Optimal designs for estimating the interesting part of a dose-effect curve

We consider a dose-finding trial in phase IIB of drug development. For choosing an appropriate design for this trial the specification of two points is critical: an appropriate model for describing the dose-effect relationship and the specification of the aims of the trial (objectives), which will be the focus in the present paper. For many practical situations it is essential to have a robust trial objective that has little risk of changing during the complete trial due to external information. An important and realistic objective of a dose-finding trial is to obtain precise information about the interesting part of the dose-effect curve. We reflect this goal in a statistical optimality criterion and derive efficient designs using optimal design theory. In particular we determine non-adaptive Bayesian optimal designs, i.e. designs which are not changed by information obtained from an interim analysis. Compared with a traditional balanced design for this trial it is shown that the optimal design is substantially more efficient. This implies either a gain in information or essential savings in sample size. Further, we investigate an adaptive Bayesian optimal design that uses two different optimal designs before and after an interim analysis, and we compare the adaptive with the non-adaptive Bayesian optimal design. The basic concept is illustrated using a modification of a recent AstraZeneca trial

Pleins et déliés dans les manuscrits de D’Alembert

Les manuscrits de D’Alembert, correspondance, notes et brouillons ou écrits inédits et projets de rééditions, soulèvent la question de leur histoire et de leur statut dans son œuvre. Ils constituent une source riche et complexe : révélatrice de sa façon de travailler mais dont l’hétérogénéité doit être évaluée. Écrits « scientifiques » et « littéraires », zones compactes et facilement identifiables aussi bien que sous-groupes de manuscrits parsemés et lacunaires paraissent souvent inclassables. Nous rendons compte de ces « pleins et déliés », de leurs promesses et de leurs exigences à partir de trois cas : les manuscrits scientifiques de D’Alembert, témoins de l’évolution de son mode de rédaction et de publication ; les copies corrigées de ses articles de l’Encyclopédie, préparatoires à une réédition organisée du même type que celle entreprise dans ses Mélanges ; les versions manuscrites, enfin, de certains de ses Éloges, témoins singuliers de son économie d’écriture.D’Alembert’s manuscripts, correspondence, notes, drafts, unpublished writings and reissue projects raise the question of their history and their status in his works. They form a rich and complex source, revealing D’Alembert’s working methods, but their heterogeneity has yet to be evaluated. Scientific and literary writings, compact and easily identifiable zones as well as subsections of dispersed and incomplete manuscripts, often appear impossible to classify. We show these “downstrokes and upstrokes”, their promises and requirements in three cases: D’Alembert’s scientific manuscripts, evidence of the evolution of his writing and publication methods; the corrected copies of his Encyclopedia articles, preliminary to the organized reissue similar to the one undertaken in his Mélanges; and finally, the manuscript versions of some of his Éloges, uncommon evidence of his writing system.Los manuscritos de D’Alembert, correspondencia, notas y borradores, o escritos inéditos y proyectos de reedición plantean la cuestión de su historia y de su situación con respecto a la obra, constituyendo una fuente rica y compleja, que revela su manera de trabajar, pero cuya heterogeneidad debe ser evaluada. Escritos “científicos” y “literarios”, zonas compactas y fácilmente identificables junto con subgrupos de manuscritos dispersos y fragmentarios que aparecen a menudo como inclasificables. Damos cuenta aquí de esos “claroscuros”, de sus promesas y sus exigencias a partir de tres casos: los manuscritos científicos de D’Alembert, testimonios de la evolución de su manera de redactar y publicar; las copias corregidas de sus