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Information-theoretic analysis of the directional influence between cellular processes
Laboratoire Biochimie - Sourabh Lahiri, Philippe Nghe, Sander J. Tans, Martin Luc Rosinberg, David Lacoste
- 12(11) - - 2017
Inferring the directionality of interactions between cellular processes is a major challenge in systems biology. Time-lagged correlations allow to discriminate between alternative models, but they still rely on assumed underlying interactions. Here, we use the transfer entropy (TE), an information-theoretic quantity that quantifies the directional influence between fluctuating variables in a model-free way. We present a theoretical approach to compute the transfer entropy, even when the noise has an extrinsic component or in the presence of feedback. We re-analyze the experimental data from Kiviet et al. (2014) where fluctuations in gene expression of metabolic enzymes and growth rate have been measured in single cells of E. coli. We confirm the formerly detected modes between growth and gene expression, while prescribing more stringent conditions on the structure of noise sources. We furthermore point out practical requirements in terms of length of time series and sampling time which must be satisfied in order to infer optimally transfer entropy from times series of fluctuations.
Single-cell deep phenotyping of IgG-secreting cells for high-resolution immune monitoring
Laboratoire Biochimie - Eyer K, Doineau RCL, Castrillon CE, Briseño-Roa L, Menrath V, Mottet G, England P, Godina A, Brient-Litzler E, Nizak C, Jensen A, Griffiths AD, Bibette J, Bruhns P4, Baudry J.
Nat Biotechnol. - 35(10) 977-982 - doi: 10.1038/nbt.3964 - 2017
Studies of the dynamics of the antibody-mediated immune response have been hampered by the absence of quantitative, high-throughput systems to analyze individual antibody-secreting cells. Here we describe a simple microfluidic system, DropMap, in which single cells are compartmentalized in tens of thousands of 40-pL droplets and analyzed in two-dimensional droplet arrays using a fluorescence relocation-based immunoassay. Using DropMap, we characterized antibody-secreting cells in mice immunized with tetanus toxoid (TT) over a 7-week protocol, simultaneously analyzing the secretion rate and affinity of IgG from over 0.5 million individual cells enriched from spleen and bone marrow. Immunization resulted in dramatic increases in the range of both single-cell secretion rates and affinities, which spanned at maximum 3 and 4 logs, respectively. We observed differences over time in dynamics of secretion rate and affinity within and between anatomical compartments. This system will not only enable immune monitoring and optimization of immunization and vaccination protocols but also potentiate antibody screening.
Emergence of a catalytic tetrad during evolution of a highly active artificial aldolase.
Laboratoire Biochimie - Obexer R, Godina A, Garrabou X, Mittl PR, Baker D, Griffiths AD, Hilvert D.
Nat Chem. - 9(1) 50-56 - doi: 10.1038/nchem.2596 - 2017
Designing catalysts that achieve the rates and selectivities of natural enzymes is a long-standing goal in protein chemistry. Here, we show that an ultrahigh-throughput droplet-based microfluidic screening platform can be used to improve a previously optimized artificial aldolase by an additional factor of 30 to give a >109 rate enhancement that rivals the efficiency of class I aldolases. The resulting enzyme catalyses a reversible aldol reaction with high stereoselectivity and tolerates a broad range of substrates. Biochemical and structural studies show that catalysis depends on a Lys-Tyr-Asn-Tyr tetrad that emerged adjacent to a computationally designed hydrophobic pocket during directed evolution. This constellation of residues is poised to activate the substrate by Schiff base formation, promote mechanistically important proton transfers and stabilize multiple transition states along a complex reaction coordinate. The emergence of such a sophisticated catalytic centre shows that there is nothing magical about the catalytic activities or mechanisms of naturally occurring enzymes, or the evolutionary process that gave rise to them.
Topological and thermodynamic factors that influence the evolution of small networks of catalytic RNA species.
Laboratoire Biochimie - Yeates JAM, Nghe P, Lehman N.
