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See detailMutant Quality Indicators
Papadakis, Mike UL; Titcheu Chekam, Thierry UL; Le Traon, Yves UL

in 13th International Workshop on Mutation Analysis (MUTATION'18) (2018)

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See detailMutating OWLs: semantic mutation testing for ontologies
Bartolini, Cesare UL

Scientific Conference (2016, February 19)

Ontologies are an essential component of semantic knowledge bases and applications, and nowadays they are used in a plethora of domains. Despite the maturity of ontology languages, support tools and ... [more ▼]

Ontologies are an essential component of semantic knowledge bases and applications, and nowadays they are used in a plethora of domains. Despite the maturity of ontology languages, support tools and engineering techniques, the testing and validation of ontologies is a field which still lacks consolidated approaches and tools. This paper attempts at partly bridging that gap, taking a first step towards the extension of mutation testing techniques to ontologies expressed in a widely-used format. Mutation testing techniques, revisited in the light of the peculiar features of the ontology language and structure, can help in the engineering and refinement of ontologies and software based on them. [less ▲]

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See detailMutation analyses and association studies to assess the role of the presenilin-associated rhomboid-like gene in Parkinson's disease
Wüst, Richard; Maurer, Brigitte; Hauser, Kathrin et al

in Neurobiology of Aging (2016), 39

Presenilin-associated rhomboid-like (PARL), a serine protease located in the inner mitochondrial membrane, has been shown to genetically interact and process PTEN-induced putative kinase a protein known ... [more ▼]

Presenilin-associated rhomboid-like (PARL), a serine protease located in the inner mitochondrial membrane, has been shown to genetically interact and process PTEN-induced putative kinase a protein known for its critical role in mitochondrial homeostasis and early-onset forms of Parkinson’s disease (PD). The identification of a PD-associated variant in the PARL gene (p.Ser77Asn) led us to assess the relevance of PARL for PD pathogenesis using a mutation screening of the coding sequences and adjacent intronic sequences. We investigated 3 single nucleotide polymorphisms (rs3792589, rs13091, and rs3732581), a synonymous base substitution (Leu79Leu) and the previously described p.Ser77Asn mutation, which were subsequently screened in more than 2000 patients and controls. Not detecting the p.Ser77Asn mutation in our cohort, nor a robust association between variations in the PARL gene and PD, the role of disease causing genetic variants in the PARL gene could not be further substantiated in our samples. Our findings indicate that PARL mutations are a rare cause of PD and genetic variants are neither strong nor common risk factors in PD. [less ▲]

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See detailMutation analysis and association studies of nuclear factor-kappaB1 in sporadic Parkinson's disease patients.
Wintermeyer, P.; Riess, O.; Schols, L. et al

in Journal of neural transmission (Vienna, Austria : 1996) (2002), 109(9), 1181-8

Biochemical and morphological studies revealed that oxidative stress and apoptosis play a role in neurodegeneration in Parkinson's disease (PD). Reactive oxygen species may be directly involved in ... [more ▼]

Biochemical and morphological studies revealed that oxidative stress and apoptosis play a role in neurodegeneration in Parkinson's disease (PD). Reactive oxygen species may be directly involved in apoptosis or via upregulation of toxic cytokines, i.e. tumor necrosis factor alpha (TNFalpha). We recently demonstrated that the TNFalpha pathway contributes to the pathogenesis of sporadic PD using a genetic approach. These signalling pathways converge to the transcription factor nuclear factor kappaB (NF-kappaB), which has been found activated in affected neurons in PD. We performed a detailed mutation analysis of the p50 subunit of NF-kappaB (NFKB1 gene) in 96 sporadic PD patients. Previously, positive association was demonstrated in this cohort to chromosome 4q21-23 containing the NFKB1 gene. We identified three base exchanges not affecting the amino acid sequence, which were found at similar frequencies in controls. Our study does not support a genetically definable role of NFKB1 in the pathogenesis of sporadic PD. [less ▲]