artículos de la Enciclopedia, preparatorias de una reedición del mismo tipo que la experimentada en sus Mélanges, y, finalmente, las versiones manuscritas de algunos de sus Éloges, testimonios singulares de su economía de escritura.Die Handschriften D’Alemberts, seine Korrespondenz, Notizen und Entwürfe, oder auch nicht editierten Schriften und Pläne für Neuausgaben werfen die Frage nach ihrer Geschichte und ihrem Status im Gesamtwerk auf. Sie bilden eine reiche und vielfältige Quelle für das Studium seiner Arbeitsweise, deren Heterogenität allerdings erst evaluiert werden muss. „Wissenschaftliche“ und „literarische“ Schriften, zusammenhängende und leicht zu identifizierende Bereiche, aber auch Untergruppen heterogener und lückenhafter Manuskripte, die oft unklassifizierbar erscheinen. Wir geben Rechenschaft von all ihren Schätzen und Möglichkeiten, indem wir von drei Fällen ausgehen: die wissenschaftlichen Manuskripte D’Alemberts als Zeugen der Entwicklung seiner Schreib- und Veröffentlichungsweise; die korrigierten Abschriften seiner Encyclopédie-Einträge als Vorbereitungen für eine Neuausgabe (ähnlich wie die seiner Mélanges); und endlich die handschriftlichen Fassungen bestimmter Éloges als einzigartige Zeugen seiner Schreibstrategie.I manoscritti di D’Alembert – lettere, note, appunti o scritti inediti, e progetti di riedizione – sollevano la questione della loro storia e del loro statuto nella sua opera. Costituiscono una fonte ricca e complessa, rivelatrice del suo modo di lavorare, ma la loro eterogeneità necessita una valutazione : scritti “scientifici” e “letterari”, zone compatte e facilmente identificabili, ma anche sottogruppi di manoscritti sparsi e lacunosi, spesso non classificabili. Qui analizziamo queste diversità, le loro promesse e le loro esigenze, a partire da tre casi: i manoscritti scientifici di D’Alembert, testimoni dell’evoluzione del suo modo di redigere e pubblicare; le copie corrette de suoi articoli dell’Encyclopédie, preparatori a una riedizione organizzata dello stesso tipo di quella delle Mélanges; infine le versioni manoscritte di alcuni dei suoi Éloges, esempi singolari della sua economia di scrittura.Os manuscritos de D’Alembert – correspondência, notas e rascunhos ou escritos inéditos e projectos de reedição – colocam a questão da sua história e do estatuto que ocupam na sua obra. Fonte rico e complexa, eles são reveladores do seu modo de trabalhar, mas têm uma heterogeneidade que precisa de ser avaliada. Escritos “científicos” e “literários”, zonas compactas e facilmente identificáveis ao lado de conjuntos de manuscritos dispersos e lacunares, tudo isso resiste a uma classificação imediata. Damos aqui conta dessa mescla de traços cheios e finos, com as suas promessas e exigências, a partir de três casos: os manuscritos científicos de D’Alembert, testemunhos de evolução no seu modo de redacção e publicação; as cópias corrigidas dos seus artigos da Enciclopédia, preparatórios de uma reedição organizada à semelhança das Mélanges; e, por último, as versões manuscritas de alguns Éloges, testemunhos singulares da economia da sua escrita

Triple iron isotope constraints on the role of ocean iron sinks in early atmospheric oxygenation

International audienceThe role that iron played in the oxygenation of Earth’s surface is equivocal. Iron could have consumed molecular oxygen when Fe3+-oxyhydroxides formed in the oceans, or it could have promoted atmospheric oxidation by means of pyrite burial. Through high-precision iron isotopic measurements of Archean-Paleoproterozoic sediments and laboratory grown pyrites, we show that the triple iron isotopic composition of Neoarchean-Paleoproterozoic pyrites requires both extensive marine iron oxidation and sulfide-limited pyritization. Using an isotopic fractionation model informed by these data, we constrain the relative sizes of sedimentary Fe3+-oxyhydroxide and pyrite sinks for Neoarchean marine iron. We show that pyrite burial could have resulted in molecular oxygen export exceeding local Fe2+ oxidation sinks, thereby contributing to early episodes of transient oxygenation of Archean surface environments

