scispace - formally typeset
Search or ask a question

Showing papers by "École normale supérieure de Cachan published in 2013"


Journal ArticleDOI
Keith Bradnam1, Joseph Fass1, Anton Alexandrov, Paul Baranay2, Michael Bechner, Inanc Birol, Sébastien Boisvert3, Jarrod Chapman4, Guillaume Chapuis5, Guillaume Chapuis6, Rayan Chikhi5, Rayan Chikhi6, Hamidreza Chitsaz7, Wen-Chi Chou8, Jacques Corbeil3, Cristian Del Fabbro9, T. Roderick Docking, Richard Durbin10, Dent Earl11, Scott J. Emrich12, Pavel Fedotov, Nuno A. Fonseca13, Ganeshkumar Ganapathy14, Richard A. Gibbs15, Sante Gnerre16, Elenie Godzaridis3, Steve Goldstein, Matthias Haimel13, Giles Hall16, David Haussler11, Joseph B. Hiatt17, Isaac Ho4, Jason T. Howard14, Martin Hunt10, Shaun D. Jackman, David B. Jaffe16, Erich D. Jarvis14, Huaiyang Jiang15, Sergey Kazakov, Paul J. Kersey13, Jacob O. Kitzman17, James R. Knight, Sergey Koren18, Tak-Wah Lam, Dominique Lavenier6, Dominique Lavenier5, François Laviolette3, Yingrui Li, Zhenyu Li, Binghang Liu, Yue Liu15, Ruibang Luo, Iain MacCallum16, Matthew D. MacManes19, Nicolas Maillet6, Sergey Melnikov, Bruno Vieira20, Delphine Naquin6, Zemin Ning10, Thomas D. Otto10, Benedict Paten11, Octávio S. Paulo20, Adam M. Phillippy18, Francisco Pina-Martins20, Michael Place, Dariusz Przybylski16, Xiang Qin15, Carson Qu15, Filipe J. Ribeiro16, Stephen Richards15, Daniel S. Rokhsar19, Daniel S. Rokhsar4, J. Graham Ruby21, J. Graham Ruby22, Simone Scalabrin9, Michael C. Schatz23, David C. Schwartz, Alexey Sergushichev, Ted Sharpe16, Timothy I. Shaw8, Jay Shendure17, Yujian Shi, Jared T. Simpson10, Henry Song15, Fedor Tsarev, Francesco Vezzi24, Riccardo Vicedomini9, Jun Wang, Kim C. Worley15, Shuangye Yin16, Siu-Ming Yiu, Jianying Yuan, Guojie Zhang, Hao Zhang, Shiguo Zhou, Ian F Korf1 
TL;DR: The Assemblathon 2 as mentioned in this paper presented a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and a snake) from 21 participating teams.
Abstract: Background - The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results - In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions - Many current genome assemblers produced useful assemblies, containing a significant representation of their genes, regulatory sequences, and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another.

690 citations


Journal ArticleDOI
Keith Bradnam, Joseph Fass, Anton Alexandrov, Paul Baranay1, Michael Bechner, Inanc Birol2, Sébastien Boisvert3, Jarrod Chapman4, Guillaume Chapuis5, Guillaume Chapuis6, Rayan Chikhi5, Rayan Chikhi6, Hamidreza Chitsaz7, Wen-Chi Chou8, Jacques Corbeil3, Cristian Del Fabbro, Roderick R. Docking2, Richard Durbin9, Dent Earl10, Scott J. Emrich11, Pavel Fedotov, Nuno A. Fonseca12, Ganeshkumar Ganapathy13, Richard A. Gibbs14, Sante Gnerre15, Elenie Godzaridis3, Steve Goldstein, Matthias Haimel12, Giles Hall15, David Haussler10, Joseph B. Hiatt16, Isaac Ho4, Jason T. Howard13, Martin Hunt9, Shaun D. Jackman2, David B. Jaffe15, Erich D. Jarvis13, Huaiyang Jiang14, Sergey Kazakov, Paul J. Kersey12, Jacob O. Kitzman16, James R. Knight, Sergey Koren17, Tak-Wah Lam18, Dominique Lavenier6, Dominique Lavenier5, Dominique Lavenier19, François Laviolette3, Yingrui Li18, Zhenyu Li, Binghang Liu, Yue Liu14, Ruibang Luo18, Iain MacCallum15, Matthew D. MacManes20, Nicolas Maillet19, Nicolas Maillet6, Sergey Melnikov, Delphine Naquin19, Delphine Naquin6, Zemin Ning9, Thomas D. Otto9, Benedict Paten10, Octávio S. Paulo21, Adam M. Phillippy17, Francisco Pina-Martins21, Michael Place, Dariusz Przybylski15, Xiang Qin14, Carson Qu14, Filipe J. Ribeiro, Stephen Richards14, Daniel S. Rokhsar4, Daniel S. Rokhsar22, J. Graham Ruby23, J. Graham Ruby24, Simone Scalabrin, Michael C. Schatz25, David C. Schwartz, Alexey Sergushichev, Ted Sharpe15, Timothy I. Shaw8, Jay Shendure16, Yujian Shi, Jared T. Simpson9, Henry Song14, Fedor Tsarev, Francesco Vezzi26, Riccardo Vicedomini27, Bruno Vieira21, Jun Wang, Kim C. Worley14, Shuangye Yin15, Siu-Ming Yiu18, Jianying Yuan, Guojie Zhang, Hao Zhang, Shiguo Zhou, Ian F Korf 
TL;DR: The Assemblathon 2 as discussed by the authors presented a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and a snake) from 21 participating teams.
Abstract: Background: The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results: In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. (Continued on next page)

