| 1. |
- Schafmayer, Clemens, et al.
(författare)
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Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms
- 2019
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 68:5, s. 854-865
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Tidskriftsartikel (refereegranskat)abstract
- Objective Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. Design Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. Results We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p< 0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3x10-10 and 0.002 (OR allelic = 1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). Conclusion I n silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.
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| 2. |
- von Hanxleden, Reinhard, et al.
(författare)
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WCET Tool Challenge 2011: Report
- 2011
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Ingår i: Proc. 11th International Workshop on Worst-Case Execution Time (WCET) Analysis (WCET 2011). - 9781632663153 ; , s. 104-138
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Konferensbidrag (refereegranskat)abstract
- Following the successful WCET Tool Challenges in 2006 and 2008, the third event in this series was organized in 2011, again with support from the ARTIST DESIGN Network of Excellence. Following the practice established in the previous Challenges, the WCET Tool Challenge 2011 (WCC'11) defined two kinds of problems to be solved by the Challenge participants with their tools, WCET problems, which ask for bounds on the execution time, and flow-analysis problems, which ask for bounds on the number of times certain parts of the code can be executed. The benchmarks to be used in WCC'11 were debie1, PapaBench, and an industrial-strength application from the automotive domain provided by Daimler. Two default execution platforms were suggested to the participants, the ARM7 as "simple target" and the MPC5553/5554 as a "complex target", but participants were free to use other platforms as well. Ten tools participated in WCC'11: aiT, AstrEe, Bound-T, FORTAS, METAMOC, OTAWA, SWEET, TimeWeaver, TuBound and WCA.
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| 3. |
- Abelev, Betty, et al.
(författare)
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Underlying Event measurements in pp collisions at root s=0.9 and 7 TeV with the ALICE experiment at the LHC
- 2012
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Ingår i: Journal of High Energy Physics. - 1029-8479. ; :7
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Tidskriftsartikel (refereegranskat)abstract
- We present measurements of Underlying Event observables in pp collisions at root s = 0 : 9 and 7 TeV. The analysis is performed as a function of the highest charged-particle transverse momentum p(T),L-T in the event. Different regions are defined with respect to the azimuthal direction of the leading (highest transverse momentum) track: Toward, Transverse and Away. The Toward and Away regions collect the fragmentation products of the hardest partonic interaction. The Transverse region is expected to be most sensitive to the Underlying Event activity. The study is performed with charged particles above three different p(T) thresholds: 0.15, 0.5 and 1.0 GeV/c. In the Transverse region we observe an increase in the multiplicity of a factor 2-3 between the lower and higher collision energies, depending on the track p(T) threshold considered. Data are compared to PYTHIA 6.4, PYTHIA 8.1 and PHOJET. On average, all models considered underestimate the multiplicity and summed p(T) in the Transverse region by about 10-30%.
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| 4. |
- Adam, Meike, et al.
(författare)
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Functional Outcomes and Quality of Life After Radical Prostatectomy Only Versus a Combination of Prostatectomy with Radiation and Hormonal Therapy
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 71:3, s. 330-336
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Tidskriftsartikel (refereegranskat)abstract
- Background: While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy.Objective: To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP.Design, setting, and participants: Among 13 150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT.Outcome measurements and statistical analyses: Urinary function, sexual function, and overall QoL were evaluated annually using self-administered validated questionnaires. Propensity score-matched and bootstrap analyses were performed, and the distributions for all functional outcomes were analyzed as a function of time after RP.Results and limitations: Patients who received RP + RT had a 4% higher overall incontinence rate 3 yr after surgery, and 1% higher rate for severe incontinence (> 3 pads/24 h) compared to matched RP-only patients. ADT further increased the overall and severe incontinence rates by 4% and 3%, respectively, compared to matched RP + RT patients. RP + RT was associated with an 18% lower rate of potency compared to RP alone, while RP + RT + ADT was associated with a further 17% reduction compared to RP + RT. Additional RT reduced QoL by 10% and additional ADT by a further 12% compared to RP only and RP + RT, respectively. The timing of RT after RP had no influence on continence, but adjuvant compared to salvage RT was associated with significantly lower potency (37% vs 45%), but higher QoL (60% vs 56%). Limitations of our study include the observational study design and potential for selection bias in the treatments received.Conclusions: Secondary RT and ADT after RP have an additive negative influence on urinary function, potency, and QoL. Patients with high-risk disease should be counseled before RP on the potential net impairment of functional outcomes due to multimodal treatment.Patient summary: Men with high-risk disease choosing surgery upfront should be counseled on the potential need for additional radiation and or androgen deprivation, and the potential net impairment of functional outcomes arising from multimodal treatment.
