| 1. |
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| 2. |
- Aprile, E., et al.
(author)
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Material radiopurity control in the XENONnT experiment
- 2022
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In: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 82:7
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Journal article (peer-reviewed)abstract
- The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and 222Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background (∼∼17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected 222Rn activity concentration in XENONnT is determined to be 4.2 (+0.5−0.7) μBq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.
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| 3. |
- Carmona-Gutierrez, D., et al.
(author)
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Guidelines and recommendations on yeast cell death nomenclature
- 2018
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In: Microbial Cell. - : Shared Science Publishers OG. - 2311-2638. ; 5:1, s. 4-31
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Research review (peer-reviewed)abstract
- Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cellular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the definition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death routines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the authors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the progress of this vibrant field of research.
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| 4. |
- Neumann, J. T., et al.
(author)
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Application of High-Sensitivity Troponin in Suspected Myocardial Infarction
- 2019
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In: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406. ; 380:26, s. 2529-2540
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Journal article (peer-reviewed)abstract
- BackgroundData regarding high-sensitivity troponin concentrations in patients presenting to the emergency department with symptoms suggestive of myocardial infarction may be useful in determining the probability of myocardial infarction and subsequent 30-day outcomes. MethodsIn 15 international cohorts of patients presenting to the emergency department with symptoms suggestive of myocardial infarction, we determined the concentrations of high-sensitivity troponin I or high-sensitivity troponin T at presentation and after early or late serial sampling. The diagnostic and prognostic performance of multiple high-sensitivity troponin cutoff combinations was assessed with the use of a derivation-validation design. A risk-assessment tool that was based on these data was developed to estimate the risk of index myocardial infarction and of subsequent myocardial infarction or death at 30 days. ResultsAmong 22,651 patients (9604 in the derivation data set and 13,047 in the validation data set), the prevalence of myocardial infarction was 15.3%. Lower high-sensitivity troponin concentrations at presentation and smaller absolute changes during serial sampling were associated with a lower likelihood of myocardial infarction and a lower short-term risk of cardiovascular events. For example, high-sensitivity troponin I concentrations of less than 6 ng per liter and an absolute change of less than 4 ng per liter after 45 to 120 minutes (early serial sampling) resulted in a negative predictive value of 99.5% for myocardial infarction, with an associated 30-day risk of subsequent myocardial infarction or death of 0.2%; a total of 56.5% of the patients would be classified as being at low risk. These findings were confirmed in an external validation data set. ConclusionsA risk-assessment tool, which we developed to integrate the high-sensitivity troponin I or troponin T concentration at emergency department presentation, its dynamic change during serial sampling, and the time between the obtaining of samples, was used to estimate the probability of myocardial infarction on emergency department presentation and 30-day outcomes.
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| 5. |
- Hinrichsen, F., et al.
(author)
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Microbial regulation of hexokinase 2 links mitochondrial metabolism and cell death in colitis
- 2021
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In: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 33:12
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Journal article (peer-reviewed)abstract
- Hexokinases (HK) catalyze the first step of glycolysis limiting its pace. HK2 is highly expressed in gut epithelium, contributes to immune responses, and is upregulated during inflammation. We examined the microbial regulation of HK2 and its impact on inflammation using mice lacking HK2 in intestinal epithelial cells (Hk2(Delta IEC)). Hk2(Delta IEC) mice were less susceptible to acute colitis. Analyzing the epithelial transcriptome from Hk2(Delta IEC) mice during colitis and using HK2-deficient intestinal organoids and Caco-2 cells revealed reduced mitochondrial respiration and epithelial cell death in the absence of HK2. The microbiota strongly regulated HK2 expression and activity. The microbially derived short-chain fatty acid (SCFA) butyrate repressed HK2 expression via histone deacetylase 8 (HDAC8) and reduced mitochondrial respiration in wild-type but not in HK2-deficient Caco-2 cells. Butyrate supplementation protected wild-type but not Hk2(Delta IEC) mice from colitis. Our findings define a mechanism how butyrate promotes intestinal homeostasis and suggest targeted HK2-inhibition as therapeutic avenue for inflammation.
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| 6. |
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| 7. |
- Chadburn, Sarah E., et al.
