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Search Results: 1 - 10 of 1861 matches for " Jannik Andersen "
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Legacy Software Restructuring: Analyzing a Concrete Case
Nicolas Anquetil,Jannik Laval
Computer Science , 2012,
Abstract: Software re-modularization is an old preoccupation of reverse engineering research. The advantages of a well structured or modularized system are well known. Yet after so much time and efforts, the field seems unable to come up with solutions that make a clear difference in practice. Recently, some researchers started to question whether some basic assumptions of the field were not overrated. The main one consists in evaluating the high-cohesion/low-coupling dogma with metrics of unknown relevance. In this paper, we study a real structuring case (on the Eclipse platform) to try to better understand if (some) existing metrics would have helped the software engineers in the task. Results show that the cohesion and coupling metrics used in the experiment did not behave as expected and would probably not have helped the maintainers reach there goal. We also measured another possible restructuring which is to decrease the number of cyclic dependencies between modules. Again, the results did not meet expectations.
Lattices and maximum flow algorithms in planar graphs
Jannik Matuschke,Britta Peis
Computer Science , 2012,
Abstract: We show that the left/right relation on the set of s-t-paths of a plane graph induces a so-called submodular lattice. If the embedding of the graph is s-t-planar, this lattice is even consecutive. This implies that Ford and Fulkerson's uppermost path algorithm for maximum flow in such graphs is indeed a special case of a two-phase greedy algorithm on lattice polyhedra. We also show that the properties submodularity and consecutivity cannot be achieved simultaneously by any partial order on the paths if the graph is planar but not s-t-planar, thus providing a characterization of this class of graphs.
Identification of Direct Target Engagement Biomarkers for Kinase-Targeted Therapeutics
Cloud P. Paweletz, Jannik N. Andersen, Roy Pollock, Kumiko Nagashima, Mansuo L. Hayashi, Shangshuan U. Yu, Hongbo Guo, Ekaterina V. Bobkova, Zangwei Xu, Alan Northrup, Peter Blume-Jensen, Ronald C. Hendrickson, An Chi
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026459
Abstract: Pharmacodynamic (PD) biomarkers are an increasingly valuable tool for decision-making and prioritization of lead compounds during preclinical and clinical studies as they link drug-target inhibition in cells with biological activity. They are of particular importance for novel, first-in-class mechanisms, where the ability of a targeted therapeutic to impact disease outcome is often unknown. By definition, proximal PD biomarkers aim to measure the interaction of a drug with its biological target. For kinase drug discovery, protein substrate phosphorylation sites represent candidate PD biomarkers. However, substrate phosphorylation is often controlled by input from multiple converging pathways complicating assessment of how potently a small molecule drug hits its target based on substrate phoshorylation measurements alone. Here, we report the use of quantitative, differential mass-spectrometry to identify and monitor novel drug-regulated phosphorylation sites on target kinases. Autophosphorylation sites constitute clinically validated biomarkers for select protein tyrosine kinase inhibitors. The present study extends this principle to phosphorylation sites in serine/threonine kinases looking beyond the T-loop autophosphorylation site. Specifically, for the 3′-phosphoinositide-dependent protein kinase 1 (PDK1), two phospho-residues p-PDK1Ser410 and p-PDK1Thr513 are modulated by small-molecule PDK1 inhibitors, and their degree of dephosphorylation correlates with inhibitor potency. We note that classical, ATP-competitive PDK1 inhibitors do not modulate PDK1 T-loop phosphorylation (p-PDK1Ser241), highlighting the value of an unbiased approach to identify drug target-regulated phosphorylation sites as these are complementary to pathway PD biomarkers. Finally, we extend our analysis to another protein Ser/Thr kinase, highlighting a broader utility of our approach for identification of kinase drug-target engagement biomarkers.
