Enhanced conformational sampling in Monte Carlo simulations of proteins: application to a constrained peptide.

A Monte Carlo simulation method for globular proteins, called extended-scaled-collective-variable (ESCV) Monte Carlo, is proposed. This method combines two Monte Carlo algorithms known as entropy-sampling and scaled-collective-variable algorithms. Entropy-sampling Monte Carlo is able to sample a large configurational space even in a disordered system that has a large number of potential barriers. In contrast, scaled-collective-variable Monte Carlo provides an efficient sampling for a system whose dynamics is highly cooperative. Because a globular protein is a disordered system whose dynamics is characterized by collective motions, a combination of these two algorithms could provide an optimal Monte Carlo simulation for a globular protein. As a test case, we have carried out an ESCV Monte Carlo simulation for a cell adhesive Arg-Gly-Asp-containing peptide, Lys-Arg-Cys-Arg-Gly-Asp-Cys-Met-Asp, and determined the conformational distribution at 300 K. The peptide contains a disulfide bridge between the two cysteine residues. This bond mimics the strong geometrical constraints that result from a protein's globular nature and give rise to highly cooperative dynamics. Computation results show that the ESCV Monte Carlo was not trapped at any local minimum and that the canonical distribution was correctly determined.

Interval bias in 2AFC detection tasks: sorting out the artifacts

Proportion correct in two-alternative forcedchoice (2AFC) detection tasks often varies when the stimulus is presented in the first or in the second interval.Reanalysis of published data reveals that these order effects (or interval bias) are strong and prevalent, refuting the standard difference model of signal detection theory. Order effects are commonly regarded as evidence that observers use an off-center criterion under the difference model with bias. We consider an alternative difference model with indecision whereby observers are occasionally undecided and guess with some bias toward one of the response options. Whether or not the data show order effects, the two models fit 2AFC data indistinguishably, but they yield meaningfully different estimates of sensory parameters. Under indeterminacy as to which model governs 2AFC performance, parameter estimates are suspect and potentially misleading. The indeterminacy can be circumvented by modifying the response format so that observers can express indecision when needed. Reanalysis of published data collected in this way lends support to the indecision model. We illustrate alternative approaches to fitting psychometric functions under the indecision model and discuss designs for 2AFC experiments that improve the accuracy of parameter estimates, whether or not order effects are apparent in the data.

Pion-kaon scattering amplitude constrained with forward dispersion relations up to 1.6 GeV

In this work we provide simple and precise parametrizations of the existing πK scattering data from threshold up to 1.6 GeV, which are constrained to satisfy forward dispersion relations as well as three additional threshold sum rules. We also provide phenomenological values of the threshold parameters and of the resonance poles that appear in elastic scattering.

Stationarity and regularity of infinite collections of sets. Applications to infinitely constrained optimization

This article continues the investigation of stationarity and regularity properties of infinite collections of sets in a Banach space started in Kruger and López (J. Optim. Theory Appl. 154(2), 2012), and is mainly focused on the application of the stationarity criteria to infinitely constrained optimization problems. We consider several settings of optimization problems which involve (explicitly or implicitly) infinite collections of sets and deduce for them necessary conditions characterizing stationarity in terms of dual space elements—normals and/or subdifferentials.

Spatiotemporal characteristics of the Huangtupo landslide in the Three Gorges region (China) constrained by radar interferometry

The Huangtupo landslide is one of the largest in the Three Gorges region, China. The county-seat town of Badong, located on the south shore between the Xiling and Wu gorges of the Yangtze River, was moved to this unstable slope prior to the construction of the Three Gorges Project, since the new Three Gorges reservoir completely submerged the location of the old city. The instability of the slope is affecting the new town by causing residential safety problems. The Huangtupo landslide provides scientists an opportunity to understand landslide response to fluctuating river water level and heavy rainfall episodes, which is essential to decide upon appropriate remediation measures. Interferometric Synthetic Aperture Radar (InSAR) techniques provide a very useful tool for the study of superficial and spatially variable displacement phenomena. In this paper, three sets of radar data have been processed to investigate the Huangtupo landslide. Results show that maximum displacements are affecting the northwest zone of the slope corresponding to Riverside slumping mass I#. The other main landslide bodies (i.e. Riverside slumping mass II#, Substation landslide and Garden Spot landslide) exhibit a stable behaviour in agreement with in situ data, although some active areas have been recognized in the foot of the Substation landslide and Garden Spot landslide. InSAR has allowed us to study the kinematic behaviour of the landslide and to identify its active boundaries. Furthermore, the analysis of the InSAR displacement time-series has helped recognize the different displacement patterns on the slope and their relationships with various triggering factors. For those persistent scatterers, which exhibit long-term displacements, they can be decomposed into a creep model (controlled by geological conditions) and a superimposed recoverable term (dependent on external factors), which appears closely correlated with reservoir water level changes close to the river's edge. These results, combined with in situ data, provide a comprehensive analysis of the Huangtupo landslide, which is essential for its management.

Time-Precision Flexible Arithmetic Unit

Paper submitted to the XVIII Conference on Design of Circuits and Integrated Systems (DCIS), Ciudad Real, España, 2003.