(author)
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Modeled Microbial Dynamics Explain the Apparent Temperature Sensitivity of Wetland Methane Emissions
- 2020
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In: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 34:11
-
Journal article (peer-reviewed)abstract
- Methane emissions from natural wetlands tend to increase with temperature and therefore may lead to a positive feedback under future climate change. However, their temperature response includes confounding factors and appears to differ on different time scales. Observed methane emissions depend strongly on temperature on a seasonal basis, but if the annual mean emissions are compared between sites, there is only a small temperature effect. We hypothesize that microbial dynamics are a major driver of the seasonal cycle and that they can explain this apparent discrepancy. We introduce a relatively simple model of methanogenic growth and dormancy into a wetland methane scheme that is used in an Earth system model. We show that this addition is sufficient to reproduce the observed seasonal dynamics of methane emissions in fully saturated wetland sites, at the same time as reproducing the annual mean emissions. We find that a more complex scheme used in recent Earth system models does not add predictive power. The sites used span a range of climatic conditions, with the majority in high latitudes. The difference in apparent temperature sensitivity seasonally versus spatially cannot be recreated by the non-microbial schemes tested. We therefore conclude that microbial dynamics are a strong candidate to be driving the seasonal cycle of wetland methane emissions. We quantify longer-term temperature sensitivity using this scheme and show that it gives approximately a 12% increase in emissions per degree of warming globally. This is in addition to any hydrological changes, which could also impact future methane emissions.
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| 8. |
- Peterziel, H, et al.
(author)
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Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM
- 2022
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In: NPJ precision oncology. - : Springer Science and Business Media LLC. - 2397-768X. ; 6:1, s. 94-
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Journal article (peer-reviewed)abstract
- The international precision oncology program INFORM enrolls relapsed/refractory pediatric cancer patients for comprehensive molecular analysis. We report a two-year pilot study implementing ex vivo drug sensitivity profiling (DSP) using a library of 75–78 clinically relevant drugs. We included 132 viable tumor samples from 35 pediatric oncology centers in seven countries. DSP was conducted on multicellular fresh tumor tissue spheroid cultures in 384-well plates with an overall mean processing time of three weeks. In 89 cases (67%), sufficient viable tissue was received; 69 (78%) passed internal quality controls. The DSP results matched the identified molecular targets, including BRAF, ALK, MET, and TP53 status. Drug vulnerabilities were identified in 80% of cases lacking actionable (very) high-evidence molecular events, adding value to the molecular data. Striking parallels between clinical courses and the DSP results were observed in selected patients. Overall, DSP in clinical real-time is feasible in international multicenter precision oncology programs.
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| 9. |
- Qiu, Chunjing, et al.
(author)
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A strong mitigation scenario maintains climate neutrality of northern peatlands
- 2022
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In: One Earth. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 5:1, s. 86-97
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Journal article (peer-reviewed)abstract
- Northern peatlands store 300–600 Pg C, of which approximately half are underlain by permafrost. Climate warming and, in some regions, soil drying from enhanced evaporation are progressively threatening this large carbon stock. Here, we assess future CO2 and CH4 fluxes from northern peatlands using five land surface models that explicitly include representation of peatland processes. Under Representative Concentration Pathways (RCP) 2.6, northern peatlands are projected to remain a net sink of CO2 and climate neutral for the next three centuries. A shift to a net CO2 source and a substantial increase in CH4 emissions are projected under RCP8.5, which could exacerbate global warming by 0.21°C (range, 0.09–0.49°C) by the year 2300. The true warming impact of peatlands might be higher owing to processes not simulated by the models and direct anthropogenic disturbance. Our study highlights the importance of understanding how future warming might trigger high carbon losses from northern peatlands.
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| 10. |
- Vuholm, S., et al.