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See detailMutation analysis and association studies of the UCHL1 gene in German Parkinson's disease patients.
Wintermeyer, P.; Krüger, Rejko UL; Kuhn, W. et al

in Neuroreport (2000), 11(10), 2079-82

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether ... [more ▼]

Recently, an Ile93Met substitution has been identified in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) gene in a single German PD family with autosomal dominant inheritance. To determine whether mutations in the UCHL1 gene are causative for Parkinson's disease (PD) a detailed mutation analysis was performed in a large sample of German sporadic and familial PD patients. We found no disease-causing mutation in the coding region of the UCHL1 gene. Direct sequencing revealed six intronic polymorphisms in the UCHL1 gene. Analysis of an S18Y polymorphism in exon 3 of the UCHL1 gene in sporadic PD patients and controls showed carriers of allele 2 (tyrosine) significantly less frequent in patients with a reduced risk of 0.57 (CI = 0.36-0.88; p = 0.012, p(c) = 0.047, chi2 = 6.31). Our study shows that sequence variations in the coding region of UCHL1 are a rare event. A protective effect of a certain UCHL1 variant in the pathogenesis of sporadic PD is suggested, underlining the relevance of UCHL1 in neurodegeneration. [less ▲]

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See detailMutation analysis of the neurofilament M gene in Parkinson's disease.
Krüger, Rejko UL; Fischer, Christian; Schulte, Thorsten et al

in Neuroscience letters (2003), 351(2), 125-9

Neurofilament M, a major component of Lewy bodies, represents an interesting candidate in the pathogenesis of Parkinson's disease (PD). We performed detailed mutation analyses of the NF-M gene in 322 ... [more ▼]

Neurofilament M, a major component of Lewy bodies, represents an interesting candidate in the pathogenesis of Parkinson's disease (PD). We performed detailed mutation analyses of the NF-M gene in 322 familial and sporadic PD patients. Two polymorphisms (Ala475Thr and Gly697Arg) occurred at similar frequencies in PD patients and controls. A Pro725Gln substitution and a deletion of valine in position 829 were identified in two PD patients. These substitutions affect residues of the NF-M protein that are highly conserved among different species. None of our patients carried the Gly336Ser substitution, which has been described in familial PD. Our results argue against a major role of NF-M in PD. However, rare variants of the NF-M gene may act as susceptibility factors for PD and functional analyses of the identified variations are warranted to decipher possible mechanisms in neurodegeneration. [less ▲]

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See detailMutation Based Test Case Generation via a Path Selection Strategy
Papadakis, Mike UL; Malevris, Nicos

in Information & Software Technology (2012), 54(9), 915-932

Context: Generally, mutation analysis has been identified as a powerful testing method. Researchers have shown that its use as a testing criterion exercises quite thoroughly the system under test while it ... [more ▼]

Context: Generally, mutation analysis has been identified as a powerful testing method. Researchers have shown that its use as a testing criterion exercises quite thoroughly the system under test while it achieves to reveal more faults than standard structural testing criteria. Despite its potential, mutation fails to be adopted in a widespread practical use and its popularity falls significantly short when compared with other structural methods. This can be attributed to the lack of thorough studies dealing with the practical problems introduced by mutation and the assessment of the effort needed when applying it. Such an incident, masks the real cost involved preventing the development of easy and effective to use strategies to circumvent this problem. Objective: In this paper, a path selection strategy for selecting test cases able to effectively kill mutants when performing weak mutation testing is presented and analysed. Method: The testing effort is highly correlated with the number of attempts the tester makes in order to generate adequate test cases. Therefore, a significant influence on the efficiency associated with a test case generation strategy greatly depends on the number of candidate paths selected in order to achieve a predefined coverage goal. The effort can thus be related to the number of infeasible paths encountered during the test case generation process. Results: An experiment, investigating well over 55 million of program paths is conducted based on a strategy that alleviates the effects of infeasible paths. Strategy details, along with a prototype implementation are reported and analysed through the experimental results obtained by its employment to a set of program units. Conclusion: The results obtained suggest that the strategy used can play an important role in making the mutation testing method more appealing and practical. [less ▲]

