| 1. |
- Breitfeld, Jana, et al.
(författare)
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Genetic dissection of serum vaspin highlights its causal role in lipid metabolism
- 2023
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Ingår i: Obesity. - 1930-7381. ; 31:11, s. 2862-2874
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. Methods: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. Results: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10−8, explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. Conclusions: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.
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| 2. |
- Anton, Arthur Markus, et al.
(författare)
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Hydrogen bonding and charge transport in a protic polymerized ionic liquid
- 2020
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-683X .- 1744-6848. ; 16:26, s. 6091-6101
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Tidskriftsartikel (refereegranskat)abstract
- Hydrogen bonding and charge transport in the protic polymerized ionic liquid poly[tris(2-(2-methoxyethoxy)ethyl)ammoniumacryloxypropyl sulfonate] (PAAPS) are studied by combining Fourier transform infrared (FTIR) and broadband dielectric spectroscopy (BDS) in a wide temperature range from 170 to 300 K. While the former enables to determine precisely the formation of hydrogen bonds and other moiety-specific quantized vibrational states, the latter allows for recording the complex conductivity in a spectral range from 10(-2)to 10(+9) Hz. A pronounced thermal hysteresis is observed for the H-bond network formation in distinct contrast to the reversibility of the effective conductivity measured by BDS. On the basis of this finding and the fact that the conductivity changes with temperature by orders of magnitude, whereas the integrated absorbance of the N-H stretching vibration (being proportional to the number density of protons in the hydrogen bond network) changes only by a factor of 4, it is concluded that charge transport takes place predominantly due to hopping conduction assisted by glassy dynamics (dynamic glass transition assisted hopping) and is not significantly affected by the establishment of H-bonds.
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| 3. |
- Apweiler, Rolf, et al.
(författare)
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Approaching clinical proteomics : current state and future fields of application in cellular proteomics
- 2009
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Ingår i: Cytometry. Part A : the journal of the International Society for Analytical Cytology. - : Wiley. - 1552-4922. ; 75A:10, s. 816-832
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Forskningsöversikt (refereegranskat)abstract
- Recent developments in proteomics technology offer new opportunities for clinical applications in hospital or specialized laboratories including the identification of novel biomarkers, monitoring of disease, detecting adverse effects of drugs, and environmental hazards. Advanced spectrometry technologies and the development of new protein array formats have brought these analyses to a standard, which now has the potential to be used in clinical diagnostics. Besides standardization of methodologies and distribution of proteomic data into public databases, the nature of the human body fluid proteome with its high dynamic range in protein concentrations, its quantitation problems, and its extreme complexity present enormous challenges. Molecular cell biology (cytomics) with its link to proteomics is a new fast moving scientific field, which addresses functional cell analysis and bioinformatic approaches to search for novel cellular proteomic biomarkers or their release products into body fluids that provide better insight into the enormous biocomplexity of disease processes and are suitable for patient stratification, therapeutic monitoring, and prediction of prognosis. Experience from studies of in vitro diagnostics and especially in clinical chemistry showed that the majority of errors occurs in the preanalytical phase and the setup of the diagnostic strategy. This is also true for clinical proteomics where similar preanalytical variables such as inter- and intra-assay variability due to biological variations or proteolytical activities in the sample will most likely also influence the results of proteomics studies. However, before complex proteomic analysis can be introduced at a broader level into the clinic, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement, and data analysis is another issue which has to be improved. In this report, we discuss the recent advances and applications that fulfill the criteria for clinical proteomics with the focus on cellular proteomics (cytoproteomics) as related to preanalytical and analytical standardization and to quality control measures required for effective implementation of these technologies and analytes into routine laboratory testing to generate novel actionable health information. It will then be crucial to design and carry out clinical studies that can eventually identify novel clinical diagnostic strategies based on these techniques and validate their impact on clinical decision making.
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| 4. |
- Apweiler, Rolf, et al.
