| 1. |
- Dabrowski, Konrad K., et al.
(författare)
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Parameterized Complexity Classification for Interval Constraints
- 2023
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Ingår i: 18th International Symposium on Parameterized and Exact Computation (IPEC 2023). - Saarbrücken/Wadern : Schloss Dagstuhl – Leibniz-Zentrum für Informatik. - 9783959773058 ; , s. 11:1-11:19
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Konferensbidrag (refereegranskat)abstract
- Constraint satisfaction problems form a nicely behaved class of problems that lends itself to complexity classification results. From the point of view of parameterized complexity, a natural task is to classify the parameterized complexity of MinCSP problems parameterized by the number of unsatisfied constraints. In other words, we ask whether we can delete at most k constraints, where k is the parameter, to get a satisfiable instance. In this work, we take a step towards classifying the parameterized complexity for an important infinite-domain CSP: Allen’s interval algebra (IA). This CSP has closed intervals with rational endpoints as domain values and employs a set A of 13 basic comparison relations such as "precedes" or "during" for relating intervals. IA is a highly influential and well-studied formalism within AI and qualitative reasoning that has numerous applications in, for instance, planning, natural language processing and molecular biology. We provide an FPT vs. W[1]-hard dichotomy for MinCSP(Γ) for all Γ ⊆ A. IA is sometimes extended with unions of the relations in A or first-order definable relations over A, but extending our results to these cases would require first solving the parameterized complexity of Directed Symmetric Multicut, which is a notorious open problem. Already in this limited setting, we uncover connections to new variants of graph cut and separation problems. This includes hardness proofs for simultaneous cuts or feedback arc set problems in directed graphs, as well as new tractable cases with algorithms based on the recently introduced flow augmentation technique. Given the intractability of MinCSP(A) in general, we then consider (parameterized) approximation algorithms. We first show that MinCSP(A) cannot be polynomial-time approximated within any constant factor and continue by presenting a factor-2 fpt-approximation algorithm. Once again, this algorithm has its roots in flow augmentation.
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| 2. |
- Diamanti, Klev, et al.
(författare)
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Maps of context-dependent putative regulatory regions and genomic signal interactions
- 2016
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 44:19, s. 9110-9120
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Tidskriftsartikel (refereegranskat)abstract
- Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected similar to 144k putative regulatory regions among the human cell-lines, with the majority of them being similar to 300 bp. We found similar to 20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.
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| 3. |
- Kruczyk, Marcin, et al.
(författare)
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Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells
- 2014
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Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1839:11, s. 1341-1350
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown.RESULTS: We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells.CONCLUSIONS: Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.
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| 6. |
- Nadin, Vincent, et al.
(författare)
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COMPASS – Comparative Analysis of Territorial Governance and Spatial Planning Systems in Europe : Applied Research 2016-2018: Final Report
- 2018
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The objective of the COMPASS project was to provide an authoritative comparative report on changes in territorial governance and spatial planning systems in Europe from 2000 to 2016. This Final Report presents the main findings, conclusions and policy recommendations. The COMPASS project compares territorial governance and spatial planning in 32 European countries (the 28 EU member states plus four ESPON partner countries). COMPASS differs from previous studies in that the accent is not on a snapshot comparison of national systems, but on identifying trends in reforms from 2000 to 2016. It also seeks to give reasons for these changes with particular reference to EU directives and policies, and to identify good practices for the cross-fertilisation of spatial development policies with EU Cohesion Policy. The research is based on expert knowledge with reference wherever possible to authoritative sources. Experts with in-depth experience of each national system were appointed to contribute to the study. The research design involved primarily collection of data from the 32 countries through questionnaires and five in-depth case studies of the interaction of EU Cohesion Policy and other sectoral policies with spatial planning and territorial governance.
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| 7. |
- Stepniak, Karolina, et al.
(författare)
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Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas
- 2021
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas. Gliomas are tumors often associated with epigenetics-related gene deregulation. Here the authors reveal an atlas of active enhancers and promoters in benign and malignant gliomas by performing whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples.
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| 8. |
- Umer, Husen M., et al.
(författare)
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A Significant Regulatory Mutation Burden at a High-Affinity Position of the CTCF Motif in Gastrointestinal Cancers
- 2016
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 37:9, s. 904-913
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Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations drive cancer and there are established ways to study those in coding sequences. It has been shown that some regulatory mutations are over-represented in cancer. We develop a new strategy to find putative regulatory mutations based on experimentally established motifs for transcription factors (TFs). In total, we find 1,552 candidate regulatory mutations predicted to significantly reduce binding affinity of many TFs in hepatocellular carcinoma and affecting binding of CTCF also in esophagus, gastric, and pancreatic cancers. Near mutated motifs, there is a significant enrichment of (1) genes mutated in cancer, (2) tumor-suppressor genes, (3) genes in KEGG cancer pathways, and (4) sets of genes previously associated to cancer. Experimental and functional validations support the findings. The strategy can be applied to identify regulatory mutations in any cell type with established TF motifs and will aid identifications of genes contributing to cancer.
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| 9. |
- Weigl, Wojciech, et al.
(författare)
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Analgesic efficacy of intrathecal fentanyl during the period of highest analgesic demand after cesarean section A randomized controlled study
- 2016
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Ingår i: Medicine. - 0025-7974 .- 1536-5964. ; 95:24
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Tidskriftsartikel (refereegranskat)abstract
- Cesarean section (CS) is one of the most common surgical procedures in female patients. We aimed to evaluate the postoperative analgesic efficacy of intrathecal fentanyl during the period of greatest postoperative analgesic demand after CS. This period was defined by detailed analysis of patient-controlled analgesia (PCA) usage. This double-blind, placebo-controlled, parallel-group randomized trial included 60 parturients who were scheduled for elective CS. Participants received spinal anesthesia with bupivacaine supplemented with normal saline (control group) or with fentanyl 25 mg (fentanyl group). To evaluate primary endpoints, we measured total pethidine consumption over the period of greatest PCA pethidine requirement. For verification of secondary endpoints, we recorded intravenous PCA requirement in other time windows, duration of effective analgesia, pain scores assessed by visual analog scale, opioid side effects, hemodynamic changes, neonatal Apgar scores, and intraoperative pain. Detailed analysis of hour-by-hour PCA opioid requirements showed that the greatest demand for analgesics among patients in the control group occurred during the first 12 hours after surgery. Patients in the fentanyl group had significantly reduced opioid consumption compared with the controls during this period and had a prolonged duration of effective analgesia. The groups were similar in visual analog scale, incidence of analgesia-related side effects (nausea/vomiting, pruritus, oversedation, and respiratory depression), and neonatal Apgar scores. Mild respiratory depression occurred in 1 patient in each group. Fewer patients experienced intraoperative pain in the fentanyl group (3% vs 23%; relative risk 6.8, 95% confidence interval 0.9-51.6). The requirement for postoperative analgesics is greatest during the first 12hours after induction of anesthesia in patients undergoing CS. The addition of intrathecal fentanyl to spinal anesthesia is effective for intraoperative analgesia and decreases opioid consumption during the period of the highest analgesic demand after CS, without an increase in maternal or neonatal side effects. We recommend using intrathecal fentanyl for CS in medical centers not using morphine or other opioids intrathecally at present.
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