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See detailLa mutation de la fonction parlementaire: le rôle des parlements dans la gouvernance économique
Allemand, Frederic UL; Martucci, Francesco

in Auby, Jean-Bernard; Idoux, Pascale (Eds.) Le Gouvernement économique européen (2017)

Placé au centre des préoccupations à la faveur des crises qui ont révélé ses insuffisances, le gouvernement économique européen demeure, en dépit des avancées récentes, un terrain évolutif encore ... [more ▼]

Placé au centre des préoccupations à la faveur des crises qui ont révélé ses insuffisances, le gouvernement économique européen demeure, en dépit des avancées récentes, un terrain évolutif encore largement en friche, propice à un travail interdisciplinaire de réflexion sur l’existant et d’invention de futurs développements, auquel la communauté des juristes doit prendre part et qu’elle doit s’efforcer d’enrichir par sa diversité. À cet égard, le présent ouvrage, loin de prétendre épuiser le sujet, se présente à la fois comme une ébauche et une invitation. Sa première partie s’interroge sur le principe même d’un gouvernement économique européen, afin de tenter d’apporter quelques réponses à la question de savoir ce qui fait en éprouver la nécessité dans un contexte juridique et politique qui repose fondamentalement sur une confiance dans le marché. La deuxième partie s’efforce de cerner ce qu’est le gouvernement économique européen, dans son état actuel, tel qu’il résulte notamment des inflexions et ajouts divers que la crise a conduit à lui apporter, sous l’angle des institutions, des principes et des méthodes de pilotage public de l’économie. Enfin, la troisième partie propose des hypothèses sur les perspectives d’évolution envisageables à ces trois égards. [less ▲]

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See detailMutation in the betaA3/A1-crystallin encoding gene Cryba1 causes a dominant cataract in the mouse.
Graw, J.; Jung, M.; Loster, J. et al

in Genomics (1999), 62(1), 67-73

During the mouse ENU mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was discovered as a progressive opacity (Po). Heterozygotes show opacification of ... [more ▼]

During the mouse ENU mutagenesis screen, mice were tested for the occurrence of dominant cataracts. One particular mutant was discovered as a progressive opacity (Po). Heterozygotes show opacification of a superficial layer of the fetal nucleus, which progresses and finally forms a nuclear opacity. Since the homozygotes have already developed the total cataract at eye opening, the mode of inheritance is semidominant. Linkage analysis was performed using a set of genome-wide microsatellite markers. The mutation was mapped to chromosome 11 distal of the marker D11Mit242 (9.3 +/- 4.4 cM) and proximal to D11Mit36 (2.3 +/- 2.3 cM). This position makes the betaA3/A1-crystallin encoding gene Cryba1 an excellent candidate gene. Mouse Cryba1 was amplified from lens mRNA. Sequence analysis revealed a mutation of a T to an A at the second base of exon 6, leading to an exchange of Trp by Arg. Computer analysis predicts that the fourth Greek key motif of the affected betaA3/A1-crystallin will not be formed. Moreover, the mutation leads also to an additional splicing signal, to the skipping of the first 3 bp of exon 6, and finally to the deletion of the Trp residue. Both types of mRNA are present in the homozygous mutant lenses. The mutation will be referred to as Cryba1(po1). This particular mouse mutation provides an excellent animal model for a human congenital zonular cataract with suture opacities, which is caused by a mutation in the homologous gene. [less ▲]

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See detailMutation in the transcriptional regulator PhoP contributes to avirulence of Mycobacterium tuberculosis H37Ra strain.
Lee, Jong Seok; Krause, Roland UL; Schreiber, Jorg et al

in Cell Host & Microbe (2008), 3(2), 97-103

Attenuated strains of mycobacteria can be exploited to determine genes essential for their pathogenesis and persistence. To this goal, we sequenced the genome of H37Ra, an attenuated variant of ... [more ▼]

