65 research outputs found
PCV23 ECONOMIC IMPACT OF CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROMES WITHOUT ST-SEGMENT ELEVATION (ACS) UNDERGOING PERCUTANEOUS CORONARY INTERVENTIONS (PCI): A EUROPEAN OVERVIEW
Commentary on the article “Postpartum women’s use of medicines and breastfeeding practices: a systematic review”
Anomalous scaling of spin accumulation in ferromagnetic tunnel devices with silicon and germanium
Modeling Inhomogeneous DNA Replication Kinetics
In eukaryotic organisms, DNA replication is initiated at a series of chromosomal locations called origins, where replication forks are assembled proceeding bidirectionally to replicate the genome. The distribution and firing rate of these origins, in conjunction with the velocity at which forks progress, dictate the program of the replication process. Previous attempts at modeling DNA replication in eukaryotes have focused on cases where the firing rate and the velocity of replication forks are homogeneous, or uniform, across the genome. However, it is now known that there are large variations in origin activity along the genome and variations in fork velocities can also take place. Here, we generalize previous approaches to modeling replication, to allow for arbitrary spatial variation of initiation rates and fork velocities. We derive rate equations for left- and right-moving forks and for replication probability over time that can be solved numerically to obtain the mean-field replication program. This method accurately reproduces the results of DNA replication simulation. We also successfully adapted our approach to the inverse problem of fitting measurements of DNA replication performed on single DNA molecules. Since such measurements are performed on specified portion of the genome, the examined DNA molecules may be replicated by forks that originate either within the studied molecule or outside of it. This problem was solved by using an effective flux of incoming replication forks at the model boundaries to represent the origin activity outside the studied region. Using this approach, we show that reliable inferences can be made about the replication of specific portions of the genome even if the amount of data that can be obtained from single-molecule experiments is generally limited
Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication
Eukaryotic genomes are duplicated from multiple replication origins exactly once per cell cycle. In Saccharomyces cerevisiae, a complex molecular network has been identified that governs the assembly of the replication machinery. Here we develop a mathematical model that links the dynamics of this network to its performance in terms of rate and coherence of origin activation events, number of activated origins, the resulting distribution of replicon sizes and robustness against DNA rereplication. To parameterize the model, we use measured protein expression data and systematically generate kinetic parameter sets by optimizing the coherence of origin firing. While randomly parameterized networks yield unrealistically slow kinetics of replication initiation, networks with optimized parameters account for the experimentally observed distribution of origin firing times. Efficient inhibition of DNA rereplication emerges as a constraint that limits the rate at which replication can be initiated. In addition to the separation between origin licensing and firing, a time delay between the activation of S phase cyclin-dependent kinase (S-Cdk) and the initiation of DNA replication is required for preventing rereplication. Our analysis suggests that distributive multisite phosphorylation of the S-Cdk targets Sld2 and Sld3 can generate both a robust time delay and contribute to switch-like, coherent activation of replication origins. The proposed catalytic function of the complex formed by Dpb11, Sld3 and Sld2 strongly enhances coherence and robustness of origin firing. The model rationalizes how experimentally observed inefficient replication from fewer origins is caused by premature activation of S-Cdk, while premature activity of the S-Cdk targets Sld2 and Sld3 results in DNA rereplication. Thus the model demonstrates how kinetic deregulation of the molecular network governing DNA replication may result in genomic instability
Antibiotic research and development: business as usual?
This article contends that poor economic incentives are an important reason for the lack of new drugs and explains how the DRIVE-AB intends to change the landscape by harnessing the expertise, motivation and diversity of its partner
Domain structure in biphenyl incommensurate phase II observed by electron paramagnetic resonance
The domain structure in incommensurate phase II of single biphenyl crystal has been observed
by investigations of the optically excited states of the Electronic Paramagnetic Resonance
(E.P.R.) deuterated naphthalene molecular probes which substitute biphenyl molecules. Our
results confirm that this phase is a 1q bi-domain one. The analysis of the spectra obtained
in X band (9.5 GHz) experiments, in relation with the spin Hamiltonian parameter properties
permits us to show that the E.P.R. probe rotates around a direction perpendicular to its long
axis while the biphenyl molecule undergoes a twist movement around this axis. They also
account for a regime which is like a “ multi-soliton " regime while the modulation is a
plane wave one in the pure single crystal. The two molecules of the high temperature cell do
not exactly experience the saure displacement field in the incommensurate phase and
consequently the two domains can be distinguished. The spin Hamiltonian parameters which
characterize the E.P.R. probes have been determined in the incommensurate phase II of
biphenyl.La structure en domaines de la phase II du biphényle est mise en évidence par les
investigations dans les états photo-excités des molécules de naphtalène deutéré, utilisées
comme sondes de Résonance Paramagnétique Electronique, se substituant de manière diluée dans
le mono-cristal de biphényle. Ceci confirme que cette phase est 1q bi-domaine. L'analyse des
spectres obtenus dans des expériences en bande X (9.5 GHz) en relation avec les propriétés de
l'hamiltonien de spin permet de montrer que la sonde moléculaire tourne autour d'une
direction perpendiculaire à son grand axe alors que la molécule de biphényle subit un
mouvement de twist autour de cet axe. Les résultats montrent que ces sondes rendent compte
d'un régime qui est comme un régime “ multi-solitons " alors que la modulation est plane
dans le cristal pur. Les deux molécules sondes de la cellule élémentaire haute température ne
subissent pas les mêmes champs de déplacements dans la phase incommensurable et en
conséquence les deux domaines peuvent être distingués. Les paramètres de l'hamiltonien de
spin qui caractérisent les sondes R.P.E. ont été déterminés dans la phase II du biphényle
Influence of an External Shear Stress on the Domain Structure in Incommensurate Phase II of Biphenyl
The incommensurate phase II of biphenyl is a bi-domain one. The naphthalene paramagnetic molecular probes used in this experiment permit the differentiation of these two domains: each Electron Paramagnetic Resonance line of the high temperature phase of biphenyl gives rise to two incommensurate lines in the phase II. But by applying a relevant shear stress, one favours one domain; this behaviour is observed on the E.P.R. spectra which exhibit only one incommensurate line. These results complete the ones obtained about the domain structure of phase II of biphenyl.La phase incommensurable II du biphényle est composée de deux domaines. La sonde paramagnétique moléculaire de naphtalène utilisée dans cette expérience de résonance paramagnétique électronique permet de différentier les deux domaines. Ainsi chaque raie R.P.E. du naphtalène de la phase haute température du biphényle donne en phase II deux raies incommensurables. Mais en appliquant une contrainte de cisaillement judicieusement choisie on favorise un domaine; ceci se voit sur le spectre R.P.E. qui ne présente alors qu'une seule raie incommensurable correspondant au domaine privilégié. Ces résultats complètent ceux obtenus précédemment sur la structure en domaines de la phase II du biphényle
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