(author)
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Whole-grain rye and wheat affect some markers of gut health without altering the fecal microbiota in healthy overweight adults: A 6-week randomized trial
- 2017
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In: Journal of Nutrition. - : Elsevier BV. - 1541-6100 .- 0022-3166. ; 147:11, s. 2067-2075
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Journal article (peer-reviewed)abstract
- Whole grains have shown potential for improving gut health, but evidence comparing different whole-grain types is lacking. Objective:We investigated whether whole-grain wheat (WGW) and whole-grain rye (WGR) improve gut health in different ways compared to refined wheat (RW), with the primary outcomes of microbiota composition and gastrointestinal (GI) symptoms. Methods: In a randomized parallel trial, 70 healthy adults (in means ± SDs; aged 51.0 ± 9.4 y, body mass index [BMI (in kg/m2)] 27.8 ± 1.9, 32:38 men:women) replaced cereal foods from their habitual diet with WGR, WGW, or RW (control). Before and after a 6-wk intervention, a spot stool sample was collected and analyzed for short-chain fatty acids and microbiota composition through the use of 16S ribosomal RNA gene-targeted high-throughput amplicon sequencing. GI symptoms and stool regularity were evaluated by questionnaires at baseline and after weeks 2, 4, and 6. Results: Intakes of whole grains were 145.2 ± 75.9, 124.2 ± 57.3, and 5.4 ± 3.2 g/d in the WGW, WGR, and RW groups, respectively. Gut microbiota composition was not affected by diet. The relative change in fecal butyrate decreased in the RW (238%) group compared to the WGW (25%, P = 0.014) and WGR groups (21%, P = 0.037). Other short-chain fatty acids were unaffected. Flatulence was more frequent following intake of WGW (OR: 2.06, 95% CI: 1.03, 4.17) and WGR (OR: 2.62, 95% CI: 1.35, 5.22) compared to RW, whereas bloating was less frequent following WGW (OR: 0.38, 95% CI: 0.18, 0.80) and WGR (OR: 0.34, 95% CI: 0.16, 0.72). Stool frequency increased following WGR but not WGW, compared to RW in weeks 2 (0.4 defecations/d, P = 0.049) and 4 (0.5 defecations/d, P = 0.043), but not in week 6. The WGW and WGR groups did not differ from each other in any of the variables tested. Conclusion: Regular consumption ofWGR andWGWaffected fecal butyrate concentration and gastrointestinal symptoms in healthy overweight adults, supporting the hypothesis thatWGR andWGWcan be included in the diet equally tomaintain gut health.
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| 11. |
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| 12. |
- Chadburn, S. E., et al.
(author)
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An observation-based constraint on permafrost loss as a function of global warming
- 2017
-
In: Nature Climate Change. - 1758-678X .- 1758-6798. ; 7:5, s. 340-344
-
Journal article (peer-reviewed)abstract
- Permafrost, which covers 15 million km(2) of the land surface, is one of the components of the Earth system that is most sensitive to warming(1,2). Loss of permafrost would radically change high-latitude hydrology and biogeochemical cycling, and could therefore provide very significant feedbacks on climate change(3-8). The latest climate models all predict warming of high-latitude soils and thus thawing of permafrost under future climate change, but with widely varying magnitudes of permafrost thaw(9,10). Here we show that in each of the models, their present-day spatial distribution of permafrost and air temperature can be used to infer the sensitivity of permafrost to future global warming. Using the same approach for the observed permafrost distribution and air temperature, we estimate a sensitivity of permafrost area loss to global mean warming at stabilization of 4.0(-1.1)(+1.0) million km(2) degrees C-1 (1 sigma confidence), which is around 20% higher than previous studies(9). Our method facilitates an assessment for COP21 climate change targets(11): if the climate is stabilized at 2 degrees C above pre-industrial levels, we estimate that the permafrost area would eventually be reduced by over 40%. Stabilizing at 1.5 degrees C rather than 2 degrees C would save approximately 2 million km(2) of permafrost.
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| 13. |
- Chadburn, Sarah E., et al.