602 citations


Book ChapterDOI
18 Aug 2013
TL;DR: In this article, a lattice-based digital signature scheme was proposed that represents an improvement, both in theory and in practice, over today's most efficient lattice primitives.
Abstract: Our main result is a construction of a lattice-based digital signature scheme that represents an improvement, both in theory and in practice, over today’s most efficient lattice schemes. The novel scheme is obtained as a result of a modification of the rejection sampling algorithm that is at the heart of Lyubashevsky’s signature scheme (Eurocrypt, 2012) and several other lattice primitives. Our new rejection sampling algorithm which samples from a bimodal Gaussian distribution, combined with a modified scheme instantiation, ends up reducing the standard deviation of the resulting signatures by a factor that is asymptotically square root in the security parameter. The implementations of our signature scheme for security levels of 128, 160, and 192 bits compare very favorably to existing schemes such as RSA and ECDSA in terms of efficiency. In addition, the new scheme has shorter signature and public key sizes than all previously proposed lattice signature schemes.

538 citations


Journal ArticleDOI
TL;DR: A new encoding of the de Bruijn graph, which occupies an order of magnitude less space than current representations, is proposed, which performed a complete de novo assembly of human genome short reads using 5.7 GB of memory in 23 hours.
Abstract: The de Bruijn graph data structure is widely used in next-generation sequencing (NGS). Many programs, e.g. de novo assemblers, rely on in-memory representation of this graph. However, current techniques for representing the de Bruijn graph of a human genome require a large amount of memory (≥30 GB). We propose a new encoding of the de Bruijn graph, which occupies an order of magnitude less space than current representations. The encoding is based on a Bloom filter, with an additional structure to remove critical false positives. An assembly software implementing this structure, Minia, performed a complete de novo assembly of human genome short reads using 5.7 GB of memory in 23 hours.

345 citations


Journal ArticleDOI
03 Sep 2013-PLOS ONE
TL;DR: This new filter reduces random noise in multicomponent DWI by locally shrinking less significant Principal Components using an overcomplete approach and is compared with state-of-the-art methods using synthetic and real clinical MR images, showing improved performance in terms of denoising quality and estimation of diffusion parameters.
Abstract: Diffusion Weighted Images (DWI) normally shows a low Signal to Noise Ratio (SNR) due to the presence of noise from the measurement process that complicates and biases the estimation of quantitative diffusion parameters. In this paper, a new denoising methodology is proposed that takes into consideration the multicomponent nature of multi-directional DWI datasets such as those employed in diffusion imaging. This new filter reduces random noise in multicomponent DWI by locally shrinking less significant Principal Components using an overcomplete approach. The proposed method is compared with state-of-the-art methods using synthetic and real clinical MR images, showing improved performance in terms of denoising quality and estimation of diffusion parameters.

334 citations


Journal ArticleDOI
TL;DR: In this paper, the longitudinal relaxation time of the electron spin associated with single nitrogen-vacancy (NV) defects hosted in nanodiamonds (NDs) was investigated.
Abstract: We report an experimental study of the longitudinal relaxation time (${T}_{1}$) of the electron spin associated with single nitrogen-vacancy (NV) defects hosted in nanodiamonds (NDs). We first show that ${T}_{1}$ decreases over three orders of magnitude when the ND size is reduced from 100 to 10 nm owing to the interaction of the NV electron spin with a bath of paramagnetic centers lying on the ND surface. We next tune the magnetic environment by decorating the ND surface with Gd${}^{3+}$ ions and observe an efficient ${T}_{1}$ quenching, which demonstrates magnetic noise sensing with a single electron spin. We estimate a sensitivity down to $\ensuremath{\approx}14$ electron spins detected within 10 s, using a single NV defect hosted in a 10-nm-size ND. These results pave the way towards ${T}_{1}$-based nanoscale imaging of the spin density in biological samples.