(författare)
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Approaching clinical proteomics : current state and future fields of application in fluid proteomics
- 2009
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Ingår i: Clinical Chemistry and Laboratory Medicine. - 1434-6621 .- 1437-4331. ; 47:6, s. 724-744
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Forskningsöversikt (refereegranskat)abstract
- The field of clinical proteomics offers opportunities to identify new disease biomarkers in body fluids, cells and tissues. These biomarkers can be used in clinical applications for diagnosis, stratification of patients for specific treatment, or therapy monitoring. New protein array formats and improved spectrometry technologies have brought these analyses to a level with potential for use in clinical diagnostics. The nature of the human body fluid proteome with its large dynamic range of protein concentrations presents problems with quantitation. The extreme complexity of the proteome in body fluids presents enormous challenges and requires the establishment of standard operating procedures for handling of specimens, increasing sensitivity for detection and bioinformatical tools for distribution of proteomic data into the public domain. From studies of in vitro diagnostics, especially in clinical chemistry, it is evident that most errors occur in the preanalytical phase and during implementation of the diagnostic strategy. This is also true for clinical proteomics, and especially for fluid proteomics because of the multiple pretreatment processes. These processes include depletion of high-abundance proteins from plasma or enrichment processes for urine where biological variation or differences in proteolytic activities in the sample along with preanalytical variables such as inter- and intra-assay variability will likely influence the results of proteomics studies. However, before proteomic analysis can be introduced at a broader level into the clinical setting, standardization of the preanalytical phase including patient preparation, sample collection, sample preparation, sample storage, measurement and data analysis needs to be improved. In this review, we discuss the recent technological advances and applications that fulfil the criteria for clinical proteomics, with the focus on fluid proteomics. These advances relate to preanalytical factors, analytical standardization and quality-control measures required for effective implementation into routine laboratory testing in order to generate clinically useful information. With new disease biomarker candidates, it will be crucial to design and perform clinical studies that can identify novel diagnostic strategies based on these techniques, and to validate their impact on clinical decision-making.
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| 5. |
- Baber, Ashleigh E., et al.
(författare)
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Stabilization of Catalytically Active Cu plus Surface Sites on TitaniumCopper Mixed-Oxide Films**
- 2014
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Ingår i: Angewandte Chemie International Edition. - : Gesellschaft Deutscher Chemiker. - 1433-7851 .- 1521-3773. ; 53:21, s. 5336-5340
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Tidskriftsartikel (refereegranskat)abstract
- The oxidation of CO is the archetypal heterogeneous catalytic reaction and plays a central role in the advancement of fundamental studies, the control of automobile emissions, and industrial oxidation reactions. Copper-based catalysts were the first catalysts that were reported to enable the oxidation of CO at room temperature, but a lack of stability at the elevated reaction temperatures that are used in automobile catalytic converters, in particular the loss of the most reactive Cu+ cations, leads to their deactivation. Using a combined experimental and theoretical approach, it is shown how the incorporation of titanium cations in a Cu2O film leads to the formation of a stable mixed-metal oxide with a Cu+ terminated surface that is highly active for CO oxidation.
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| 6. |
- Björck, Markus, 1987-
(författare)
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Regulation of proton-coupled electron transfer in cytochrome c oxidase : The role of membrane potential, proton pathways and ATP
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cytochrome c oxidase (CytcO) is the final electron acceptor of the respiratory chain. In this chain a current of electrons, derived from degradation of nutrients, along with protons, are used to reduce oxygen to water. The reaction is exergonic and the excess energy is used to pump protons across the membrane. This proton-coupled electron transfer is regulated, for example, by the membrane potential, the composition of the membrane and the ATP/ADP concentrations. Here, we have investigated the mechanism of this regulation. Specifically, we investigated ligand binding to CytcO in mitochondria, which provides mechanistic information about CytcO in its native environment. In addition to CytcO, a water soluble protein, flavohemoglobin (yHb) was found to bind CO and we found that it is localized in the intermembrane space (IMS). We also extracted CytcO from mitochondria without detergent using the styrene maleic acid (SMA) co-polymer. We could show that the SMA-extracted CytcO behaved similarly in its reaction with O2 and CO as CytcO in mitochondria.In mitochondria and bacterial membranes CytcO transports charges against a transmembrane electrochemical gradient. We induced a membrane potential across sub-mitochondrial particles (SMPs) by addition of ATP and measured single CytcO turnover. Our results indicate that proton transfer, but not electron transfer, across the membrane is affected by the membrane potential.In yeast CytcO subunit Cox13 has been shown to play a role in ATP/ADP binding to regulate activity. We have solved the structure of Cox13 using NMR and identified the residues that constitute the ATP-binding site, which is located at the C-terminus.Finally we showed that the main proton-transfer pathways in yeast CytcO function similarly to their bacterial counterparts and that the proposed H-pathway, absent in bacteria, is not responsible for proton translocation in mitochondrial CytcO from S. cerevisiae.
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| 7. |
- Blochwitz, Torsten, et al.
(författare)
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Functional Mockup Interface 2.0: The Standard for Tool independent Exchange of Simulation Models
- 2012
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Ingår i: Proceedings of the 9th International Modelica Conference. - : Linköping University Electronic Press. - 9789175198262 ; , s. 173-184
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Konferensbidrag (refereegranskat)abstract
- The Functional Mockup Interface (FMI) is a tool independent standard for the exchange of dynamic models and for co simulation. The first version, FMI 1.0, was published in 2010. Already more than 30 tools support FMI 1.0. In this paper an overview about the recently published version 2.0 of FMI is given that combines the formerly separated interfaces for Model Exchange and Co-Simulation in one standard. Based on the experience on using FMI 1.0, many small details have been improved and new features ease the usability and increase the performance especially for larger models. Additionally, a free FMI compliance checker will become soon available and FMI models from different tools are made available on the web to simplify testing.
