| 1. |
- Hess, Timo, et al.
(författare)
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Dissecting the genetic heterogeneity of gastric cancer
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 92
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Tidskriftsartikel (refereegranskat)abstract
- Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture.Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO.Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level.Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO.
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| 2. |
- Brown, Richard J. P., et al.
(författare)
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Liver-expressed Cd302 and Cr1l limit hepatitis C virus cross-species transmission to mice
- 2020
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Ingår i: Science Advances. - : American Association for the Advancement of Science. - 2375-2548. ; 6:45
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis C virus (HCV) has no animal reservoir, infecting only humans. To investigate species barrier determinants limiting infection of rodents, murine liver complementary DNA library screening was performed, identifying transmembrane proteins Cd302 and Cr1l as potent restrictors of HCV propagation. Combined ectopic expression in human hepatoma cells impeded HCV uptake and cooperatively mediated transcriptional dysregulation of a noncanonical program of immunity genes. Murine hepatocyte expression of both factors was constitutive and not interferon inducible, while differences in liver expression and the ability to restrict HCV were observed between the murine orthologs and their human counterparts. Genetic ablation of endogenous Cd302 expression in human HCV entry factor transgenic mice increased hepatocyte permissiveness for an adapted HCV strain and dysregulated expression of metabolic process and host defense genes. These findings highlight human-mouse differences in liver-intrinsic antiviral immunity and facilitate the development of next-generation murine models for preclinical testing of HCV vaccine candidates.
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| 3. |
- Falk, Martin, et al.
(författare)
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Parallelized Agent-based Simulation on CPU and Graphics Hardware for Spatial and Stochastic Models in Biology
- 2011
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Ingår i: Proceedings of the 9th International Conference on Computational Methods in Systems Biology, CMSB'112011. - New York, NY, USA : ACM Press. - 9781450308175 ; , s. 73-82
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Konferensbidrag (refereegranskat)abstract
- The complexity of biological systems is enormous, even when considering a single cell where a multitude of highly parallel and intertwined processes take place on the molecular level. This paper focuses on the parallel simulation of signal transduction processes within a cell carried out solely on the graphics processing unit (GPU). Each signaling molecule is represented by an agent performing a discretetime continuous-space random walk to model its diffusion through the cell. Since the interactions and reactions between the agents can be competitive and are interdependent, we propose spatial partitioning for the reaction detection to overcome the data dependencies in the parallel execution of reactions. In addition, we present a simple way to simulate the Michaelis-Menten kinetics in our particle-based method using a per-particle delay. We apply this agent-based simulation to model signal transduction in the MAPK (Mitogen-Activated Protein Kinase) cascade both with and without cytoskeletal filaments. Finally, we compare the speed-up of our GPU simulation with a parallelized CPU version resulting in a twelvefold speedup.
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| 4. |
- Kositzki, Ramona, et al.
(författare)
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Electronic and molecular structure relations in diiron compounds mimicking the [FeFe]-hydrogenase active site studied by X-ray spectroscopy and quantum chemistry
- 2017
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Ingår i: Dalton Transactions. - : ROYAL SOC CHEMISTRY. - 1477-9226 .- 1477-9234. ; 46:37, s. 12544-12557
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Tidskriftsartikel (refereegranskat)abstract
- Synthetic diiron compounds of the general formula Fe-2(mu-S2R)(CO)(n)(L)(6-n) (R = alkyl or aromatic groups; L = CN- or phosphines) are versatile models for the active-site cofactor of hydrogen turnover in [FeFe]-hydrogenases. A series of 18 diiron compounds, containing mostly a dithiolate bridge and terminal ligands of increasing complexity, was characterized by X-ray absorption and emission spectroscopy in combination with density functional theory. Fe K-edge absorption and K beta main-line emission spectra revealed the varying geometry and the low-spin state of the Fe(I) centers. Good agreement between experimental and calculated core-to-valence-excitation absorption and radiative valence-to-core-decay emission spectra revealed correlations between spectroscopic and structural features and provided access to the electronic configuration. Four main effects on the diiron core were identified, which were preferentially related to variation either of the dithiolate or of the terminal ligands. Alteration of the dithiolate bridge affected mainly the Fe-Fe bond strength, while more potent donor substitution and ligand field asymmetrization changed the metal charge and valence level localization. In contrast, cyanide ligation altered all relevant properties and, in particular, the frontier molecular orbital energies of the diiron core. Mutual benchmarking of experimental and theoretical parameters provides guidelines to verify the electronic properties of related diiron compounds.