209 citations


Journal ArticleDOI
TL;DR: In this paper, the most recent developments in the above mentioned fields of fluorescence spectroelectrochemistry, coupled detection of fluorescence and electrochemical signals and design of molecules and materials exhibiting electrofluorochromic properties are reviewed.
Abstract: Electrofluorochromism deals with electrochemical monitoring of luminescence features There are several reasons to be interested in that field The first one is the design of displays working in a similar way to electrochromic devices, substituting colors due to absorption with colors due to emission, thus producing much higher brilliance This requires designing smart molecules and materials, which are likely to exhibit reversible switch of emission by controlling their redox state There are also a lot of analytical applications, especially in biochemical issues, where in situ dual detection of electrochemical and fluorescence signals can lead to very sensitive and selective biosensors To achieve this goal, instrumental developments are necessary, involving, among others, beyond diffraction limit and single molecule detection optical techniques This paper reviews the most recent developments in the above mentioned fields of fluorescence spectroelectrochemistry, coupled detection of fluorescence and electrochemical signals and design of molecules and materials exhibiting electrofluorochromic properties The first part describes the required features for molecular systems to exhibit a reversible switch in their luminescence properties according to a change in their redox state Examples among organic and organometallic dyes and redox labelled fluorophores are listed The second part focuses on the instrumental development in fluorescence spectroelectrochemistry and recent coupling of electrochemical techniques with fluorescence microscopy Finally, some applications and devices are presented in the last part of this review This should give an overview of this emerging research field at the interface between physics, chemistry and biology

203 citations


Journal ArticleDOI
TL;DR: The isolated electronic spin system of the Nitrogen-Vacancy (NV) center in diamond offers unique possibilities to be employed as a nanoscale sensor for detection and imaging of weak magnetic fields as discussed by the authors.
Abstract: The isolated electronic spin system of the Nitrogen-Vacancy (NV) centre in diamond offers unique possibilities to be employed as a nanoscale sensor for detection and imaging of weak magnetic fields. Magnetic imaging with nanometric resolution and field detection capabilities in the nanotesla range are enabled by the atomic-size and exceptionally long spin-coherence times of this naturally occurring defect. The exciting perspectives that ensue from these characteristics have triggered vivid experimental activities in the emerging field of "NV magnetometry". It is the purpose of this article to review the recent progress in high-sensitivity nanoscale NV magnetometry, generate an overview of the most pertinent results of the last years and highlight perspectives for future developments. We will present the physical principles that allow for magnetic field detection with NV centres and discuss first applications of NV magnetometers that have been demonstrated in the context of nano magnetism, mesoscopic physics and the life sciences.

168 citations


Journal ArticleDOI
TL;DR: Three-dimensional, vectorial and quantitative measurements of the stray magnetic field emitted by a vortex in a ferromagnetic square dot, including the detection of the vortex core are reported.
Abstract: Despite decades of advances in magnetic imaging, obtaining direct, quantitative information with nanometre scale spatial resolution remains an outstanding challenge. Recently, a technique has emerged that employs a single nitrogen-vacancy defect in diamond as an atomic-size magnetometer, which promises significant advances. However, the effectiveness of the technique when applied to magnetic nanostructures remains to be demonstrated. Here we use a scanning nitrogen-vacancy magnetometer to image a magnetic vortex, which is one of the most iconic objects of nanomagnetism, owing to the small size (~10 nm) of the vortex core. We report three-dimensional, vectorial and quantitative measurements of the stray magnetic field emitted by a vortex in a ferromagnetic square dot, including the detection of the vortex core. We find excellent agreement with micromagnetic simulations, both for regular vortex structures and for higher-order magnetization states. These experiments establish scanning nitrogen-vacancy magnetometry as a practical and unique tool for fundamental studies in nanomagnetism. Obtaining quantitative information on nanoscale magnetic structures is a challenge. Here, the authors apply scanning probe magnetometry based on a single nitrogen-vacancy defect in diamond to quantitatively map the stray magnetic field emitted by a vortex state in a ferromagnetic dot.

165 citations


Journal ArticleDOI
TL;DR: In this article, a consistent force-based blended model that couples peridynamics and classical elasticity is presented using nonlocal weights composed of integrals of blending functions, which achieves desired properties of multiscale material models such as satisfying Newton's third law and passing the patch test.