Influence of Factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study
Thomas Benfield, Karen Ejrn?s, Klaus Juul, Christian ?stergaard, Jannik Helweg-Larsen, Nina Weis, Lea Munthe-Fog, Gitte Kronborg, Marianne Andersen, Anne Tybj?rg-Hansen, B?rge G Nordestgaard, Peter Garred
Critical Care , 2010, DOI: 10.1186/cc8899
Abstract: A genetic association study involving four case cohorts comprising two Gram negative sepsis, one invasive pneumococcal disease and one intensive care unit cohort with a total of 1,249 patients. Controls were derived from a population-based cohort study (N = 8,147). DNA from patients and controls was genotyped for the FVL mutation.When all patients were investigated together no significant difference in the frequency of FVL mutation was observed compared with controls (odds ratio (OR), 1.03; 95% confidence interval (CI), 0.83 to 1.29). However, when stratified among patients admitted to intensive care (N = 237), susceptibility and the likelihood of long-term death was influenced by the FVL mutation. In adjusted logistic regression analysis, FVL carriers had an increased risk of ICU admission compared to non-carriers (OR 1.62; 95% CI, 1.08 to 2.42). In adjusted Cox regression analysis, FVL carriers were at increased risk of long-term death compared to non-carriers (relative risk 1.78; 95% CI, 1.13 to 2.81). FVL carrier status did not predict either susceptibility to or outcome from Gram negative, Escherichia coli or Streptococcus pneumoniae sepsis.Overall, the FVL mutation did not appear to increase the risk of admission due to severe invasive infections. Nevertheless, in the subgroup of patients admitted to intensive care an increased risk and a poorer long-term outcome for individuals with critical illness were observed for FVL mutation carriers.Critical illness associated with sepsis and the systemic inflammatory response syndrome (SIRS) is an important cause of morbidity and mortality [1-3]. In recent years, a growing number of discoveries have identified the importance of host genetic factors in SIRS and sepsis outcomes [4].One human genetic factor that may be involved is factor V but its role is controversial. A single non-synonymous amino acid substitution (Arg506Gln) in factor V, the factor V Leiden (FVL) mutation, causes resistance to activated protein C (APC
Infrequent detection of Pneumocystis jirovecii by PCR in oral wash specimens from TB patients with or without HIV and healthy contacts in Tanzania
Lotte Jensen, Andreas V Jensen, George Praygod, Jeremiah Kidola, Daniel Faurholt-Jepsen, John Changalucha, Nyagosya Range, Henrik Friis, Jannik Helweg-Larsen, Jorgen S Jensen, Aase B Andersen
BMC Infectious Diseases , 2010, DOI: 10.1186/1471-2334-10-140
Abstract: A prospective study of 384 patients initiating treatment for sputum smear-positive and smear-negative TB and 100 healthy household contacts and neighbourhood controls.DNA from oral wash specimens was examined by PCR for P. jirovecii. All patients delivered sputum for TB microscopy and culture. Healthy contacts and community controls were clinically assessed and all study subjects were HIV tested and had CD4 cell counts determined. Clinical status and mortality was assessed after a follow-up period of 5 months.384 patients and 100 controls were included, 53% and 8% HIV positive respectively. A total number of 65 patients and controls (13.6%) were at definitive risk for PCP based on CD4 counts <200 cells per mm3 and no specific PCP prophylaxis. Only a single patient (0.3% of the patients) was PCR positive for P. jirovecii. None of the healthy household contacts or neighbourhood controls had PCR-detectable P. jirovecii DNA in their oral wash specimens regardless of HIV-status.The prevalence of P. jirovecii as detected by PCR on oral wash specimens was very low among TB patients with or without HIV and healthy individuals in Tanzania. Colonisation by P. jirovecii was not detected among healthy controls. The present findings may encourage diagnostic use of this non-invasive method.Pneumocystis jirovecii pneumonia (PCP) remains a relatively common and serious opportunistic infection among HIV infected in Western countries, even in the era of antiretroviral therapy (ART) [1,2]. In Africa, PCP is common and often fatal in HIV infected infants less than 1 year of age [3]. Data regarding adult patients from Uganda [4], Malawi [5] and Ethiopia [6] have shown P. jirovecii prevalence varying from 9% to 38% among smear-negative, mainly HIV-positive TB patients.The present study was inspired by results of a study performed in Mwanza, Tanzania, in which we observed a HIV prevalence of 63% among patients with smear-negative TB, according to WHO classification [7]. Among the smear-po
A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors
Andrey Loboda, Michael Nebozhyn, Rich Klinghoffer, Jason Frazier, Michael Chastain, William Arthur, Brian Roberts, Theresa Zhang, Melissa Chenard, Brian Haines, Jannik Andersen, Kumiko Nagashima, Cloud Paweletz, Bethany Lynch, Igor Feldman, Hongyue Dai, Pearl Huang, James Watters