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| 5. |
- Basiouni, Shereen, et al.
(författare)
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Anti-Inflammatory and Antioxidative Phytogenic Substances against Secret Killers in Poultry : Current Status and Prospects
- 2023
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Ingår i: Veterinary Sciences. - : MDPI. - 2306-7381. ; 10:1
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Forskningsöversikt (refereegranskat)abstract
- Chronic stress is recognized as a secret killer in poultry. It is associated with systemic inflammation due to cytokine release, dysbiosis, and the so-called leaky gut syndrome, which mainly results from oxidative stress reactions that damage the barrier function of the cells lining the gut wall. Poultry, especially the genetically selected broiler breeds, frequently suffer from these chronic stress symptoms when exposed to multiple stressors in their growing environments. Since oxidative stress reactions and inflammatory damages are multi-stage and long-term processes, overshooting immune reactions and their down-stream effects also negatively affect the animal’s microbiota, and finally impair its performance and commercial value. Means to counteract oxidative stress in poultry and other animals are, therefore, highly welcome. Many phytogenic substances, including flavonoids and phenolic compounds, are known to exert anti-inflammatory and antioxidant effects. In this review, firstly, the main stressors in poultry, such as heat stress, mycotoxins, dysbiosis and diets that contain oxidized lipids that trigger oxidative stress and inflammation, are discussed, along with the key transcription factors involved in the related signal transduction pathways. Secondly, the most promising phytogenic substances and their current applications to ameliorate oxidative stress and inflammation in poultry are highlighted.Simple SummaryChronic stress and inflammation, known also as “secret killers” in animals, can lead to lipid peroxidation, protein oxidation and nitration, DNA damage, and finally apoptosis. This is due to an imbalance between free radical generation and endogenous antioxidant defense, which in turn possess detrimental impacts on the health and performance of animals. In this review, we discuss the mechanistic pathways of oxidative stress and inflammation associated with the main secret killers in poultry, namely heat stress, dysbiosis, leaky gut syndrome, and mycotoxins. Additionally, we shed light on the potential use, challenges, and future prospects of phytogenic bioactive substances in mitigating oxidative stress and inflammation in poultry.
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| 6. |
- Beisvåg, Vidar, et al.
(författare)
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Contributions of the EMERALD project to assessing and improving microarray data quality
- 2011
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Ingår i: BioTechniques. - : Future Science Ltd. - 0736-6205 .- 1940-9818. ; 50:1, s. 27-31
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Tidskriftsartikel (refereegranskat)abstract
- While minimum information about a microarray experiment (MIAME) standards have helped to increase the value of the microarray data deposited into public databases like ArrayExpress and Gene Expression Omnibus (GEO), limited means have been available to assess the quality of this data or to identify the procedures used to normalize and transform raw data. The EMERALD FP6 Coordination Action was designed to deliver approaches to assess and enhance the overall quality of microarray data and to disseminate these approaches to the microarray community through an extensive series of workshops, tutorials, and symposia. Tools were developed for assessing data quality and used to demonstrate how the removal of poor-quality data could improve the power of statistical analyses and facilitate analysis of multiple joint microarray data sets. These quality metrics tools have been disseminated through publications and through the software package arrayQualityMetrics. Within the framework provided by the Ontology of Biomedical Investigations, ontology was developed to describe data transformations, and software ontology was developed for gene expression analysis software. In addition, the consortium has advocated for the development and use of external reference standards in microarray hybridizations and created the Molecular Methods (MolMeth) database, which provides a central source for methods and protocols focusing on microarray-based technologies.
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| 7. |
- Cardoso-Moreira, Margarida, et al.
(författare)
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Gene expression across mammalian organ development
- 2019
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Ingår i: Nature. - : NATURE PUBLISHING GROUP. - 0028-0836 .- 1476-4687. ; 571:7766, s. 505-
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.