155 citations


Book ChapterDOI
TL;DR: The Gaussian Process Upper Confidence Bound and Pure exploration algorithm (GP-UCB-PE) is introduced which combines the UCB strategy and Pure Exploration in the same batch of evaluations along the parallel iterations and proves theoretical upper bounds on the regret with batches of size K for this procedure.
Abstract: In this paper, we consider the challenge of maximizing an unknown function f for which evaluations are noisy and are acquired with high cost. An iterative procedure uses the previous measures to actively select the next estimation of f which is predicted to be the most useful. We focus on the case where the function can be evaluated in parallel with batches of fixed size and analyze the benefit compared to the purely sequential procedure in terms of cumulative regret. We introduce the Gaussian Process Upper Confidence Bound and Pure Exploration algorithm (GP-UCB-PE) which combines the UCB strategy and Pure Exploration in the same batch of evaluations along the parallel iterations. We prove theoretical upper bounds on the regret with batches of size K for this procedure which show the improvement of the order of sqrt{K} for fixed iteration cost over purely sequential versions. Moreover, the multiplicative constants involved have the property of being dimension-free. We also confirm empirically the efficiency of GP-UCB-PE on real and synthetic problems compared to state-of-the-art competitors.

Journal ArticleDOI
21 Jan 2013-Analyst
TL;DR: RLS spectroscopy is shown to be useful for studying analyte-induced gold nanoparticle assembly and nanoparticle chemistry, which can induce radical changes in the plasmonic resonances responsible for the strong light scattering.
Abstract: Dark field resonant light scattering by gold and silver nanoparticles enables the detection and spectroscopy of such particles with high sensitivity, down to the single-particle level, and can be used to implement miniaturised optical detection schemes for chemical and biological analysis. Here, we present a straightforward optical spectroscopic methodology for the quantitative spectrometric study of resonant light scattering (RLS) by nanoparticles. RLS spectroscopy is complementary to UV-visible absorbance measurements, and we apply it to the characterisation and comparison of different types of gold, silver and gold-silver alloy nanoparticles. The potential of gold and silver particles as alternatives for fluorescent probes in certain applications is discussed. RLS spectroscopy is shown to be useful for studying analyte-induced gold nanoparticle assembly and nanoparticle chemistry, which can induce radical changes in the plasmonic resonances responsible for the strong light scattering. Furthermore, the feasibility of dark field RLS detection and quantitation of metal nanoparticles in microfluidic volumes is demonstrated, opening interesting possibilities for the further development of microfluidic detection schemes.

Journal ArticleDOI
TL;DR: It is shown that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin, becoming susceptible to PARP inhibitor-induced apoptosis.
Abstract: Non-small cell lung carcinoma patients are frequently treated with cisplatin (CDDP), most often yielding temporary clinical responses. Here, we show that PARP1 is highly expressed and constitutively hyperactivated in a majority of human CDDP-resistant cancer cells of distinct histologic origin. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated proteins (PAR(high)) responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs by initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Moreover, PARP1-overexpressing tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself. Thus, a majority of CDDP-resistant cancer cells appear to develop a dependency to PARP1, becoming susceptible to PARP inhibitor-induced apoptosis.

Journal ArticleDOI
TL;DR: In this article, the authors apply a simple algorithm in an automated determination of the eclipse times for all 2157 Kepler eclipsing binaries, based on a constant period model, and the resulting O - C (observed minus calculated times) curves are then visually inspected for periodicities in order to find triple-star candidates.
Abstract: We present the results of a search through the photometric database of Kepler eclipsing binaries looking for evidence of hierarchical triple-star systems. The presence of a third star orbiting the binary can be inferred from eclipse timing variations. We apply a simple algorithm in an automated determination of the eclipse times for all 2157 binaries. The ''calculated'' eclipse times, based on a constant period model, are subtracted from those observed. The resulting O - C (observed minus calculated times) curves are then visually inspected for periodicities in order to find triple-star candidates. After eliminating false positives due to the beat frequency between the {approx}1/2 hr Kepler cadence and the binary period, 39 candidate triple systems were identified. The periodic O - C curves for these candidates were then fit for contributions from both the classical Roemer delay and so-called physical delay, in an attempt to extract a number of the system parameters of the triple. We discuss the limitations of the information that can be inferred from these O - C curves without further supplemental input, e.g., ground-based spectroscopy. Based on the limited range of orbital periods for the triple-star systems to which this search is sensitive, we can extrapolatemore » to estimate that at least 20% of all close binaries have tertiary companions.« less