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| 7. |
- Ayob, Leith, et al.
(författare)
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ABC om Wernickes encefalopati
- 2022
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Ingår i: Psykoser och andra psykosliknande tillstånd. - Stockholm : Läkartidningen Förlag AB. - 9789198509830 ; , s. 86-93
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 8. |
- Baqué, Mickael, et al.
(författare)
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Biosignature stability in space enables their use for life detection on Mars
- 2022
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Ingår i: Science Advances. - : NLM (Medline). - 2375-2548. ; 8:36
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Tidskriftsartikel (refereegranskat)abstract
- Two rover missions to Mars aim to detect biomolecules as a sign of extinct or extant life with, among other instruments, Raman spectrometers. However, there are many unknowns about the stability of Raman-detectable biomolecules in the martian environment, clouding the interpretation of the results. To quantify Raman-detectable biomolecule stability, we exposed seven biomolecules for 469 days to a simulated martian environment outside the International Space Station. Ultraviolet radiation (UVR) strongly changed the Raman spectra signals, but only minor change was observed when samples were shielded from UVR. These findings provide support for Mars mission operations searching for biosignatures in the subsurface. This experiment demonstrates the detectability of biomolecules by Raman spectroscopy in Mars regolith analogs after space exposure and lays the groundwork for a consolidated space-proven database of spectroscopy biosignatures in targeted environments.
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| 9. |
- Beyler, Maryline, et al.
(författare)
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Pentacoordinate iron complexes as functional models of the distal iron in [FeFe] hydrogenases
- 2011
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Ingår i: Chemical Communications. - : Royal Society of Chemistry (RSC). - 1359-7345 .- 1364-548X. ; 47:42, s. 11662-11664
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Tidskriftsartikel (refereegranskat)abstract
- Mononuclear pentacoordinate iron complexes with a free coordination site were prepared as mimics of the distal Fe (Fe(d)) in the active site of [FeFe] hydrogenases. The complexes catalyze the electrochemical reduction of protons at mild overpotential.
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| 10. |
- Forssén, B., et al.
(författare)
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Lithium use among psychiatric patients – a risk factor for hypernatremia?
- 2018
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Ingår i: Journal of Psychosomatic Research. - : Elsevier. - 0022-3999 .- 1879-1360. ; 109, s. 103-103
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Aims: Hypernatremia is a serious condition that can potentially become life threatening. It is known, but not well-studied, that lithium can induce nephrogenic diabetes insipidus and thereby increase the risk for hypernatremia. In this study, we tested the hypothesis that lithium was a risk factor for hypernatremia in patients with severe affective disorders. Methods: A retrospective study of hypernatremia episodes in all patients aged 18 years or over in the county of Norrbotten who received treatment with lithium or any other mood stabilizing medication during 1997-2013. We identified all episodes of hypernatremia during this period and compared the patients using lithium with those who did not. Results: We identified a total of 204 hypernatremia episodes in 185 patients. For all the 204 episodes, infection (37%) was the dominating cause. Harmful use of substances including alcohol came second. Lithium was only identified as a cause for hypernatremia in 1 % of all the episodes. In patients aged 65 years or less, harmful use of substances including alcohol was the most common cause. Infection was the dominating cause in patients >65 years. There was no significant difference in hypernatremia episodes between lithium users and non-lithium users. Patients who had suffered episodes of hyponatremia or died of these were significantly older. Conclusion: Lithium does not increase the risk of hypernatremia in patients with severe affective disorder compared to patients who do not use lithium. However, in some patients using lithium, severe episodes of hypernatremia can still occur. Thus, clinicians need to remain vigilant. There is a need for more research concerning other risk factors that may contribute to hypernatremia in patients with severe affective disorder.
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