(author)
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Carbon stocks and fluxes in the high latitudes : using site-level data to evaluate Earth system models
- 2017
-
In: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 14:22, s. 5143-5169
-
Journal article (peer-reviewed)abstract
- It is important that climate models can accurately simulate the terrestrial carbon cycle in the Arctic due to the large and potentially labile carbon stocks found in permafrost-affected environments, which can lead to a positive climate feedback, along with the possibility of future carbon sinks from northward expansion of vegetation under climate warming. Here we evaluate the simulation of tundra carbon stocks and fluxes in three land surface schemes that each form part of major Earth system models (JSBACH, Germany; JULES, UK; ORCHIDEE, France). We use a site-level approach in which comprehensive, high-frequency datasets allow us to disentangle the importance of different processes. The models have improved physical permafrost processes and there is a reasonable correspondence between the simulated and measured physical variables, including soil temperature, soil moisture and snow. We show that if the models simulate the correct leaf area index (LAI), the standard C3 photosynthesis schemes produce the correct order of magnitude of carbon fluxes. Therefore, simulating the correct LAI is one of the first priorities. LAI depends quite strongly on climatic variables alone, as we see by the fact that the dynamic vegetation model can simulate most of the differences in LAI between sites, based almost entirely on climate inputs. However, we also identify an influence from nutrient limitation as the LAI becomes too large at some of the more nutrient-limited sites. We conclude that including moss as well as vascular plants is of primary importance to the carbon budget, as moss contributes a large fraction to the seasonal CO2 flux in nutrient-limited conditions. Moss photosynthetic activity can be strongly influenced by the moisture content of moss, and the carbon uptake can be significantly different from vascular plants with a similar LAI. The soil carbon stocks depend strongly on the rate of input of carbon from the vegetation to the soil, and our analysis suggests that an improved simulation of photosynthesis would also lead to an improved simulation of soil carbon stocks. However, the stocks are also influenced by soil carbon burial (e.g. through cryoturbation) and the rate of heterotrophic respiration, which depends on the soil physical state. More detailed below-ground measurements are needed to fully evaluate biological and physical soil processes. Furthermore, even if these processes are well modelled, the soil carbon profiles cannot resemble peat layers as peat accumulation processes are not represented in the models. Thus, we identify three priority areas for model development: (1) dynamic vegetation including (a) climate and (b) nutrient limitation effects; (2) adding moss as a plant functional type; and an (3) improved vertical profile of soil carbon including peat processes.
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| 14. |
- Claeys, Shana, et al.
(author)
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ALK positively regulates MYCN activity through repression of HBP1 expression
- 2019
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:15, s. 2690-2705
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Journal article (peer-reviewed)abstract
- ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI3K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI3K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
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| 15. |
- Haller, Paul M., et al.
(author)
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Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus
- 2023
-
In: European Journal of Preventive Cardiology. - 2047-4873 .- 2047-4881. ; 30:12, s. 1218-1226
-
Journal article (peer-reviewed)abstract
- AIMS: The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes. 'METHODS AND RESULTS: We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan-Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P < 0.001), accompanied by an increase in the c-index (increase to 0.81).CONCLUSION: Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.
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| 16. |
- Hirose, Misa, et al.
(author)
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Enzymatic autoantibody glycan hydrolysis alleviates autoimmunity against type VII collagen
- 2012
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In: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 39:4, s. 304-314
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Journal article (peer-reviewed)abstract
- Autoantibody-mediated diseases comprise a heterogeneous group of disorders in which the pathogenic potential of autoantibodies has been clearly demonstrated. In general, their treatment relies on the long-term use of systemic corticosteroids and other immunosuppressants that are associated with considerable adverse reactions. EndoS, an endoglycosidase derived from Streptococcus pyogenes, specifically hydrolyzes the N-linked glycan of native IgG and has previously been shown to modulate the interaction between the Fc portion of autoantibody and Fc gamma receptors on leukocytes. Here, different models of autoimmunity to type VII collagen, a structural protein of the dermal-epidermal junction (DEJ), were employed to explore the therapeutic potential of EndoS. First, pretreatment of otherwise pathogenic anti-murine type VII collagen (mCOL7) IgG with EndoS significantly reduced split formation at the DEJ in cryosections of murine skin and abrogated clinical disease in mice. Next, the effect of EndoS was also seen when the enzyme was injected into mice after pathogenic anti-mCOL7 IgG had been administered. Finally, to mimic the patient situation even closer, EndoS was applied in mice that had already developed clinical disease after immunization with mCOL7. In all EndoS-treated mice, disease progression was stopped, and in the majority of mice, clinical disease even regressed. Of note, EndoS was shown to hydrolyze already in vivo-bound pathogenic autoantibodies. In addition, EndoS treatment decreased lesional expression of activating Fc gamma Rs while increasing Fc gamma RIIB expression. (C) 2012 Elsevier Ltd. All rights reserved.
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| 17. |
- Khan, J, et al.