RNA. - 23(7) 1088-1096 - doi: 10.1261/rna.061093.117 - 2017
An RNA-directed recombination reaction can result in a network of interacting RNA species. It is now becoming increasingly apparent that such networks could have been an important feature of the RNA world during the nascent evolution of life on the Earth. However, the means by which such small RNA networks assimilate other available genotypes in the environment to grow and evolve into the more complex networks that are thought to have existed in the prebiotic milieu are not known. Here, we used the ability of fragments of the Azoarcus group I intron ribozyme to covalently self-assemble via genotype-selfish and genotype-cooperative interactions into full-length ribozymes to investigate the dynamics of small (three- and four-membered) networks. We focused on the influence of a three-membered core network on the incorporation of additional nodes, and on the degree and direction of connectivity as single new nodes are added to this core. We confirmed experimentally the predictions that additional links to a core should enhance overall network growth rates, but that the directionality of the link (a "giver" or a "receiver") impacts the growth of the core itself. Additionally, we used a simple mathematical model based on the first-order effects of lower-level interactions to predict the growth of more complex networks, and find that such a model can, to a first approximation, predict the ordinal rankings of nodes once a steady-state distribution has been reached.
Synthesis of new hydrophilic rhodamine based enzymatic substrates compatible with droplet-based microfluidic assays
Laboratoire Biochimie - Johan Fenneteau, Dany Chauvin,b Andrew D. Griffiths,b Clément Nizak,b and Janine Cossy
Chem. Comm. - 53 5437-5440 - DOI: 10.1039/C7CC01506B - 2017
Here we report the conception, synthesis and evaluation of new hydrophilic rhodamine-based enzymatic substrates for detection of peptidase activity compatible with high-throughput screening using droplet-based microfluidics.
Droplet-based microfluidic high-throughput screening of heterologous enzymes secreted by the yeast Yarrowia lipolytica
Laboratoire Biochimie - Beneyton T, Thomas S, Griffiths AD, Nicaud JM, Drevelle A, Rossignol T.
Microb Cell Fact. - 16(1) 18 - doi: 10.1186/s12934-017-0629-5. - 2017
Droplet-based microfluidics is becoming an increasingly attractive alternative to microtiter plate techniques for enzymatic high-throughput screening (HTS), especially for exploring large diversities with lower time and cost footprint. In this case, the assayed enzyme has to be accessible to the substrate within the water-in-oil droplet by being ideally extracellular or displayed at the cell surface. However, most of the enzymes screened to date are expressed within the cytoplasm of Escherichia coli cells, which means that a lysis step must take place inside the droplets for enzyme activity to be assayed. Here, we take advantage of the excellent secretion abilities of the yeast Yarrowia lipolytica to describe a highly efficient expression system particularly suitable for the droplet-based microfluidic HTS.
Five hydrolytic genes from Aspergillus niger genome were chosen and the corresponding five Yarrowia lipolytica producing strains were constructed. Each enzyme (endo-β-1,4-xylanase B and C; 1,4-β-cellobiohydrolase A; endoglucanase A; aspartic protease) was successfully overexpressed and secreted in an active form in the crude supernatant. A droplet-based microfluidic HTS system was developed to (a) encapsulate single yeast cells; (b) grow yeast in droplets; (c) inject the relevant enzymatic substrate; (d) incubate droplets on chip; (e) detect enzymatic activity; and (f) sort droplets based on enzymatic activity. Combining this integrated microfluidic platform with gene expression in Y. lipolytica results in remarkably low variability in the enzymatic activity at the single cell level within a given monoclonal population (<5%). Xylanase, cellobiohydrolase and protease activities were successfully assayed using this system. We then used the system to screen for thermostable variants of endo-β-1,4-xylanase C in error-prone PCR libraries. Variants displaying higher thermostable xylanase activities compared to the wild-type were isolated (up to 4.7-fold improvement).
Yarrowia lipolytica was used to express fungal genes encoding hydrolytic enzymes of interest. We developed a successful droplet-based microfluidic platform for the high-throughput screening (105 strains/h) of Y. lipolytica based on enzyme secretion and activity. This approach provides highly efficient tools for the HTS of recombinant enzymatic activities. This should be extremely useful for discovering new biocatalysts via directed evolution or protein engineering approaches and should lead to major advances in microbial cell factory development.
Derivation of nearest-neighbor DNA parameters in magnesium from single molecule experiments.
Laboratoire Biochimie - Huguet JM1,2, Ribezzi-Crivellari M3, Bizarro CV4, Ritort F1,5.
