledge resources and can therefore be used to support the integration and the management of distributed CAPP knowledge in Manufacturing Change Management (MCM), as well as its access and re-use. That is also valid for Assembly-, Logistics- and Layout Planning (ALLP). On the one hand, a collaborative planning in a machine-readable and integrated representation will be possible as well as an optimization for mass production. On the other hand, within a cloud-based semantic knowledge repository, that knowledge can be shared with all partners and contributors. To combine all these functionalities, in 2016 we have already introduced a method, called Knowledge-based Production Planning (KPP). We outlined the theoretical advantages of integrating CAPP with Collaborative Manufacturing Change Management (CMCM) in the last year at MSEC16. In this Paper, we will demonstrate our first implementations of the KPP application with an integrated visual direct manipulative process editor as well as a first prototype of our mediator architecture with a semantic integration including a query library based on the KPP ontology.
|
|
| 10. |
- Gernhardt, Benjamin, et al.
(author)
-
Knowledge-Based Production Planning Within the Reference Planning Process Supporting Manufacturing Change Management
- 2016
-
In: Proceedings of the ASME 11TH International Manufacturing Science and Engineering Conference, 2016, VOL 2. - : AMER SOC MECHANICAL ENGINEERS.
-
Conference paper (peer-reviewed)abstract
- The manufacturing of a product takes place in several partial steps and these mostly in different locations to save tax or to use the best providers. Therefore, in the era of Internet of Things (IoT) and modem Intelligent Production Environments (IPE) are going to be inevitably based on a cloud-based repository and distributed architecture to make data and information accessible everywhere as well as development processes and knowledge available for worldwide cooperation. Semantic approaches for knowledge representation and management as well as knowledge sharing, access, and re-use can support Collaborative Adaptive Production Process Planning (CAPP) in a flexible, efficient, and effective way. Thus, semantic representations of such CAPP knowledge integrated into a machine readable process formalization is a key enabling factor for sharing such knowledge in cloud-based knowledge repositories supporting CAPP scenarios as required for e.g., Small and Medium Enterprises (SMEs). When such contributors work together on a product component production planning, they exchange component production and manufacturing change information between different planning subsystems which require, e.g., a standardized product-feature and production-machine feature representation. These data exchanges are mostly based on applying the already established Standard for the Exchange of Product model data (STEP) for the computer-interpretable representation and exchange of product manufacturing information. Furthermore, the planning process can be supported by so-called Function Block (FB) based knowledge representation models, serving as a high-level planning-process knowledge-resource template. Web-based and at the same time Cloud-based tool suites, which are based on process-oriented semantic knowledge-representation methodologies, such as Process-oriented Knowledge-based Innovation Management (German: Wissens-basiertes Prozess-orientiertes Innovations Management, WPIM) can satisfy the needs of representing such planning processes and their knowledge resources. In this way, WPIM can be used to support the integration and management of distributed CAPP knowledge, as well as its access and re-use in Manufacturing Change Management (MCM) including Assembly-, Logistics and Layout Planning (ALLP). Therefore, also a collaborative planning and optimization for mass production in a machine readable and integrated representation is possible. On the other hand, that knowledge can be shared within a cloud-based semantic knowledge repository. To integrate all these functionalities, this paper introduces a new method, called Knowledge-based Production Planning (KPP) and outlines the advantages of integrating CAPP with Collaborative Manufacturing Change Management (CMCM). In this way, an enabling basis for achieving ALLP interoperability in Distributed Collaborative Manufacturing and Logistics will be demonstrated.
|
|