Journal ArticleDOI
TL;DR: In this article, a multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT).
Abstract: Several mathematical formulations have analyzed the time-dependent behaviour of a tumor mass However, most of these propose simplifications that compromise the physical soundness of the model Here, multiphase porous media mechanics is extended to model tumor evolution, using governing equations obtained via the Thermodynamically Constrained Averaging Theory (TCAT) A tumor mass is treated as a multiphase medium composed of an extracellular matrix (ECM); tumor cells (TC), which may become necrotic depending on the nutrient concentration and tumor phase pressure; healthy cells (HC); and an interstitial fluid (IF) for the transport of nutrients The equations are solved by a Finite Element method to predict the growth rate of the tumor mass as a function of the initial tumor-to-healthy cell density ratio, nutrient concentration, mechanical strain, cell adhesion and geometry Results are shown for three cases of practical biological interest such as multicellular tumor spheroids (MTS) and tumor cords First, the model is validated by experimental data for time-dependent growth of an MTS in a culture medium The tumor growth pattern follows a biphasic behaviour: initially, the rapidly growing tumor cells tend to saturate the volume available without any significant increase in overall tumor size; then, a classical Gompertzian pattern is observed for the MTS radius variation with time A core with necrotic cells appears for tumor sizes larger than 150 μm, surrounded by a shell of viable tumor cells whose thickness stays almost constant with time A formula to estimate the size of the necrotic core is proposed In the second case, the MTS is confined within a healthy tissue The growth rate is reduced, as compared to the first case – mostly due to the relative adhesion of the tumor and healthy cells to the ECM, and the less favourable transport of nutrients In particular, for tumor cells adhering less avidly to the ECM, the healthy tissue is progressively displaced as the malignant mass grows, whereas tumor cell infiltration is predicted for the opposite condition Interestingly, the infiltration potential of the tumor mass is mostly driven by the relative cell adhesion to the ECM In the third case, a tumor cord model is analyzed where the malignant cells grow around microvessels in a 3D geometry It is shown that tumor cells tend to migrate among adjacent vessels seeking new oxygen and nutrient This model can predict and optimize the efficacy of anticancer therapeutic strategies It can be further developed to answer questions on tumor biophysics, related to the effects of ECM stiffness and cell adhesion on tumor cell proliferation

Journal ArticleDOI
16 Apr 2013-Versus
TL;DR: In this paper, the authors discuss the link between intermediaries and information, through an analysis of the functions they ful!ll that may explain their emergence, as well as the opportunistic behavior of intermediaries in relation to information "ows".
Abstract: Sociology and economics tend to focus more and more on the intermediaries involved in economic and social relations, in the shape of distributors, matchmakers, consultants, and evaluators. Once they are distinguished according to their forms, their types of intervention and their effects, the intermediaries are a helpful category in order to study the social organization of markets as well as the changes that operate on them, especially regarding the social and economic values of goods, individuals and organizations. We discuss in the !rst section the link between intermediaries and information, through an analysis of the functions they ful!ll that may explain their emergence, as well as the opportunistic behavior of intermediaries in relation to information "ows. In the second section, we adopt a more pragmatist perspective on issues of valuation mainly based on ”economics of convention”, which emphasizes the collective dynamics of valuation. We show how intermediaries contribute to de!ne valuation through their different activities and foster valuation frames that can improve the coordination of actors, but also reorganize the markets in different ways. We suggest an analytical distinction between the distribution, the temporality and the generality of the frames, and raise the issue of the valuation power of market intermediaries, their legitimation and the eventual regulation of their activities.

Book ChapterDOI
23 Sep 2013
TL;DR: The Gaussian Process Upper Confidence Bound and Pure Exploration (GP-UCB-PE) algorithm as discussed by the authors combines the UCB strategy and pure exploration in the same batch of evaluations along the parallel iterations.
Abstract: In this paper, we consider the challenge of maximizing an unknown function f for which evaluations are noisy and are acquired with high cost. An iterative procedure uses the previous measures to actively select the next estimation of f which is predicted to be the most useful. We focus on the case where the function can be evaluated in parallel with batches of fixed size and analyze the benefit compared to the purely sequential procedure in terms of cumulative regret. We introduce the Gaussian Process Upper Confidence Bound and Pure Exploration algorithm (GP-UCB-PE) which combines the UCB strategy and Pure Exploration in the same batch of evaluations along the parallel iterations. We prove theoretical upper bounds on the regret with batches of size K for this procedure which show the improvement of the order of $\sqrt{K}$ for fixed iteration cost over purely sequential versions. Moreover, the multiplicative constants involved have the property of being dimension-free. We also confirm empirically the efficiency of GP-UCB-PE on real and synthetic problems compared to state-of-the-art competitors.