(author)
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Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks
- 2001
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 7:6, s. 673-679
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Journal article (peer-reviewed)abstract
- The purpose of this study was to develop a method of classifying cancers to specific diagnosticcategories based on their gene expression signatures using artificial neural networks (ANNs).We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancersbelong to four distinct diagnostic categories and often present diagnostic dilemmas in clinicalpractice. The ANNs correctly classified all samples and identified the genes most relevant to theclassification. Expression of several of these genes has been reported in SRBCTs, but most havenot been associated with these cancers. To test the ability of the trained ANN models to recognizeSRBCTs, we analyzed additional blinded samples that were not previously used for the trainingprocedure, and correctly classified them in all cases. This study demonstrates the potentialapplications of these methods for tumor diagnosis and the identification of candidate targets fortherapy.
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| 18. |
- M Del Campo, J, et al.
(author)
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Phase II randomized study of trabectedin given as two different every 3 weeks dose schedules (1.5 mg/m(2) 24 h or 1.3 mg/m(2) 3 h) to patients with relapsed, platinum-sensitive, advanced ovarian cancer
- 2009
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In: ANNALS OF ONCOLOGY. - : Elsevier BV. - 0923-7534. ; 20:11, s. 1794-802
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Journal article (peer-reviewed)abstract
- Patients and methods: Patients previously treated with less than two or two previous chemotherapy lines were randomized to receive trabectedin 1.5 mg/m(2) 24 h (arm A, n = 54) or 1.3 mg/m(2) 3 h (arm B, n = 53). Objective response rate (ORR) per RECIST was the primary efficacy end point. Toxic effects were graded according to the National Cancer Institute-Common Toxicity Criteria v. 2.0. Results: ORR was 38.9% [95% confidence interval (CI) 25.9% to 53.1%; arm A] and 35.8% (95% CI 23.1% to 50.2%; arm B) (intention-to-treat primary analysis). Median time to progression was 6.2 months (95% CI 5.3-8.6 months; arm A) and 6.8 months (95% CI 4.6-7.4 months; arm B). Frequent severe adverse events were nausea/vomiting (24%, arm A; 15%, arm B) and fatigue (15%, arm A; 10%, arm B). Common severe laboratory abnormalities were transient, noncumulative neutropenia (55%, arm A; 37%, arm B) and transaminase increases (alanine aminotransferase, 55%, arm A; 59%, arm B). Conclusions: Both every-3-weeks trabectedin regimes, 1.5 mg/m(2) 24 h and 1.3 mg/m(2) 3 h, were active and reasonably well tolerated in AOC platinum-sensitive patients. Trabectedin every-3-weeks has promising activity and deserves to be further evaluated in relapsed AOC.
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| 19. |
- Mueller, Anna A., et al.
(author)
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An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection
- 2016
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In: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:6
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Journal article (peer-reviewed)abstract
- Salmonella Typhimurium (S. Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S. Tm infections in knockout mice, cytokine inhibition and -injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf(-/-) ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S. Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
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| 20. |
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| 21. |
- Renette, Cas, et al.
(author)
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Simulating the effect of subsurface drainage on the thermal regime and ground ice in blocky terrain in Norway
- 2023
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In: Earth Surface Dynamics. - : Copernicus GmbH. - 2196-6311 .- 2196-632X. ; 11:1, s. 33-50
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Journal article (peer-reviewed)abstract