Calculation Methodology for Flexible Arithmetic Processing

Paper submitted to the IFIP International Conference on Very Large Scale Integration (VLSI-SOC), Darmstadt, Germany, 2003.

Hough Transform recursive evaluation using Distributed Arithmetic

Paper submitted to the IFIP International Conference on Very Large Scale Integration (VLSI-SOC), Darmstadt, Germany, 2003.

Constrained self-organizing feature map to preserve feature extraction topology

In many classification problems, it is necessary to consider the specific location of an n-dimensional space from which features have been calculated. For example, considering the location of features extracted from specific areas of a two-dimensional space, as an image, could improve the understanding of a scene for a video surveillance system. In the same way, the same features extracted from different locations could mean different actions for a 3D HCI system. In this paper, we present a self-organizing feature map able to preserve the topology of locations of an n-dimensional space in which the vector of features have been extracted. The main contribution is to implicitly preserving the topology of the original space because considering the locations of the extracted features and their topology could ease the solution to certain problems. Specifically, the paper proposes the n-dimensional constrained self-organizing map preserving the input topology (nD-SOM-PINT). Features in adjacent areas of the n-dimensional space, used to extract the feature vectors, are explicitly in adjacent areas of the nD-SOM-PINT constraining the neural network structure and learning. As a study case, the neural network has been instantiate to represent and classify features as trajectories extracted from a sequence of images into a high level of semantic understanding. Experiments have been thoroughly carried out using the CAVIAR datasets (Corridor, Frontal and Inria) taken into account the global behaviour of an individual in order to validate the ability to preserve the topology of the two-dimensional space to obtain high-performance classification for trajectory classification in contrast of non-considering the location of features. Moreover, a brief example has been included to focus on validate the nD-SOM-PINT proposal in other domain than the individual trajectory. Results confirm the high accuracy of the nD-SOM-PINT outperforming previous methods aimed to classify the same datasets.

Proposal for a treatise on arithmetic, 1803

Handwritten proposal for the printing of a treatise on arithmetic by Croswell.

Arithmetic copybook : manuscript, [17--]

Arithmetic copybook containing mathematical rules, problems, proofs, and charts of weights and measures.

Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents & metal coordination-controlled and bifunctional catalysis toward tertiary β-Ketols

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.

The harsh reality of Ukraine's fiscal arithmetic. Bruegel Policy Contribution ISSUE 2015/07, June 2015

Ukraine is struggling with both external aggression and the dramatically poor shape of its economy. The pace of political and institutional change has so far been too slow to prevent the deepening of the fiscal and balance-of-payments crises, while business confidence continues to be undermined. • Unfortunately, the 2015 International Monetary Fund Extended Fund Facility programme repeats many weaknesses of the 2014 IMF Stand-by Arrangement: slow pace of fiscal adjustment especially in the two key areas of energy prices and pension entitlements, lack of a comprehensive structural and institutional reform vision, and insufficient external financing to close the expected balance-of-payments gap and allow Ukraine to return to debt sustainability in the long term. • The reform process in Ukraine must be accelerated and better managed. A frontloaded fiscal adjustment is necessary to stabilise public finances and the balance-of-payments, and to bring inflation down. The international community, especially the European Union, should offer sufficient financial aid backed by strong conditionality, technical assistance and support to Ukraine’s independence and territorial integrity.

A probabilistic assessment of calcium carbonate export and dissolution in the modern ocean

The marine cycle of calcium carbonate (CaCO3) is an important element of the carbon cycle and co-governs the distribution of carbon and alkalinity within the ocean. However, CaCO3 export fluxes and mechanisms governing CaCO3 dissolution are highly uncertain. We present an observationally constrained, probabilistic assessment of the global and regional CaCO3 budgets. Parameters governing pelagic CaCO3 export fluxes and dissolution rates are sampled using a Monte Carlo scheme to construct a 1000-member ensemble with the Bern3D ocean model. Ensemble results are constrained by comparing simulated and observation-based fields of excess dissolved calcium carbonate (TA*). The minerals calcite and aragonite are modelled explicitly and ocean–sediment fluxes are considered. For local dissolution rates, either a strong or a weak dependency on CaCO3 saturation is assumed. In addition, there is the option to have saturation-independent dissolution above the saturation horizon. The median (and 68 % confidence interval) of the constrained model ensemble for global biogenic CaCO3 export is 0.90 (0.72–1.05) Gt C yr−1, that is within the lower half of previously published estimates (0.4–1.8 Gt C yr−1). The spatial pattern of CaCO3 export is broadly consistent with earlier assessments. Export is large in the Southern Ocean, the tropical Indo–Pacific, the northern Pacific and relatively small in the Atlantic. The constrained results are robust across a range of diapycnal mixing coefficients and, thus, ocean circulation strengths. Modelled ocean circulation and transport timescales for the different set-ups were further evaluated with CFC11 and radiocarbon observations. Parameters and mechanisms governing dissolution are hardly constrained by either the TA* data or the current compilation of CaCO3 flux measurements such that model realisations with and without saturation-dependent dissolution achieve skill. We suggest applying saturation-independent dissolution rates in Earth system models to minimise computational costs.