Journal ArticleDOI
TL;DR: A microfluidic chemostat consisting of 600 sub-micron trapping/growth channels connected to two feeding channels is designed and demonstrated by tracking with sub-diffraction resolution the movements of fluorescently tagged loci in more than one thousand cells on a single device.
Abstract: We designed a microfluidic chemostat consisting of 600 sub-micron trapping/growth channels connected to two feeding channels. The microchemostat traps E. coli cells and forces them to grow in lines for over 50 generations. Excess cells, including the mother cells captured at the start of the process, are removed from both ends of the growth channels by the media flow. With the aid of time-lapse microscopy, we have monitored dynamic properties such as growth rate and GFP expression at the single-cell level for many generations while maintaining a population of bacteria of similar age. We also use the microchemostat to show how the population responds to dynamic changes in the environment. Since more than 100 individual bacterial cells are aligned and immobilized in a single field of view, the microchemostat is an ideal platform for high-throughput intracellular measurements. We demonstrate this capability by tracking with sub-diffraction resolution the movements of fluorescently tagged loci in more than one thousand cells on a single device. The device yields results comparable to conventional agar microscopy experiments with substantial increases in throughput and ease of analysis.


Journal ArticleDOI
TL;DR: A nonintrusive reduced‐order modeling method based on the notion of space‐time‐parameter proper orthogonal decomposition (POD) for approximating the solution of nonlinear parametrized time‐dependent partial differential equations that leads to reduced‐ order models that accurately capture the behavior of the field variables as a function of the spatial coordinates, the parameter vector and time.
Abstract: We propose a nonintrusive reduced-order modeling method based on the notion of space-time-parameter proper orthogonal decomposition (POD) for approximating the solution of nonlinear parametrized time-dependent partial differential equations. A two-level POD method is introduced for constructing spatial and temporal basis functions with special properties such that the reduced-order model satisfies the boundary and initial conditions by construction. A radial basis function approximation method is used to estimate the undetermined coefficients in the reduced-order model without resorting to Galerkin projection. This nonintrusive approach enables the application of our approach to general problems with complicated nonlinearity terms. Numerical studies are presented for the parametrized Burgers' equation and a parametrized convection-reaction-diffusion problem. We demonstrate that our approach leads to reduced-order models that accurately capture the behavior of the field variables as a function of the spatial coordinates, the parameter vector and time. © 2013 Wiley Periodicals, Inc. Numer Methods Partial Differential Eq 2013

Journal ArticleDOI
TL;DR: The crystal structure of Mut101 in complex with IN is determined and it is shown that the compound binds to the LEDGF-binding pocket, promoting conformational changes of IN which explain at the atomic level the allosteric effect of the IN/LEDGF interaction inhibitor on IN functions.
Abstract: LEDGF/p75 (LEDGF) is the main cellular cofactor of HIV-1 integrase (IN). It acts as a tethering factor for IN, and targets the integration of HIV in actively transcribed gene regions of chromatin. A recently developed class of IN allosteric inhibitors can inhibit the LEDGF-IN interaction. We describe a new series of IN-LEDGF allosteric inhibitors, the most active of which is Mut101. We determined the crystal structure of Mut101 in complex with IN and showed that the compound binds to the LEDGF-binding pocket, promoting conformational changes of IN which explain at the atomic level the allosteric effect of the IN/LEDGF interaction inhibitor on IN functions. In vitro, Mut101 inhibited both IN-LEDGF interaction and IN strand transfer activity while enhancing IN-IN interaction. Time of addition experiments indicated that Mut101 behaved as an integration inhibitor. Mut101 was fully active on HIV-1 mutants resistant to INSTIs and other classes of anti-HIV drugs, indicative that this compound has a new mode of action. However, we found that Mut101 also displayed a more potent antiretroviral activity at a post-integration step. Infectivity of viral particles produced in presence of Mut101 was severely decreased. This latter effect also required the binding of the compound to the LEDGF-binding pocket. Mut101 has dual anti-HIV-1 activity, at integration and post-integration steps of the viral replication cycle, by binding to a unique target on IN (the LEDGF-binding pocket). The post-integration block of HIV-1 replication in virus-producer cells is the mechanism by which Mut101 is most active as an antiretroviral. To explain this difference between Mut101 antiretroviral activity at integration and post-integration stages, we propose the following model: LEDGF is a nuclear, chromatin-bound protein that is absent in the cytoplasm. Therefore, LEDGF can outcompete compound binding to IN in the nucleus of target cells lowering its antiretroviral activity at integration, but not in the cytoplasm where post-integration production of infectious viral particles takes place.

Journal ArticleDOI
TL;DR: In this paper, the fundamental concept of skin model has been developed as an alternative to the nominal model and covers geometric deviations that are expected, predicted or already observed in real manufacturing processes.