- Ground temperatures in coarse, blocky deposits such as mountain blockfields and rock glaciers have long been observed to be lower in comparison with other (sub)surface material. One of the reasons for this negative temperature anomaly is the lower soil moisture content in blocky terrain, which decreases the duration of the zero curtain in autumn. Here we used the CryoGrid community model to simulate the effect of drainage on the ground thermal regime and ground ice in blocky terrain permafrost at two sites in Norway. The model set-up is based on a one-dimensional model domain and features a surface energy balance, heat conduction and advection, as well as a bucket water scheme with adjustable lateral drainage. We used three idealized subsurface stratigraphies, blocks only, blocks with sediment and sediment only, which can be either drained (i.e. with strong lateral subsurface drainage) or undrained (i.e. without drainage), resulting in six scenarios. The main difference between the three stratigraphies is their ability to retain water against drainage: while the blocks only stratigraphy can only hold small amounts of water, much more water is retained within the sediment phase of the two other stratigraphies, which critically modifies the freeze-thaw behaviour. The simulation results show markedly lower ground temperatures in the blocks only, drained scenario compared to other scenarios, with a negative thermal anomaly of up to 2.2 degrees C. For this scenario, the model can in particular simulate the time evolution of ground ice, with build-up during and after snowmelt and spring and gradual lowering of the ice table in the course of the summer season. The thermal anomaly increases with larger amounts of snowfall, showing that well-drained blocky deposits are less sensitive to insulation by snow than other soils. We simulate stable permafrost conditions at the location of a rock glacier in northern Norway with a mean annual ground surface temperature of 2.0-2.5 degrees C in the blocks only, drained simulations. Finally, transient simulations since 1951 at the rock glacier site (starting with permafrost conditions for all stratigraphies) showed a complete loss of perennial ground ice in the upper 5 m of the ground in the blocks with sediment, drained run; a 1.6 m lowering of the ground ice table in the sediment only, drained run; and only 0.1 m lowering in the blocks only, drained run. The interplay between the subsurface water-ice balance and ground freezing/thawing driven by heat conduction can at least partly explain the occurrence of permafrost in coarse blocky terrain below the elevational limit of permafrost in non-blocky sediments. It is thus important to consider the subsurface water-ice balance in blocky terrain in future efforts in permafrost distribution mapping in mountainous areas. Furthermore, an accurate prediction of the evolution of the ground ice table in a future climate can have implications for slope stability, as well as water resources in arid environments.
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| 22. |
- Sayedi, Sayedeh Sara, et al.
(author)
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Subsea permafrost carbon stocks and climate change sensitivity estimated by expert assessment
- 2020
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In: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 15:12
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Journal article (peer-reviewed)abstract
- The continental shelves of the Arctic Ocean and surrounding seas contain large stocks of organic matter (OM) and methane (CH4), representing a potential ecosystem feedback to climate change not included in international climate agreements. We performed a structured expert assessment with 25 permafrost researchers to combine quantitative estimates of the stocks and sensitivity of organic carbon in the subsea permafrost domain (i.e. unglaciated portions of the continental shelves exposed during the last glacial period). Experts estimated that the subsea permafrost domain contains similar to 560 gigatons carbon (GtC; 170-740, 90% confidence interval) in OM and 45 GtC (10-110) in CH4. Current fluxes of CH4 and carbon dioxide (CO2) to the water column were estimated at 18 (2-34) and 38 (13-110) megatons C yr(-1), respectively. Under Representative Concentration Pathway (RCP) RCP8.5, the subsea permafrost domain could release 43 Gt CO2-equivalent (CO(2)e) by 2100 (14-110) and 190 Gt CO(2)e by 2300 (45-590), with similar to 30% fewer emissions under RCP2.6. The range of uncertainty demonstrates a serious knowledge gap but provides initial estimates of the magnitude and timing of the subsea permafrost climate feedback.
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| 23. |
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| 24. |
- Vuori, Matti A., et al.
(author)
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Diabetes status-related differences in risk factors and mediators of heart failure in the general population : results from the MORGAM/BiomarCaRE consortium
- 2021
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In: Cardiovascular Diabetology. - : BioMed Central. - 1475-2840. ; 20:1
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Journal article (peer-reviewed)abstract
