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Mechanical forces revert and stop the growth of cancer cells

Mechanical forces revert and stop the growth of cancer cells | Cell Biology | Scoop.it

Researchers at Lawrence Berkeley National Laboratory and UC Berkeley have put the squeeze — literally — on malignant mammary cells to guide them back into a normal growth pattern.

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Cellular polarity in aging: role of redox regulation and nutrition

Cellular polarity in aging: role of redox regulation and nutrition | Cell Biology | Scoop.it

Cellular polarity concerns the spatial asymmetric organization of cellular components and structures. Such organization is important not only for biological behavior at the individual cell level, but also for the 3D organization of tissues and organs in living organisms. Processes like cell migration and motility, asymmetric inheritance, and spatial organization of daughter cells in tissues are all dependent of cell polarity. Many of these processes are compromised during aging and cellular senescence. For example, permeability epithelium barriers are leakier during aging; elderly people have impaired vascular function and increased frequency of cancer, and asymmetrical inheritance is compromised in senescent cells, including stem cells. Here, we review the cellular regulation of polarity, as well as the signaling mechanisms and respective redox regulation of the pathways involved in defining cellular polarity. Emphasis will be put on the role of cytoskeleton and the AMP-activated protein kinase pathway. We also discuss how nutrients can affect polarity-dependent processes, both by direct exposure of the gastrointestinal epithelium to nutrients and by indirect effects elicited by the metabolism of nutrients, such as activation of antioxidant response and phase-II detoxification enzymes through the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In summary, cellular polarity emerges as a key process whose redox deregulation is hypothesized to have a central role in aging and cellular senescence.

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Cancer-promoting protein is vital to safe division of tumor cells

Cancer-promoting protein is vital to safe division of tumor cells | Cell Biology | Scoop.it

Researchers have caught a protein they previously implicated in a variety of cancer-promoting roles performing a vital function in cell division, survival and development of brain tumors.

 

 

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Senescent cells harbour features of the cancer epigenome

Senescent cells harbour features of the cancer epigenome | Cell Biology | Scoop.it

Altered DNA methylation and associated destabilization of genome integrity and function is a hallmark of cancer. Replicative senescence is a tumour suppressor process that imposes a limit on the proliferative potential of normal cells that all cancer cells must bypass. Here we show by whole-genome single-nucleotide bisulfite sequencing that replicative senescent human cells exhibit widespread DNA hypomethylation and focal hypermethylation. Hypomethylation occurs preferentially at gene-poor, late-replicating, lamin-associated domains and is linked to mislocalization of the maintenance DNA methyltransferase (DNMT1) in cells approaching senescence. Low-level gains of methylation are enriched in CpG islands, including at genes whose methylation and silencing is thought to promote cancer. Gains and losses of methylation in replicative senescence are thus qualitatively similar to those in cancer, and this ‘reprogrammed’ methylation landscape is largely retained when cells bypass senescence. Consequently, the DNA methylome of senescent cells might promote malignancy, if these cells escape the proliferative barrier.

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RABL6A, a Novel RAB-Like Protein, Controls Centrosome Amplification and Chromosome Instability in Primary Fibroblasts

RABL6A, a Novel RAB-Like Protein, Controls Centrosome Amplification and Chromosome Instability in Primary Fibroblasts | Cell Biology | Scoop.it

RABL6A (RAB-like 6 isoform A) is a novel protein that was originally identified based on its association with the Alternative Reading Frame (ARF) tumor suppressor. ARF acts through multiple p53-dependent and p53-independent pathways to prevent cancer. How RABL6A functions, to what extent it depends on ARF and p53 activity, and its importance in normal cell biology are entirely unknown. We examined the biological consequences of RABL6A silencing in primary mouse embryo fibroblasts (MEFs) that express or lack ARF, p53 or both proteins. We found that RABL6A depletion caused centrosome amplification, aneuploidy and multinucleation in MEFs regardless of ARF and p53 status. The centrosome amplification in RABL6A depleted p53−/− MEFs resulted from centrosome reduplication via Cdk2-mediated hyperphosphorylation of nucleophosmin (NPM) at threonine-199. Thus, RABL6A prevents centrosome amplification through an ARF/p53-independent mechanism that restricts NPM-T199 phosphorylation. These findings demonstrate an essential role for RABL6A in centrosome regulation and maintenance of chromosome stability in non-transformed cells, key processes that ensure genomic integrity and prevent tumorigenesis.

 

 

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Researchers at Penn Uncover Mechanism Behind Blood Stem Cells' Longevity

Researchers at Penn Uncover Mechanism Behind Blood Stem Cells' Longevity | Cell Biology | Scoop.it

The blood stem cells that live in bone marrow are at the top of a complex family tree. Such stem cells split and divide down various pathways that ultimately produce red cells, white cells and platelets. These “daughter” cells must be produced at a rate of about one million per second to constantly replenish the body’s blood supply.

Researchers have long wondered what allows these stem cells to persist for decades, when their progeny last for days, weeks or months before they need to be replaced. Now, a study from the University of Pennsylvania has uncovered one of the mechanisms that allow these stem cells to keep dividing in perpetuity.