Journal ArticleDOI
TL;DR: Group differences may be better characterized by a different speed of maturation rather than shape differences at a given age, and this method is applied to analyze the differences in the growth of the hippocampus in children diagnosed with autism, developmental delays and in controls.
Abstract: This paper proposes an original approach for the statistical analysis of longitudinal shape data. The proposed method allows the characterization of typical growth patterns and subject-specific shape changes in repeated time-series observations of several subjects. This can be seen as the extension of usual longitudinal statistics of scalar measurements to high-dimensional shape or image data. The method is based on the estimation of continuous subject-specific growth trajectories and the comparison of such temporal shape changes across subjects. Differences between growth trajectories are decomposed into morphological deformations, which account for shape changes independent of the time, and time warps, which account for different rates of shape changes over time. Given a longitudinal shape data set, we estimate a mean growth scenario representative of the population, and the variations of this scenario both in terms of shape changes and in terms of change in growth speed. Then, intrinsic statistics are derived in the space of spatiotemporal deformations, which characterize the typical variations in shape and in growth speed within the studied population. They can be used to detect systematic developmental delays across subjects. In the context of neuroscience, we apply this method to analyze the differences in the growth of the hippocampus in children diagnosed with autism, developmental delays and in controls. Result suggest that group differences may be better characterized by a different speed of maturation rather than shape differences at a given age. In the context of anthropology, we assess the differences in the typical growth of the endocranium between chimpanzees and bonobos. We take advantage of this study to show the robustness of the method with respect to change of parameters and perturbation of the age estimates.

Journal ArticleDOI
TL;DR: Current knowledge relating to both delivery systems and combinations of inducing factors including chemicals which are used to generate human iPS cells are covered.
Abstract: The unlimited proliferation capacity of embryonic stem cells (ESCs) combined with their pluripotent differentiation potential in various lineages raised great interest in both the scientific community and the public at large with hope for future prospects of regenerative medicine. However, since ESCs are derived from human embryos, their use is associated with significant ethical issues preventing broad studies and therapeutic applications. To get around this bottleneck, Takahashi and Yamanaka have recently achieved the conversion of adult somatic cells into ES-like cells via the forced expression of four transcription factors: Oct3/4, Sox2, Klf4 and c-Myc. This first demonstration attracted public attention and opened a new field of stem cells research with both cognitive – such as disease modeling - and therapeutic prospects. This pioneer work just received the 2012 Nobel Prize in Physiology or Medicine. Many methods have been reported since 2006, for the generation of induced pluripotent stem (iPS) cells. Most strategies currently under use are based on gene delivery via gamma-retroviral or lentiviral vectors; some experiments have also been successful using plasmids or transposons-based systems and few with adenovirus. However, most experiments involve integration in the host cell genome with an identified risk for insertional mutagenesis and oncogenic transformation. To circumvent such risks which are deemed incompatible with therapeutic prospects, significant progress has been made with transgene-free reprogramming methods based on e.g.: sendai virus or direct mRNA or protein delivery to achieve conversion of adult cells into iPS. In this review we aim to cover current knowledge relating to both delivery systems and combinations of inducing factors including chemicals which are used to generate human iPS cells. Finally, genetic instability resulting from the reprogramming process is also being considered as a safety bottleneck for future clinical translation and stem cell-therapy prospects based on iPS.

Journal ArticleDOI
TL;DR: In this paper, a potential flow model for a large flap-type oscillating wave energy converter in the open ocean is derived via series expansion in terms of the Chebyshev polynomials of the second kind and even order.
Abstract: A potential flow model is derived for a large flap-type oscillating wave energy converter in the open ocean. Application of Green’s integral theorem in the fluid domain yields a hypersingular integral equation for the jump in potential across the flap. The solution is found via a series expansion in terms of the Chebyshev polynomials of the second kind and even order. Several relationships are then derived between the hydrodynamic parameters of the system. Comparison is made between the behaviour of the converter in the open ocean and in a channel. The degree of accuracy of wave tank experiments aiming at reproducing the performance of the device in the open ocean is quantified. A parametric analysis of the system is then undertaken. In particular, it is shown that increasing the flap width has the beneficial effect of broadening the bandwidth of the capture factor curve. This phenomenon can be exploited in random seas to achieve high levels of efficiency.

Journal ArticleDOI
TL;DR: In this article, the authors investigated the influence of highly purified, nano-sized attapulgite clays on the rate of structural rebuilding of cement pastes and found that the purified clays significantly accelerate the recovery of pastes, especially at early ages.

Book ChapterDOI
01 Jan 2013
TL;DR: In this paper, it was shown that the stochastic Navier-Stokes equations (SNSE) in dimension three are weak in the sense of the theory of partial differential equations (PDE).
Abstract: The theory of the stochastic Navier–Stokes equations (SNSE) has known a lot of important advances those last 20 years. Existence and uniqueness have been studied in various articles (see for instance [1, 35, 911, 13, 15, 21, 28, 30, 49, 51, 52, 66, 67]) and this part of the theory is well understood. Most of the deterministic results have been generalized to the stochastic context and it is now known that as in the deterministic case the SNSE has unique global strong solutions in dimension two. In dimension three, there exist global weak solutions and uniqueness is also a completely open problem in the stochastic case. The solutions in dimension three are weak in the sense of the theory of partial differential equations and in the sense of stochastic equations: the solutions are not smooth in space and they satisfy the SNSE only in the sense of the martingale problem. In Sect. 2 of these notes, we recall briefly these results and give the ideas of the proof.