- Background: The risk of heart failure among diabetic individuals is high, even under tight glycemic control. The correlates and mediators of heart failure risk in individuals with diabetes need more elucidation in large population-based cohorts with long follow-up times and a wide panel of biologically relevant biomarkers.Methods: In a population-based sample of 3834 diabetic and 90,177 non-diabetic individuals, proportional hazards models and mediation analysis were used to assess the relation of conventional heart failure risk factors and biomarkers with incident heart failure.Results: Over a median follow-up of 13.8 years, a total of 652 (17.0%) and 5524 (6.1%) cases of incident heart failure were observed in participants with and without diabetes, respectively. 51.4% were women and the mean age at baseline was 48.7 (standard deviation [SD] 12.5) years. The multivariable-adjusted hazard ratio (HR) for heart failure among diabetic individuals was 2.70 (95% confidence interval, 2.49–2.93) compared to non-diabetic participants. In the multivariable-adjusted Cox models, conventional cardiovascular disease risk factors, such as smoking (diabetes: HR 2.07 [1.59–2.69]; non-diabetes: HR 1.85 [1.68–2.02]), BMI (diabetes: HR 1.30 [1.18–1.42]; non-diabetes: HR 1.40 [1.35–1.47]), baseline myocardial infarction (diabetes: HR 2.06 [1.55–2.75]; non-diabetes: HR 2.86 [2.50–3.28]), and baseline atrial fibrillation (diabetes: HR 1.51 [0.82–2.80]; non-diabetes: HR 2.97 [2.21–4.00]) had the strongest associations with incident heart failure. In addition, biomarkers for cardiac strain (represented by nT-proBNP, diabetes: HR 1.26 [1.19–1.34]; non-diabetes: HR 1.43 [1.39–1.47]), myocardial injury (hs-TnI, diabetes: HR 1.10 [1.04–1.16]; non-diabetes: HR 1.13 [1.10–1.16]), and inflammation (hs-CRP, diabetes: HR 1.13 [1.03–1.24]; non-diabetes: HR 1.29 [1.25–1.34]) were also associated with incident heart failure. In general, all these associations were equally strong in non-diabetic and diabetic individuals. However, the strongest mediators of heart failure in diabetes were the direct effect of diabetes status itself (relative effect share 43.1% [33.9–52.3] and indirect effects (effect share 56.9% [47.7-66.1]) mediated by obesity (BMI, 13.2% [10.3–16.2]), cardiac strain/volume overload (nT-proBNP, 8.4% [-0.7–17.4]), and hyperglycemia (glucose, 12.0% [4.2–19.9]).Conclusions: The findings suggest that the main mediators of heart failure in diabetes are obesity, hyperglycemia, and cardiac strain/volume overload. Conventional cardiovascular risk factors are strongly related to incident heart failure, but these associations are not stronger in diabetic than in non-diabetic individuals. Active measurement of relevant biomarkers could potentially be used to improve prevention and prediction of heart failure in high-risk diabetic patients.
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- Westermann, Alexander J., et al.
(author)
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The Major RNA-Binding Protein ProQ Impacts Virulence Gene Expression in Salmonella enterica Serovar Typhimurium
- 2019
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In: mBio. - : American Society for Microbiology. - 2161-2129 .- 2150-7511. ; 10:1
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Journal article (peer-reviewed)abstract
- FinO domain proteins such as ProQ of the model pathogen Salmonella enterica have emerged as a new class of major RNA-binding proteins in bacteria. ProQ has been shown to target hundreds of transcripts, including mRNAs from many virulence regions, but its role, if any, in bacterial pathogenesis has not been studied. Here, using a Dual RNA-seq approach to profile ProQ-dependent gene expression changes as Salmonella infects human cells, we reveal dysregulation of bacterial motility, chemotaxis, and virulence genes which is accompanied by altered MAPK (mitogen-activated protein kinase) signaling in the host. Comparison with the other major RNA chaperone in Salmonella, Hfq, reinforces the notion that these two global RNA-binding proteins work in parallel to ensure full virulence. Of newly discovered infection-associated ProQ-bound small noncoding RNAs (sRNAs), we show that the 3′UTR-derived sRNA STnc540 is capable of repressing an infection-induced magnesium transporter mRNA in a ProQ-dependent manner. Together, this comprehensive study uncovers the relevance of ProQ for Salmonella pathogenesis and highlights the importance of RNA-binding proteins in regulating bacterial virulence programs.IMPORTANCE The protein ProQ has recently been discovered as the centerpiece of a previously overlooked “third domain” of small RNA-mediated control of gene expression in bacteria. As in vitro work continues to reveal molecular mechanisms, it is also important to understand how ProQ affects the life cycle of bacterial pathogens as these pathogens infect eukaryotic cells. Here, we have determined how ProQ shapes Salmonella virulence and how the activities of this RNA-binding protein compare with those of Hfq, another central protein in RNA-based gene regulation in this and other bacteria. To this end, we apply global transcriptomics of pathogen and host cells during infection. In doing so, we reveal ProQ-dependent transcript changes in key virulence and host immune pathways. Moreover, we differentiate the roles of ProQ from those of Hfq during infection, for both coding and noncoding transcripts, and provide an important resource for those interested in ProQ-dependent small RNAs in enteric bacteria.
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