Search results for "relation"

Assessment of mechanisms driving non-linear dose-response relationships in genotoxicity testing.

2014

In genetic toxicology, risk assessment has traditionally adopted linear dose-responses for any compound that causes genotoxic effects. Increasing evidence of non-linear dose-responses, however, suggests potential cellular tolerance to low levels of many genotoxicants with diverse modes of action. Such putative non-linear dose-responses need to be substantiated by strong mechanistic data that identifies the mechanisms responsible for the tolerance to low doses. This can be achieved by experimental demonstration of cytoprotective mechanisms and by providing experimental support for the existence of tolerance mechanisms against low dose effects. By highlighting key experiments into low dose me…

Structure-Function Relationship of Substituted Bromomethylcoumarins in Nucleoside Specificity of RNA Alkylation

2013

Selective alkylation of RNA nucleotides is an important field of RNA biochemistry, e.g. in applications of fluorescent labeling or in structural probing experiments, yet detailed structure-function studies of labeling agents are rare. Here, bromomethylcoumarins as reactive compounds for fluorescent labeling of RNA are developed as an attractive scaffold on which electronic properties can be modulated by varying the substituents. Six different 4-bromomethyl-coumarins of various substitution patterns were tested for nucleotide specificity of RNA alkylation using tRNA from Escherichia coli as substrate. Using semi-quantitative LC-MS/MS analysis, reactions at mildly acidic and slightly alkaline…

The American nuclear family in the TV series "The Simpsons"

1999

Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides

2012

Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3- carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylati…

Synthesis and biological activities of a new class of heat shock protein 90 inhibitors, designed by energy-based pharmacophore virtual screening

2013

The design through energy-based pharmacophore virtual screening has led to aminocyanopyridine derivatives as efficacious new inhibitors of Hsp90. The synthesized compounds showed a good affinity for the Hsp90 ATP binding site in the competitive binding assay. Moreover, they showed an excellent antiproliferative activity against a large number of human tumor cell lines. Further biological studies on the derivative with the higher EC50 confirmed its specific influence on the cellular pathways involving Hsp90.

Effects of amsacrine (m-AMSA), a new aminoacridine antitumor drug, on the rabbit heart.

1983

There is emerging clinical evidence that amsacrine (m-AMSA) administration may be associated with cardiotoxic effects such as severe, even fatal, ventricular arrhythmias and impairment of the inotropic performance of the heart. Information on the cardiac effects of m-AMSA in animals is scanty. Studies on mice, dogs, and monkeys have not evidenced the cardiotoxicity of the compound. The data presented in this paper show that m-AMSA causes acute ECG alterations in normal rabbits and a dose-related negative inotropic effect on the isolated rabbit heart, suggesting that this species may be a useful model for the study of the cardiac actions of this antiblastic.

Appearance as the Arrival of the Future

2017

AMBIGUITIES of language often indicate a problematic subject matter. That is the case with the word "appear" (erscheinen). When I say that an acquaintance (or someone with whom I was previously unacquainted) "appeared" to me, in order to speak with me, the meaning is: he came to me, he showed up in my habitat, perhaps at my home. He did not only seem (scheinen) to be there; he really was there. When something appears to us, it does not only seem to be with us, it actually is present. Appearance and existence are here very closely connected. But on the other hand, my acquaintance still exists even when he does not appear to me. Whether that would still be true if he appeared nowhere whether …

Time trials versus time-to-exhaustion tests: Effects on critical power, W0, and oxygen-uptake kinetics

2018

Purpose: To investigate single-day time-to-exhaustion (TTE) and time-trial (TT) -based laboratory tests values of critical power (CP), W prime (W0), and respective oxygen-uptake-kinetic responses. Methods: Twelve cyclists performed a maximal ramp test followed by 3 TTE and 3 TT efforts interspersed by 60 min recovery between efforts. Oxygen uptake (VO 2) was measured during all trials. The mean response time was calculated as a description of the overall VO 2-kinetic response from the onset to 2 min of exercise. Results: TTE-determined CP was 279 ± 52 W, and TT-determined CP was 276 ± 50 W (P = .237). Values of W0 were 14.3 ± 3.4 kJ (TTE W0) and 16.5 ± 4.2 kJ (TT W0) (P = .028). While a hig…

Topological Approach to Analgesia

1994

Groupe de travail sur l'analyse régionale de la relation formation-emploi : problématiques et méthodes

1990

International audience; Depuis une vingtaine d'années, et plus encore depuis la mise en place de la décentralisation, des systèmes d'aide à la décision sont demandés par les décideurs régionaux et locaux en matière de formation initiale et continue. Pour tirer les leçons des expériences passées et formuler des propositions pour le développement des observatoires régionaux de l'emploi et de la formation, prévus dans le cadre des contrats de Plan Etat - Région, le C.E.R.E.Q. a pris l'initiative de réunir un groupe de travail, dont les premières réflexions sont relatées ici. Il insiste particulièrement sur la prise en compte de l'évolution socio-économique des comportements et des stratégies d…