Book
06 May 2013
TL;DR: This unique book on modern topology looks well beyond traditional treatises and explores spaces that may, but need not, be Hausdorff, essential for domain theory, the cornerstone of semantics of computer languages.
Abstract: This unique book on modern topology looks well beyond traditional treatises and explores spaces that may, but need not, be Hausdorff. This is essential for domain theory, the cornerstone of semantics of computer languages, where the Scott topology is almost never Hausdorff. For the first time in a single volume, this book covers basic material on metric and topological spaces, advanced material on complete partial orders, Stone duality, stable compactness, quasi-metric spaces and much more. An early chapter on metric spaces serves as an invitation to the topic (continuity, limits, compactness, completeness) and forms a complete introductory course by itself. Graduate students and researchers alike will enjoy exploring this treasure trove of results. Full proofs are given, as well as motivating ideas, clear explanations, illuminating examples, application exercises and some more challenging problems for more advanced readers.

Journal ArticleDOI
TL;DR: The results suggest that ifosfamide nephrotoxicity in a liver–kidney micro fluidic co‐culture model using HepaRG‐MDCK cells is induced by the metabolism of ifOSfamide into chloroacetaldehyde whereas this pathway is not functional in HepG2/C3a‐M DCK model.
Abstract: In this article, we present a liver-kidney co-culture model in a micro fluidic biochip. The liver was modeled using HepG2/C3a and HepaRG cell lines and the kidney using MDCK cell lines. To demonstrate the synergic interaction between both organs, we investigated the effect of ifosfamide, an anticancerous drug. Ifosfamide is a prodrug which is metabolized by the liver to isophosforamide mustard, an active metabolite. This metabolism process also leads to the formation of chloroacetaldehyde, a nephrotoxic metabolite and acrolein a urotoxic one. In the biochips of MDCK cultures, we did not detect any nephrotoxic effects after 72 h of 50 µM ifosfamide exposure. However, in the liver-kidney biochips, the same 72 h exposure leads to a nephrotoxicity illustrated by a reduction of the number of MDCK cells (up to 30% in the HepaRG-MDCK) when compared to untreated co-cultures or treated MDCK monocultures. The reduction of the MDCK cell number was not related to a modification of the cell cycle repartition in ifosfamide treated cases when compared to controls. The ifosfamide biotransformation into 3-dechloroethylifosfamide, an equimolar byproduct of the chloroacetaldehyde production, was detected by mass spectrometry at a rate of apparition of 0.3 ± 0.1 and 1.1 ± 0.3 pg/h/biochips in HepaRG monocultures and HepaRG-MDCK co-cultures respectively. Any metabolite was detected in HepG2/C3a cultures. Furthermore, the ifosfamide treatment in HepaRG-MDCK co-culture system triggered an increase in the intracellular calcium release in MDCK cells on contrary to the treatment on MDCK monocultures. As 3-dechloroethylifosfamide is not toxic, we have tested the effect of equimolar choloroacetaldehyde concentration onto the MDCK cells. At this concentration, we found a quite similar calcium perturbation and MDCK nephrotoxicity via a reduction of 30% of final cell numbers such as in the ifosfamide HepaRG-MDCK co-culture experiments. Our results suggest that ifosfamide nephrotoxicity in a liver-kidney micro fluidic co-culture model using HepaRG-MDCK cells is induced by the metabolism of ifosfamide into chloroacetaldehyde whereas this pathway is not functional in HepG2/C3a-MDCK model. This study demonstrates the interest in the development of systemic organ-organ interactions using micro fluidic biochips. It also illustrated their potential in future predictive toxicity model using in vitro models as alternative methods.

Journal ArticleDOI
TL;DR: Different aspects of the direct laser writing based on ultralow one-photon absorption (LOPA) technique are investigated and compared with the TPA technique, showing several advantages, such as simplicity and low cost.
Abstract: We demonstrate a new 3D fabrication method to achieve the same results as those obtained by the two-photon excitation technique, by using a simple one-photon elaboration method in a very low absorption regime. Desirable 2D and 3D submicrometric structures, such as spiral, chiral, and woodpile architectures, with feature size as small as 190 nm have been fabricated, by using just a few milliwatts of a continuous-wave laser at 532 nm and a commercial SU8 photoresist. Different aspects of the direct laser writing based on ultralow one-photon absorption (LOPA) technique are investigated and compared with the TPA technique, showing several advantages, such as simplicity and low cost.