Nucleic Acids Res. - 120 158101 - doi: 10.1093/nar/gkx1161. - 2017
DNA hybridization is an essential molecular reaction in biology with many applications. The nearest-neighbor (NN) model for nucleic acids predicts DNA thermodynamics using energy values for the different base pair motifs. These values have been derived from melting experiments in monovalent and divalent salt and applied to predict melting temperatures of oligos within a few degrees. However, an improved determination of the NN energy values and their salt dependencies in magnesium is still needed for current biotechnological applications seeking high selectivity in the hybridization of synthetic DNAs. We developed a methodology based on single molecule unzipping experiments to derive accurate NN energy values and initiation factors for DNA. A new set of values in magnesium is derived, which reproduces unzipping data and improves melting temperature predictions for all available oligo lengths, in a range of temperature and salt conditions where correlation effects between the magnesium bound ions are weak. The NN salt correction parameters are shown to correlate to the GC content of the NN motifs. Our study shows the power of single-molecule force spectroscopy assays to unravel novel features of nucleic acids such as sequence-dependent salt corrections.
Evolutionary Applications
Laboratoire Biochimie - Calcagno, V., Mitoyen, C., Audiot, P., Ponsard, S., Gao, G.-Z., Lu, Z.-Z., Wang, Z.-Y., He, K.-L., and Bourguet, D. Parallel
Semin Cell Dev Biol. - 10 9 - DOI: 10.1111/eva.12481 - 2017
Maize was introduced into opposite sides of Eurasia 500 years ago, in Western Europe and in Asia. This caused two host-shifts in the phytophagous genus Ostrinia; O. nubilalis (the European corn borer; ECB) and O. furnacalis (the Asian corn borer; ACB) are now major pests of maize worldwide. They originated independently from Dicot-feeding ancestors, similar to O. scapulalis(the Adzuki bean borer; ABB). Unlike other host-plants, maize is yearly harvested, and harvesting practices impose severe mortality on larvae found above the cut-off line. Positive geotaxis in the ECB has been proposed as a behavioural adaptation to harvesting practices, allowing larvae to move below the cut-off line and thus escape harvest mortality. Here, we test whether the same behavioural adaptation evolved independently in Europe and in Asia. We sampled eight genetically differentiated ECB, ACB and ABB populations in France and China and monitored geotaxis through the entire larval development in artificial stacks mimicking maize stems. We find that all ECB and ACB populations show a similar tendency to move down during the latest larval stages, a behaviour not observed in any European or Asian ABB population. The behaviour is robustly expressed regardless of larval density, development mode or environmental conditions. Our results indicate that maize introduction triggered parallel behavioural adaptations in Europe and Asia, harvest selection presumably being the main driver.
Caveolin-1 Expression Increases upon Maturation in Dendritic Cells and Promotes Their Migration to Lymph Nodes Thereby Favoring the Induction of CD8 T Cell Responses.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Oyarce C, Cruz-Gomez S, Galvez-Cancino F, Vargas P, Moreau HD, Diaz-Valdivia N, Diaz J, Salazar-Onfray FA, Pacheco R6, Lennon-Dumenil AM, Quest AFG, Lladser A.
Front Immunol - 13;8 1794 - doi: 10.3389/fimmu.2017.01794 - 2017
Dendritic cell (DC) trafficking from peripheral tissues to lymph nodes (LNs) is a key step required to initiate T cell responses against pathogens as well as tumors. In this context, cellular membrane protrusions and the actin cytoskeleton are essential to guide DC migration towards chemotactic signals. Caveolin-1 (CAV1) is a scaffolding protein that modulates signaling pathways leading to remodeling of the actin cytoskeleton and enhanced migration of cancer cells. However, whether CAV1 is relevant for DC function and specifically for DC migration to LNs is unknown. Here, we show that CAV1 expression is upregulated in DCs upon LPS- and TNF-α-induced maturation. CAV1 deficiency did not affect differentiation, maturation, or the ability of DCs to activate CD8+ T cells in vitro. However, CAV1-deficient (CAV1-/-) DCs displayed reduced in vivo trafficking to draining LNs in control and inflammatory conditions. In vitro, CAV1-/- DCs showed reduced directional migration in CCL21 gradients in transwell assays without affecting migration velocity in confined microchannels or three-dimensional collagen matrices. In addition, CAV1-/- DCs displayed reduced activation of the small GTPase Rac1, a regulator of actin cytoskeletal remodeling, and lower numbers of F-actin-forming protrusions. Furthermore, mice adoptively transferred with peptide-pulsed CAV1-/- DCs showed reduced CD8+ T cell responses and antitumor protection. Our results suggest that CAV1 promotes the activation of Rac1 and the formation of membrane protrusions that favor DC chemotactic trafficking toward LNs where they can initiate cytotoxic T cell responses.
ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X receptors.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Sáez PJ, Vargas P, Shoji KF, Harcha PA, Lennon-Duménil AM, Sáez JC
Sci Signal. - 10(506) 7107 - doi: 10.1126/scisignal.aah7107. - 2017
Upon its release from injured cells, such as infected, transformed, inflamed, or necrotic cells, extracellular adenosine-5'-triphosphate (ATP) acts as a danger signal that recruits phagocytes, such as neutrophils, macrophages, and dendritic cells (DCs), to the site of injury. The sensing of extracellular ATP occurs through purinergic (P2) receptors. We investigated the cellular mechanisms linking purinergic signaling to DC motility. We found that ATP stimulated fast DC motility through an autocrine signaling loop, which was initiated by the activation of P2X7 receptors and further amplified by pannexin 1 (Panx1) channels. Upon stimulation of the P2X7 receptor by ATP, Panx1 contributed to fast DC motility by increasing the permeability of the plasma membrane, which resulted in supplementary ATP release. In the absence of Panx1, DCs failed to increase their speed of migration in response to ATP, despite exhibiting a normal P2X7 receptor-mediated Ca2+ response. In addition to DC migration, Panx1 channel- and P2X7 receptor-dependent signaling was further required to stimulate the reorganization of the actin cytoskeleton. In vivo, functional Panx1 channels were required for the homing of DCs to lymph nodes, although they were dispensable for DC maturation. These data suggest that P2X7 receptors and Panx1 channels are crucial players in the regulation of DC migration to endogenous danger signals.
Lysosome signaling controls the migration of dendritic cells.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Bretou M, Sáez PJ, Sanséau D, Maurin M, Lankar D, Chabaud M, Spampanato C, Malbec O, Barbier L, Muallem S, Maiuri P, Ballabio A, Helft J, Piel M, Vargas P, Lennon-Duménil AM.
Sci Immunol - 2(16) 9573. - doi: 10.1126/sciimmunol.aak9573. - 2017
Dendritic cells (DCs) patrol their environment by linking antigen acquisition by macropinocytosis to cell locomotion. DC activation upon bacterial sensing inhibits macropinocytosis and increases DC migration, thus promoting the arrival of DCs to lymph nodes for antigen presentation to T cells. The signaling events that trigger such changes are not fully understood. We show that lysosome signaling plays a critical role in this process. Upon bacterial sensing, lysosomal calcium is released by the ionic channel TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1), which activates the actin-based motor protein myosin II at the cell rear, promoting fast and directional migration. Lysosomal calcium further induces the activation of the transcription factor EB (TFEB), which translocates to the nucleus to maintain TRPML1 expression. We found that the TRPML1-TFEB axis results from the down-regulation of macropinocytosis after bacterial sensing by DCs. Lysosomal signaling therefore emerges as a hitherto unexpected link between macropinocytosis, actomyosin cytoskeleton organization, and DC migration.
Mechanisms for fast cell migration in complex environments.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Vargas P, Barbier L, Sáez PJ, Piel M.
Curr Opin Cell Biol - 48 72-78 - doi: 10.1016/ - 2017
Cell migration depends on a combination of the cell's intrinsic capacity to move and the proper interpretation of external cues. This multistep process enables leukocytes to travel long distances in organs in just a few hours. This fast migration is partly due to the leukocytes' high level of plasticity, which helps them to adapt to a changing environment. Here, we review recent progress in understanding the mechanisms used by leukocytes to move rapidly and efficiently in intricate anatomical landscapes. We shall focus on specific cytoskeletal rearrangements used by neutrophils and dendritic cells to migrate within confined environments. Lastly, we will describe the properties that facilitate the rapid migration of leukocyte in complex tissue geometries.
Fluorescence eXclusion Measurement of volume in live cells.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Cadart C, Zlotek-Zlotkiewicz E, Venkova L, Thouvenin O, Racine V, Le Berre M, Monnier S, Piel M.