Attenuated strains of mycobacteria can be exploited to determine genes essential for their pathogenesis and persistence. To this goal, we sequenced the genome of H37Ra, an attenuated variant of Mycobacterium tuberculosis H37Rv strain. Comparison with H37Rv revealed three unique coding region polymorphisms. One polymorphism was located in the DNA-binding domain of the transcriptional regulator PhoP, causing the protein's diminished DNA-binding capacity. Temporal gene expression profiles showed that several genes with reduced expression in H37Ra were also repressed in an H37Rv phoP knockout strain. At later time points, genes of the dormancy regulon, typically expressed in a state of nonreplicating persistence, were upregulated in H37Ra. Complementation of H37Ra with H37Rv phoP partially restored its persistence in a murine macrophage infection model. Our approach demonstrates the feasibility of identifying minute but distinct differences between isogenic strains and illustrates the consequences of single point mutations on the survival stratagem of M. tuberculosis. [less ▲]

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See detailMutation Testing Advances: An Analysis and Survey
Papadakis, Mike UL; Kintis, Marinos UL; Zhang, Jie et al

in Advances in Computers (2017)

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See detailMutation Testing Strategies using Mutant Classification
Papadakis, Mike UL; Le Traon, Yves UL

in Abstract book of 28th Symposium On Applied Computing (2013)

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See detailMutation-based Generation of Software Product Line Test Configurations
Henard, Christopher UL; Papadakis, Mike UL; Le Traon, Yves UL

in Symposium on Search-Based Software Engineering (SSBSE 2014) (2014)

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See detailMutationen im VSP13D-Gen verursachen eine oftmals frühkindliche spastische Ataxie
Grünewald, Anne UL

in DGNeurologie (2018), 1(1), 58-59

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See detailLes mutations de la société française : les grandes questions économiques et sociales
Castel, Robert; Chauvel, Louis UL; et, al.

Book published by La découverte (2013)

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See detailMutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency
Brooks-Wilson, A.; Marcil, M.; Clee, S. M. et al

in Nature Genetics (1999), 22(4), 336-45

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See detailMutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts.
Rakovic, Aleksandar; Grünewald, Anne UL; Kottwitz, Jan et al

in PloS one (2011), 6(3), 16746

PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and ... [more ▼]

PINK1 and Parkin mutations cause recessive Parkinson's disease (PD). In Drosophila and SH-SY5Y cells, Parkin is recruited by PINK1 to damaged mitochondria, where it ubiquitinates Mitofusins and consequently promotes mitochondrial fission and mitophagy.Here, we investigated the impact of mutations in endogenous PINK1 and Parkin on the ubiquitination of mitochondrial fusion and fission factors and the mitochondrial network structure. Treating control fibroblasts with mitochondrial membrane potential (Deltapsi) inhibitors or H(2)O(2) resulted in ubiquitination of Mfn1/2 but not of OPA1 or Fis1. Ubiquitination of Mitofusins through the PINK1/Parkin pathway was observed within 1 h of treatment. Upon combined inhibition of Deltapsi and the ubiquitin proteasome system (UPS), no ubiquitination of Mitofusins was detected. Regarding morphological changes, we observed a trend towards increased mitochondrial branching in PD patient cells upon mitochondrial stress.For the first time in PD patient-derived cells, we demonstrate that mutations in PINK1 and Parkin impair ubiquitination of Mitofusins. In the presence of UPS inhibitors, ubiquitinated Mitofusin is deubiquitinated by the UPS but not degraded, suggesting that the UPS is involved in Mitofusin degradation. [less ▲]

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See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

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See detailMutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes
Schubert, Julian; Siekierska, Aleksandra; Langlois, Melanie UL et al

in Nature Genetics (2014), 46(12), 1327-32

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile ... [more ▼]

Febrile seizures affect 2–4% of all children1 and have a strong genetic component2. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)3, 4, 5 have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B6, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees7, 8 identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes. [less ▲]

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See detailMutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness.
Wortmann, Saskia B.; Vaz, Frederic M.; Gardeitchik, Thatjana et al

in Nature genetics (2012), 44(7), 797-802

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3 ... [more ▼]

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34:1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. [less ▲]

Detailed reference viewed: 238 (1 UL)