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- Schiller, D, et al.
(författare)
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The Human Affectome
- 2024
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Ingår i: Neuroscience and biobehavioral reviews. - 1873-7528. ; 158, s. 105450-
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Tidskriftsartikel (refereegranskat)
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| 2. |
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| 3. |
- Gabel, Gabor, et al.
(författare)
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Parallel Murine and Human Aortic Wall Genomics Reveals Metabolic Reprogramming as Key Driver of Abdominal Aortic Aneurysm Progression
- 2021
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Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980 .- 2047-9980. ; 10:17
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Tidskriftsartikel (refereegranskat)abstract
- Background: While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin-II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease.Methods and Results: This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15)-mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self-limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation.Conclusions: Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.
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| 6. |
- Pergola, C, et al.
(författare)
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ERK-mediated regulation of leukotriene biosynthesis by androgens: a molecular basis for gender differences in inflammation and asthma
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 105:50, s. 19881-19886
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Tidskriftsartikel (refereegranskat)abstract
- 5-Lipoxygenase initiates the biosynthesis of leukotrienes, lipid mediators involved in normal host defense and in inflammatory and allergic disorders. Despite an obvious gender bias in leukotriene-related diseases (e.g., asthma), gender aspects have been neglected in studies on leukotrienes and 5-lipoxygenase. Here, we show that leukotriene formation in stimulated whole blood or neutrophils from males is substantially lower compared with females, accompanied by changed 5-lipoxygenase trafficking. This is due to gender-specific differential activation of extracellular signal-regulated kinases (ERKs). The differences are directly related to variant male/female testosterone plus 5α-dihydrotestosterone levels, and addition of 5α-dihydrotestosterone to female blood or neutrophils reduced the high (female) LT biosynthesis capacity to low (male) levels. In conclusion, regulation of ERKs and leukotriene formation by androgens constitutes a molecular basis for gender differences in the inflammatory response, and in inflammatory diseases such as asthma.
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| 9. |
- Skoglund, Pontus, et al.
(författare)
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Separating endogenous ancient DNA from modern-day contamination: application to a Siberian Neandertal
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:6, s. 2229-2234
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Tidskriftsartikel (refereegranskat)abstract
- One of the main impediments for obtaining DNA sequences from ancient humanskeletons is the presence of contaminating modern human DNA molecules in many fossil samples and laboratory reagents. However, DNA fragments isolated from ancient specimens show a characteristic DNA damage pattern, caused by miscoding lesions, that differs from present-day DNA sequences. Here, we develop a framework for evaluating the likelihood of a sequence originating from a model with post-mortem degradation (PMD)—summarized in a PMD score—which allows the identification of DNA fragments that are unlikely to originate from present-day sources. We apply this approach to a contaminated Neandertal specimen from the Okladnikov cave in Siberia in order to isolate its endogenous DNA from modern human contaminants, and show that the reconstructed mitochondrial genome sequence is more closely related to the variation of Western Neandertals than what was discernible from previous analyses. Our method opens up the potential for genomic analysis of contaminated fossil material.
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