Methods Cell Biol. - 139 103-120 - doi: 10.1016/bs.mcb.2016.11.009 - 2017
Volume is a basic physical property of cells; however, it has been poorly investigated in cell biology so far, mostly because it is difficult to measure it precisely. Recently, large efforts were made to experimentally measure mammalian cell size and used mass, density, or volume as proxies for cell size. Here, we describe a method enabling cell volume measurements for single living cells. The method is based on the principle of fluorescent dye exclusion and can be easily implemented in cell biology laboratories. As this method is very versatile, it can be used for cells of different sizes, adherent or growing in suspension, over several cell cycles and is independent of cell shape changes. The method is also compatible with traditional cell biology tools such as epifluorescence imaging or drug treatments.
Micromanipulation of daughter cells for the study of cytokinetic abscission
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Lafaurie-Janvore J, Lafaurie C, Piel M.
Methods Cell Biol. - 137 187-203 - DOI: 10.1016/bs.mcb.2016.04.012 - 2017
The last step of cytokinesis, abscission, consists in the severing of the intercellular bridge connecting the two daughter cells. Because daughter cells move randomly on regular cell culture substrates, the use of adhesive micropatterns facilitates the observation of the intercellular bridge and its severing. Here we propose general rules to design micropatterns optimized to study this process. In particular, these micropatterns allow a good stabilization of the daughter cells and a predictable positioning of the intercellular bridge. We suggest a series of micropatterns controlling various cellular parameters such as distance between daughter cells or daughter cells polarization. We give recommendations for videomicroscopy acquisition during cell division and propose automated image analysis methods using kymograph analysis or bridge detection. Finally, we detail methods to artificially cut the intercellular bridge using UV-based laser ablation or using two-photons laser ablation.
Forcing Entry into the Nucleus.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Lomakin A, Nader G, Piel M.
Dev Cell - 43(5) 547-548 - doi: 10.1016/j.devcel.2017.11.015. - 2017
Nuclear pore complexes tightly regulate nucleo-cytoplasmic transport, controlling the nuclear concentration of several transcription factors. In a recent issue of Cell, Elosegui-Artola et al. (2017) show that nuclear deformation modulates the nuclear entry rates of YAP/TAZ via nuclear pore stretching, clarifying how forces affect gene transcription.
UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Sophia Maschalidi, Paula Nunes-Hasler, Clarissa R Nascimento, Ignacio Sallent, Valérie Lannoy, Meriem Garfa-Traore, Nicolas Cagnard, Fernando E Sepulveda, Pablo Vargas, Ana-Maria Lennon-Duménil, Peter van Endert, Thierry Capiod, Nicolas Demaurex, Guillau
Nat Commun - 1640 - DOI : 10.1038/s41467-017-01601-5 - 2017
Dendritic cells (DC) have the unique ability to present exogenous antigens via the major histocompatibility complex class I pathway to stimulate naive CD8 T cells. In DCs with a non-functional mutation in Unc93b1 (3d mutation), endosomal acidification, phagosomal maturation, antigen degradation, antigen export to the cytosol and the function of the store-operated-Ca-entry regulator STIM1 are impaired. These defects result in compromised antigen cross-presentation and anti-tumor responses in 3d-mutated mice. Here, we show that UNC93B1 interacts with the calcium sensor STIM1 in the endoplasmic reticulum, a critical step for STIM1 oligomerization and activation. Expression of a constitutively active STIM1 mutant, which no longer binds UNC93B1, restores antigen degradation and cross-presentation in 3d-mutated DCs. Furthermore, ablation of STIM1 in mouse and human cells leads to a decrease in cross-presentation. Our data indicate that the UNC93B1 and STIM1 cooperation is important for calcium flux and antigen cross-presentation in DCs
A tuneable microfluidic system for long duration chemotaxis experiments in a 3D collagen matrix.
Laboratoire Biologie cellulaire systémique de la polarité et de la division - Aizel K1, Clark AG, Simon A, Geraldo S, Funfak A, Vargas P, Bibette J, Vignjevic DM, Bremond N.