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| 8. |
- Dantonello, Tobias M, et al.
(författare)
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Challenges in the Local Treatment of Large Abdominal Embryonal Rhabdomyosarcoma
- 2014
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Ingår i: Annals of Surgical Oncology. - : Springer Science and Business Media LLC. - 1068-9265 .- 1534-4681. ; 21:11, s. 3579-3586
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Embryonal rhabdomyosarcoma is the most common pediatric soft tissue sarcoma. The best local treatment in large, nonmetastatic primary unresected nongenitourinary embryonal rhabdomyosarcoma of the abdomen (LARME) is however unclear.METHODS:We analyzed patients with LARME treated in four consecutive CWS trials. All diagnoses were confirmed by reference reviews. Treatment included multiagent chemotherapy and local treatment of the primary tumor with surgery and/or radiotherapy. The impact of primary debulking surgery (PDS) also was studied.RESULTS:One hundred patients <21 years with a median age of 4 years had LARME. Sixty-one of them had a tumor >10 cm in diameter at diagnosis. PDS was performed in 19 of 100 children. The outcomes of patients with PDS were similar to those of the other patients. In 36 children, the tumor was resected after induction chemotherapy; 60 RME were irradiated. The toxic effects of radiochemotherapy were not significantly increased compared with the nonirradiated patients. With a median follow-up of 10 years, the 5-year EFS and OS were 52 ± 10 and 65 ± 9 %, respectively. Significant risk factors in multivariate analysis were age >10 years; no achievement of complete remission; and inadequate secondary local treatment, defined as incomplete secondary resection or no radiation.CONCLUSIONS:Children with LARME have a fair prognosis, despite an often huge tumor size and unfavorable primary site, if the tumors can either be resected or irradiated following induction chemotherapy. PDS was only performed in a small subgroup. Radiation performed concomitantly with chemotherapy did not increase the acute toxicity significantly.
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| 9. |
- Diehl, Roland, et al.
(författare)
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Early Ni-56 decay gamma rays from SN2014J suggest an unusual explosion
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 345:6201, s. 1162-1165
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Tidskriftsartikel (refereegranskat)abstract
- Type Ia supernovae result from binary systems that include a carbon-oxygen white dwarf, and these thermonuclear explosions typically produce 0.5 solar mass of radioactive Ni-56. The Ni-56 is commonly believed to be buried deeply in the expanding supernova cloud. In SN2014J, we detected the lines at 158 and 812 kiloelectron volts from Ni-56 decay (time similar to 8.8 days) earlier than the expected several-week time scale, only similar to 20 days after the explosion and with flux levels corresponding to roughly 10% of the total expected amount of Ni-56. Some mechanism must break the spherical symmetry of the supernova and at the same time create a major amount of Ni-56 at the outskirts. A plausible explanation is that a belt of helium from the companion star is accreted by the white dwarf, where this material explodes and then triggers the supernova event.
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| 10. |
- Fehr, Andre, et al.
(författare)
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Mucoepidermoid carcinoma of the salivary glands revisited with special reference to histologic grading and CRTC1/3-MAML2 genotyping.
- 2021
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Ingår i: Virchows Archiv : an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 479
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Tidskriftsartikel (refereegranskat)abstract
- Mucoepidermoid carcinoma (MEC) is the most common carcinoma of the salivary glands. Here, we have used two large patient cohorts with MECs comprising 551 tumors to study clinical, histological, and molecular predictors of survival. One cohort (n = 167), with known CRCT1/3-MAML2 fusion status, was derived from the Hamburg Reference Centre (HRC; graded with the AFIP and Brandwein systems) and the other (n = 384) was derived from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW; graded with the AFIP system). The reliability of both the AFIP and Brandwein grading systems was excellent (n = 155). The weighted kappa for inter-rater agreement was 0.81 (95% CI 0.65-0.97) and 0.83 (95% CI 0.71-0.96) for the AFIP and Brandwein systems, respectively. The 5-year relative survival was 79.7% (95% CI 73.2-86.2%). Although the Brandwein system resulted in a higher rate of G3-MECs, survival in G3-tumors (AFIP or Brandwein grading) was markedly worse than in G1/G2-tumors. Survival in > T2 tumors was markedly worse than in those with lower T-stage. Also, fusion-negative MECs had a worse 5-year progression-free survival. The frequency of fusion-positive MECs in the HRC cohort was 78.4%, of which the majority (86.7%) was G1/G2-tumors. In conclusion, the AFIP and Brandwein systems are useful in estimating prognosis and to guide therapy for G3-MECs. However, their significance regarding young age (≤ 30 years) and location-dependent heterogeneity of in particular G2-tumors is more questionable. We conclude that CRTC1/3-MAML2 testing is a useful adjunct to histologic scoring of MECs and for pinpointing tumors with poor prognosis with higher precision, thus avoiding overtreatment.
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