BMC Medical Genomics , 2010, DOI: 10.1186/1755-8794-3-26
Abstract: We used the coherent expression of RAS pathway-related genes across multiple datasets to derive a RAS pathway gene expression signature and generate RAS pathway activation scores in pre-clinical cancer models and human tumors. We then related this signature to KRAS mutation status and drug response data in pre-clinical and clinical datasets.The RAS signature score is predictive of KRAS mutation status in lung tumors and cell lines with high (> 90%) sensitivity but relatively low (50%) specificity due to samples that have apparent RAS pathway activation in the absence of a KRAS mutation. In lung and breast cancer cell line panels, the RAS pathway signature score correlates with pMEK and pERK expression, and predicts resistance to AKT inhibition and sensitivity to MEK inhibition within both KRAS mutant and KRAS wild-type groups. The RAS pathway signature is upregulated in breast cancer cell lines that have acquired resistance to AKT inhibition, and is downregulated by inhibition of MEK. In lung cancer cell lines knockdown of KRAS using siRNA demonstrates that the RAS pathway signature is a better measure of dependence on RAS compared to KRAS mutation status. In human tumors, the RAS pathway signature is elevated in ER negative breast tumors and lung adenocarcinomas, and predicts resistance to cetuximab in metastatic colorectal cancer.These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.Signal transduction in response to growth factor receptor activation in tumors is a complex process that involves downstream signaling through the RAS (reviewed in [1]) and PI3K (reviewed in [2]) signaling pathways. These pathways are among the best characterized in cancer biology, involve a network of protein and lipid kinases working in concert to regulate diverse biolo
Mechanical properties of polycrystalline graphene based on a realistic atomistic model
Jani Kotakoski,Jannik C. Meyer
Physics , 2012, DOI: 10.1103/PhysRevB.85.195447
Abstract: Graphene can at present be grown at large quantities only by the chemical vapor deposition method, which produces polycrystalline samples. Here, we describe a method for constructing realistic polycrystalline graphene samples for atomistic simulations, and apply it for studying their mechanical properties. We show that cracks initiate at points where grain boundaries meet and then propagate through grains predominantly in zigzag or armchair directions, in agreement with recent experimental work. Contrary to earlier theoretical predictions, we observe normally distributed intrinsic strength (~ 50% of that of the mono-crystalline graphene) and failure strain which do not depend on the misorientation angles between the grains. Extrapolating for grain sizes above 15 nm results in a failure strain of ~ 0.09 and a Young's modulus of ~ 600 GPa. The decreased strength can be adequately explained with a conventional continuum model when the grain boundary meeting points are identified as Griffith cracks.
Progressive Gaussian Filtering
Uwe D. Hanebeck,Jannik Steinbring
Mathematics , 2012,
Abstract: In this paper, we propose a progressive Bayesian procedure, where the measurement information is continuously included into the given prior estimate (although we perform observations at discrete time steps). The key idea is to derive a system of ordinary first-order differential equations (ODE) by employing a new coupled density representation comprising a Gaussian density and its Dirac Mixture approximation. The ODE is used for continuously tracking the true non-Gaussian posterior by its best matching Gaussian approximation. The performance of the new filter is evaluated in comparison with state-of-the-art filters by means of a canonical benchmark example, the discrete-time cubic sensor problem.
Stable Flows over Time
ágnes Cseh,Jannik Matuschke,Martin Skutella
Algorithms , 2013, DOI: 10.3390/a6030532
Abstract: In this paper, the notion of stability is extended to network flows over time. As a useful device in our proofs, we present an elegant preflow-push variant of the Gale-Shapley algorithm that operates directly on the given network and computes stable flows in pseudo-polynomial time, both in the static flow and the flow over time case. We show periodical properties of stable flows over time on networks with an infinite time horizon. Finally, we discuss the influence of storage at vertices, with different results depending on the priority of the corresponding holdover edges.
1/N-expansions in non-relativistic quantum mechanics
Niels Emil Jannik Bjerrum-Bohr
Physics , 2003,
Abstract: An extensive number of numerical computations of energy 1/$N$ series using a recursive Taylor series method are presented in this paper. The series are computed to a high order of approximation and their behaviour on increasing the order of approximation is examined.
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