Sci Immunol - 17(22) 3851-3861 - doi: 10.1039/c7lc00649g. - 2017
In many cell types, migration can be oriented towards a chemical stimulus. In mammals, for example, embryonic cells migrate to follow developmental cues, immune cells migrate toward sites of inflammation, and cancer cells migrate away from the primary tumour and toward blood vessels during metastasis. Understanding how cells migrate in 3D environments in response to chemical cues is thus crucial to understanding directed migration in normal and disease states. To date, chemotaxis in mammalian cells has been primarily studied using 2D migration models. However, it is becoming increasingly clear that the mechanisms by which cells migrate in 2D and 3D environments dramatically differ, and cells in their native environments are confronted with a complex chemical milieu. To address these issues, we developed a microfluidic device to monitor the behaviour of cells embedded in a 3D collagen matrix in the presence of complex concentration fields of chemoattractants. This tuneable microsystem enables the generation of (1) homogeneous, stationary gradients set by a purely diffusive mechanism, or (2) spatially evolving, stationary gradients, set by a convection-diffusion mechanism. The device allows for stable gradients over several days and is large enough to study the behaviour of large cell aggregates. We observe that primary mature dendritic cells respond uniformly to homogeneous diffusion gradients, while cell behaviour is highly position-dependent in spatially variable convection-diffusion gradients. In addition, we demonstrate a directed response of cancer cells migrating away from tumour-like aggregates in the presence of soluble chemokine gradients. Together, this microfluidic device is a powerful system to observe the response of different cells and aggregates to tuneable chemical gradients.
Optimizing Hyperuniformity in Self-Assembled Bidisperse Emulsions
Laboratoire Biophysique et Evolution - Joshua Ricouvier, Romain Pierrat, Rémi Carminati, Patrick Tabeling, and Pavel Yazhgur
Phys. Rev. Lett. - 119 208001 - - 2017
We study long range density fluctuations (hyperuniformity) in two-dimensional jammed packings of bidisperse droplets. Taking advantage of microfluidics, we systematically span a large range of size and concentration ratios of the two droplet populations. We identify various defects increasing long range density fluctuations mainly due to organization of local particle environment. By choosing an appropriate bidispersity, we fabricate materials with a high level of hyperuniformity. Interesting transparency properties of these optimized materials are established based on numerical simulations.
Paper-based RNA detection and multiplexed analysis for Ebola virus diagnostics
Laboratoire Biophysique et Evolution - Laura Magro, Béatrice Jacquelin, Camille Escadafal, Pierre Garneret, Aurélia Kwasiborski, Jean-Claude Manuguerra, Fabrice Monti, Anavaj Sakuntabhai, Jessica Vanhomwegen, Pierre Lafaye & Patrick Tabeling
Scientific Reports - 1347 (2017) - - 2017
The most performing techniques enabling early diagnosis of infectious diseases rely on nucleic acid detection. Today, because of their high technicality and cost, nucleic acid amplification tests (NAAT) are of benefit only to a small fraction of developing countries population. By reducing costs, simplifying procedures and enabling multiplexing, paper microfluidics has the potential to considerably facilitate their accessibility. However, most of the studies performed in this area have not quit the lab. This letter brings NAAT on paper closer to the field, by using clinical samples and operating in a resource-limited setting. We first performed isothermal reverse transcription and Recombinase Polymerase Amplification (RT-RPA) of synthetic Ribonucleic Acid (RNA) of Ebola virus using paper microfluidics devices. We further applied this method in Guinea to detect the presence of Ebola virus in human sample RNA extracts, with minimal facilities (carry-on detection device and freeze-dried reagents on paper). RT-RPA results were available in few minutes and demonstrate a sensitivity of 90.0% compared to the gold-standard RT-PCR on a set of 43 patient samples. Furthermore, the realization of a nine-spot multilayered device achieving the parallel detection of three distinct RNA sequences opens a route toward the detection of multiple viral strains or pathogens.
In situ targeted activation of an anticancer agent using ultrasound-triggered release of composite droplets
Laboratoire Biophysique et Evolution - Bezagu M, Clarhaut J, Renoux B, Monti F, Tanter M, Tabeling P, Cossy J, Couture O, Papot S, Arseniyadis S.
Eur J Med Chem. - 42 44014 - doi: 10.1016/j.ejmech.2017.03.057 - 2017
The efficiency of a drug is usually highly dependent on the way it is administered or delivered. As such, targeted-therapy, which requires conceiving drug-delivery vehicles that will change their state from a relatively stable structure with a very slow leak-rate to an unstable structure with a fast release, clearly improves the pharmacokinetics, the absorption, the distribution, the metabolism and the therapeutic index of a given drug. In this context, we have developed a particularly effective double stimuli-responsive drug-delivery method allowing an ultrasound-induced release of a monomethylauristatin E-glucuronide prodrug and its subsequent activation by a β-glucuronidase. This led to an increase of cytotoxicity of about 80% on cancer cells.


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