Extreme-ultraviolet vector-vortex beams from high harmonic generation

[EN]Structured light in the short-wavelength regime opens exciting avenues for the study of ultrafast spin and electronic dynamics. Here, we demonstrate theoretically and experimentally the generation of vector-vortex beams (VVB) in the extreme ultraviolet through high-order harmonic generation (HHG). The up-conversion of VVB, which are spatially tailored in their spin and orbital angular momentum, is ruled by the conservation of the topological Pancharatnam charge in HHG. Despite the complex propagation of the driving beam, high-harmonic VVB are robustly generated with smooth propagation properties. Remarkably, we find out that the conversion efficiency of high-harmonic VVB increases with the driving topological charge. Our work opens the possibility to synthesize attosecond helical structures with spatially varying polarization, a unique tool to probe spatiotemporal dynamics in inhomogeneous media or polarization-dependent systems.European Research Council (851201); Ministerio de Ciencia de Innovación y Universidades, Agencia Estatal de Investigación and European Social Fund (PID2019-106910GB-I00, RYC-2017-22745); Junta de Castilla y León and FEDER Funds (SA287P18); Université Paris-Saclay (2012-0333T-OASIS, 50110000724-OPTX, PhOM REC-2019-074-MAOHAm); Conseil Régional, Île-de-France (501100003990); Barcelona Supercomputing Center (FI-2020-3-0013)

Extreme-ultraviolet structured beams via high harmonic generation

Funding European Research Council (851201); Ministerio de Ciencia de Innovación y Universidades, Agencia Estatal de Investigaci ́on and European Social Fund (PID2019106910GB-I00, RYC-2017-22745); Junta de Castilla y León and FEDER Funds (SA287P18); Université ParisSaclay (2012-0333TOASIS, 50110000724-OPTX, PhOM REC-2019-074-MAOHAm); Conseil Régional, I ˆle-de-France (501100003990); Barcelona Supercomputing Center (FI2020-3-0013).Vigorous efforts to harness the topological properties of light have enabled a multitude of novel applications. Translating the applications of structured light to higher spatial and temporal resolutions mandates their controlled generation, manipulation, and thorough characterization in the short-wavelength regime. Here, we resort to high-order harmonic generation (HHG) in a noble gas to upconvert near-infrared (IR) vector, vortex, and vector-vortex driving beams that are tailored, respectively, in their spin angular momentum (SAM), orbital angular momentum (OAM), and simultaneously in their SAM and OAM. We show that HHG enables the controlled generation of extreme-ultraviolet (EUV) vector beams exhibiting various spatially dependent polarization distributions, or EUV vortex beams with a highly twisted phase. Moreover, we demonstrate the generation of EUV vector-vortex beams (VVB) bearing combined characteristics of vector and vortex beams. We rely on EUV wavefront sensing to unambiguously affirm the topological charge scaling of the HHG beams with the harmonic order. Interestingly, our work shows that HHG allows for a synchronous controlled manipulation of SAM and OAM. These EUV structured beams bring in the promising scenario of their applications at nanometric spatial and sub-femtosecond temporal resolutions using a table-top harmonic source