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| 8. |
- Gavelli, Francesco, et al.
(författare)
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Extravascular lung water levels are associated with mortality : a systematic review and meta-analysis
- 2022
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Ingår i: Critical Care. - : BMC. - 1364-8535 .- 1466-609X. ; 26:1
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Forskningsöversikt (refereegranskat)abstract
- Background The prognostic value of extravascular lung water (EVLW) measured by transpulmonary thermodilution (TPTD) in critically ill patients is debated. We performed a systematic review and meta-analysis of studies assessing the effects of TPTD-estimated EVLW on mortality in critically ill patients. Methods Cohort studies published in English from Embase, MEDLINE, and the Cochrane Database of Systematic Reviews from 1960 to 1 June 2021 were systematically searched. From eligible studies, the values of the odds ratio (OR) of EVLW as a risk factor for mortality, and the value of EVLW in survivors and non-survivors were extracted. Pooled OR were calculated from available studies. Mean differences and standard deviation of the EVLW between survivors and non-survivors were calculated. A random effects model was computed on the weighted mean differences across the two groups to estimate the pooled size effect. Subgroup analyses were performed to explore the possible sources of heterogeneity. Results Of the 18 studies included (1296 patients), OR could be extracted from 11 studies including 905 patients (464 survivors vs. 441 non-survivors), and 17 studies reported EVLW values of survivors and non-survivors, including 1246 patients (680 survivors vs. 566 non-survivors). The pooled OR of EVLW for mortality from eleven studies was 1.69 (95% confidence interval (CI) [1.22; 2.34], p < 0.0015). EVLW was significantly lower in survivors than non-survivors, with a mean difference of -4.97 mL/kg (95% CI [-6.54; -3.41], p < 0.001). The results regarding OR and mean differences were consistent in subgroup analyses. Conclusions The value of EVLW measured by TPTD is associated with mortality in critically ill patients and is significantly higher in non-survivors than in survivors. This finding may also be interpreted as an indirect confirmation of the reliability of TPTD for estimating EVLW at the bedside. Nevertheless, our results should be considered cautiously due to the high risk of bias of many studies included in the meta-analysis and the low rating of certainty of evidence. Trial registration the study protocol was prospectively registered on PROSPERO: CRD42019126985.
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| 9. |
- Khmelinskii, Anton, et al.
(författare)
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Protein quality control at the inner nuclear membrane
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 516:7531, s. 410-
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear envelope is a double membrane that separates the nucleus from the cytoplasm. The inner nuclear membrane (INM) functions in essential nuclear processes including chromatin organization and regulation of gene expression(1). The outer nuclear membrane is continuous with the endoplasmic reticulum and is the site of membrane protein synthesis. Protein homeostasis in this compartment is ensured by endoplasmic-reticulum-associated protein degradation (ERAD) pathways that in yeast involve the integral membrane E3 ubiquitin ligases Hrd1 and Doa10 operating with the E2 ubiquitin-conjugating enzymes Ubc6 and Ubc7 (refs 2, 3). However, little is known about protein quality control at the INM. Here we describe a protein degradation pathway at the INM in yeast (Saccharomyces cerevisiae) mediated by the Asicomplex consisting of the RING domain proteins Asi1 and Asi3 (ref. 4). We report that the Asi complex functions together with the ubiquitin-conjugating enzymes Ubc6 and Ubc7 to degrade soluble and integral membrane proteins. Genetic evidence suggests that the Asi ubiquitin ligase defines a pathway distinct from, but complementary to, ERAD. Using unbiased screening with a novel genome-wide yeast library based on a tandem fluorescent protein timer(5), we identify more than 50 substrates of the Asi, Hrd1 and Doa10 E3 ubiquitin ligases. We show that the Asi ubiquitin ligase is involved in degradation of mislocalized integral membrane proteins, thus acting to maintain and safeguard the identity of the INM.
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| 10. |
- Maier, Hannes, et al.
(författare)
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Consensus Statement on Bone Conduction Devices and Active Middle Ear Implants in Conductive and Mixed Hearing Loss
- 2022
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Ingår i: Otology and Neurotology. - : Lippincott, Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 43:5, s. 513-529
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Tidskriftsartikel (refereegranskat)abstract
- Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
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