Extreme-ultraviolet structured beams via high harmonic generation

Funding European Research Council (851201); Ministerio de Ciencia de Innovación y Universidades, Agencia Estatal de Investigaci ́on and European Social Fund (PID2019106910GB-I00, RYC-2017-22745); Junta de Castilla y León and FEDER Funds (SA287P18); Université ParisSaclay (2012-0333TOASIS, 50110000724-OPTX, PhOM REC-2019-074-MAOHAm); Conseil Régional, I ˆle-de-France (501100003990); Barcelona Supercomputing Center (FI2020-3-0013).Vigorous efforts to harness the topological properties of light have enabled a multitude of novel applications. Translating the applications of structured light to higher spatial and temporal resolutions mandates their controlled generation, manipulation, and thorough characterization in the short-wavelength regime. Here, we resort to high-order harmonic generation (HHG) in a noble gas to upconvert near-infrared (IR) vector, vortex, and vector-vortex driving beams that are tailored, respectively, in their spin angular momentum (SAM), orbital angular momentum (OAM), and simultaneously in their SAM and OAM. We show that HHG enables the controlled generation of extreme-ultraviolet (EUV) vector beams exhibiting various spatially dependent polarization distributions, or EUV vortex beams with a highly twisted phase. Moreover, we demonstrate the generation of EUV vector-vortex beams (VVB) bearing combined characteristics of vector and vortex beams. We rely on EUV wavefront sensing to unambiguously affirm the topological charge scaling of the HHG beams with the harmonic order. Interestingly, our work shows that HHG allows for a synchronous controlled manipulation of SAM and OAM. These EUV structured beams bring in the promising scenario of their applications at nanometric spatial and sub-femtosecond temporal resolutions using a table-top harmonic source

Décomposition en valeurs singulières randomisée et positionnement multidimensionel à base de tâches

The multidimensional scaling (MDS) is an important and robust algorithm for representing individual cases of a dataset out of their respective dissimilarities. However, heuristics, possibly trading-off with robustness, are often preferred in practice due to the potentially prohibitive memory and computational costs of the MDS. The recent introduction of random projection techniques within the MDS allowed it to be become competitive on larger testcases. The goal of this manuscript is to propose a high-performance distributed-memory MDS based on random projection for processing data sets of even larger size (up to one million items). We propose a task-based design of the whole algorithm and we implement it within an efficient software stack including state-of-the-art numerical solvers, runtime systems and communication layers. The outcome is the ability to efficiently apply robust MDS to large datasets on modern supercomputers. We assess the resulting algorithm and software stack to the point cloud visualization for analyzing distances between sequencesin metabarcoding.Le positionnement multidimensionnel (MDS) est un algorithme important et robuste pour représenter les cas individuels d’un ensemble de données en fonction de leurs dissimilarités respectives. Cependant, les heuristiques, qui peuvent être un compromis avec la robustesse, sont souvent préférées en pratique en raison de sa consommation mémoire et de ses coûts potentiellement prohibitifs. L’introduction récente de techniques de projection aléatoire dans le MDS lui a permis de devenir compétitif sur des cas test plus importants. L’objectif de ce manuscrit est de proposer un MDS haute performance basé sur la projection aléatoire pour le traitement d’ensembles de données de taille encore plus grande (jusqu’à un million d’éléments). Nous proposons une conception de l’algorithme et nous l’implémentons dans une pile logicielle efficace, comprenant des solveurs numériques de pointe ainsi des systèmes d’exécution et des couches de communication optimisés. L’aboutissement de ce travail résultat est la capacité d’appliquer efficacement le MDS robuste à de grands ensembles de données sur des super-ordinateurs modernes. Nous évaluons l’algorithme etla pile logicielle résultants à la visualisation de nuages de points pour l’analyse des distances entre séquences de metabarcoding

Acquisition of isotopic composition for surface snow in East Antarctica and the links to climatic parameters

The isotopic compositions of oxygen and hydrogen in ice cores are invaluable tools for the reconstruction of past climate variations. Used alone, they give insights into the variations of the local temperature, whereas taken together they can provide information on the climatic conditions at the point of origin of the moisture. However, recent analyses of snow from shallow pits indicate that the climatic signal can become erased in very low accumulation regions, due to local processes of snow reworking. The signal-to-noise ratio decreases and the climatic signal can then only be retrieved using stacks of several snow pits. Obviously, the signal is not completely lost at this stage, otherwise it would be impossible to extract valuable climate information from ice cores as has been done, for instance, for the last glaciation. To better understand how the climatic signal is passed from the precipitation to the snow, we present here results from varied snow samples from East Antarctica. First, we look at the relationship between isotopes and temperature from a geographical point of view, using results from three traverses across Antarctica, to see how the relationship is built up through the distillation process. We also take advantage of these measures to see how second-order parameters (d-excess and O-17-excess) are related to delta O-18 and how they are controlled. d-excess increases in the interior of the continent (i.e., when delta O-18 decreases), due to the distillation process, whereas O-17-excess decreases in remote areas, due to kinetic fractionation at low temperature. In both cases, these changes are associated with the loss of original information regarding the source. Then, we look at the same relationships in precipitation samples collected over 1 year at Dome C and Vostok, as well as in surface snow at Dome C. We note that the slope of the delta O-18 vs. temperature (T) relationship decreases in these samples compared to those from the traverses, and thus caution is advocated when using spatial slopes for past climate reconstruction. The second-order parameters behave in the same way in the precipitation as in the surface snow from traverses, indicating that similar processes are active and that their interpretation in terms of source climatic parameters is strongly complicated by local temperature effects in East Antarctica. Finally we check if the same relationships between delta O-18 and second-order parameters are also found in the snow from four snow pits. While the d-excess remains opposed to delta O-18 in most snow pits, the O-17-excess is no longer positively correlated to delta O-18 and even shows anti-correlation to delta O-18 at Vostok. This may be due to a stratospheric influence at this site and/or to post-deposition processes

Replication Fork Polarity Gradients Revealed by Megabase-Sized U-Shaped Replication Timing Domains in Human Cell Lines

In higher eukaryotes, replication program specification in different cell types remains to be fully understood. We show for seven human cell lines that about half of the genome is divided in domains that display a characteristic U-shaped replication timing profile with early initiation zones at borders and late replication at centers. Significant overlap is observed between U-domains of different cell lines and also with germline replication domains exhibiting a N-shaped nucleotide compositional skew. From the demonstration that the average fork polarity is directly reflected by both the compositional skew and the derivative of the replication timing profile, we argue that the fact that this derivative displays a N-shape in U-domains sustains the existence of large-scale gradients of replication fork polarity in somatic and germline cells. Analysis of chromatin interaction (Hi-C) and chromatin marker data reveals that U-domains correspond to high-order chromatin structural units. We discuss possible models for replication origin activation within U/N-domains. The compartmentalization of the genome into replication U/N-domains provides new insights on the organization of the replication program in the human genome

Evidence for Sequential and Increasing Activation of Replication Origins along Replication Timing Gradients in the Human Genome

Genome-wide replication timing studies have suggested that mammalian chromosomes consist of megabase-scale domains of coordinated origin firing separated by large originless transition regions. Here, we report a quantitative genome-wide analysis of DNA replication kinetics in several human cell types that contradicts this view. DNA combing in HeLa cells sorted into four temporal compartments of S phase shows that replication origins are spaced at 40 kb intervals and fire as small clusters whose synchrony increases during S phase and that replication fork velocity (mean 0.7 kb/min, maximum 2.0 kb/min) remains constant and narrowly distributed through S phase. However, multi-scale analysis of a genome-wide replication timing profile shows a broad distribution of replication timing gradients with practically no regions larger than 100 kb replicating at less than 2 kb/min. Therefore, HeLa cells lack large regions of unidirectional fork progression. Temporal transition regions are replicated by sequential activation of origins at a rate that increases during S phase and replication timing gradients are set by the delay and the spacing between successive origin firings rather than by the velocity of single forks. Activation of internal origins in a specific temporal transition region is directly demonstrated by DNA combing of the IGH locus in HeLa cells. Analysis of published origin maps in HeLa cells and published replication timing and DNA combing data in several other cell types corroborate these findings, with the interesting exception of embryonic stem cells where regions of unidirectional fork progression seem more abundant. These results can be explained if origins fire independently of each other but under the control of long-range chromatin structure, or if replication forks progressing from early origins stimulate initiation in nearby unreplicated DNA. These findings shed a new light on the replication timing program of mammalian genomes and provide a general model for their replication kinetics