 

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Novel Functions of Core Cell Cycle Regulators in Neuronal Migration

Novel Functions of Core Cell Cycle Regulators in Neuronal Migration | Cell Biology | Scoop.it

The cerebral cortex is one of the most intricate regions of the brain, which required elaborated cell migration patterns for its development. Experimental observations show that projection neurons migrate radially within the cortical wall, whereas interneurons migrate along multiple tangential paths to reach the developing cortex. Tight regulation of the cell migration processes ensures proper positioning and functional integration of neurons to specific cerebral cortical circuits. Disruption of neuronal migration often lead to cortical dysfunction and/or malformation associated with neurological disorders. Unveiling the molecular control of neuronal migration is thus fundamental to understand the physiological or pathological development of the cerebral cortex. Generation of functional cortical neurons is a complex and stratified process that relies on decision of neural progenitors to leave the cell cycle and generate neurons that migrate and differentiate to reach their final position in the cortical wall. Although accumulating work shed some light on the molecular control of neuronal migration, we currently do not have a comprehensive understanding of how cell cycle exit and migration/differentiation are coordinated at the molecular level. The current chapter tends to lift the veil on this issue by discussing how core cell cycle regulators, and in particular p27Kip1 acts as a multifunctional protein to control critical steps of neuronal migration through activities that go far beyond cell cycle regulation.

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Molecular Biology of Cancer

Molecular Biology of Cancer | Cell Biology | Scoop.it

There are multiple factors involved in the causation of cancer, and both external and intrinsic events play a role in the malignant transformation of cells. An understanding of the biochemical abnormalities in tumor cells and the differences from normal cellular biology can lead to the development of effective, nontoxic, tumor-specific treatments.

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A study on cell migration provides insights into the movement of cancer cells

A study on cell migration provides insights into the movement of cancer cells | Cell Biology | Scoop.it

Jordi Casanova, head of the "Morphogenesis in Drosophila" lab at IRB Barcelona and CSIC research professor, and Gaëlle Lebreton, postdoctoral fellow in the same group, have published a study performed using Drosophila melanogaster in the Journal of Cell Science. This work reveals that in a multiple movement, a single cell can act as the leader and can drag the rest with it. The scientists have studied the tracheal development of Drosophila in vivo and describe the morphological characteristics of the leading cell and provide molecular details about how it drives the movement.

 

 

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Radmis, a Novel Mitotic Spindle Protein that Functions in Cell Division of Neural Progenitors

Radmis, a Novel Mitotic Spindle Protein that Functions in Cell Division of Neural Progenitors | Cell Biology | Scoop.it

Developmental dynamics of neural stem/progenitor cells (NSPCs) are crucial for embryonic and adult neurogenesis, but its regulatory factors are not fully understood. By differential subtractive screening with NSPCs versus their differentiated progenies, we identified the radmis (radial fiber and mitotic spindle)/ckap2l gene, a novel microtubule-associated protein (MAP) enriched in NSPCs. Radmis is a putative substrate for the E3-ubiquitin ligase, anaphase promoting complex/cyclosome (APC/C), and is degraded via the KEN box. Radmis was highly expressed in regions of active neurogenesis throughout life, and its distribution was dynamically regulated during NSPC division. In embryonic and perinatal brains, radmis localized to bipolar mitotic spindles and radial fibers (basal processes) of dividing NSPCs. As central nervous system development proceeded, radmis expression was lost in most brain regions, except for several neurogenic regions. In adult brain, radmis expression persisted in the mitotic spindles of both slowly-dividing stem cells and rapid amplifying progenitors. Overexpression of radmis in vitro induced hyper-stabilization of microtubules, severe defects in mitotic spindle formation, and mitotic arrest. In vivo gain-of-function using in utero electroporation revealed that radmis directed a reduction in NSPC proliferation and a concomitant increase in cell cycle exit, causing a reduction in the Tbr2-positive basal progenitor population and shrinkage of the embryonic subventricular zone. Besides, radmis loss-of-function by shRNAs induced the multipolar mitotic spindle structure, accompanied with the catastrophe of chromosome segregation including the long chromosome bridge between two separating daughter nuclei. These findings uncover the indispensable role of radmis in mitotic spindle formation and cell-cycle progression of NSPCs.

 

 

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Cell Migration Consortium Updates, research papers, workshops and conferences

Hang et al. have established a method to facilitate the mass-spectrometry-based phosphorylation analysis of vascular endothelial cells cultured on collagen gels in order to further our understanding of angiogenesis — in particular, how inflammation influences this process. Having generated a strategy to maximize the yield of cell lysate for processing, the authors quantified phosphoprotein signaling by human dermal microvascular endothelial cells treated with the angiogenic factor vascular endothelial growth factor (VEGF) in the absence or presence of the angiostatic chemokine platelet factor 4 (PF-4). Of 22 proteins with data available at all time points tested over a 48-hour period, 17 showed statistically significant differences in signaling dynamics following the addition of PF-4. Some of these proteins and their phosphorylation sites, such as annexin A2, EphA2, Fyn, glycogen synthase kinase-3β, Lyn, p38α, paxillin and SHC1, have reported functions in different cell types that are consistent with a potential influence on cell polarization and migration during angiogenesis. Subsequent application of a network correlation model to the large data set revealed that, notably, many of the correlations involving migratory pathways occurred around the EphA2 receptor tyrosine kinase in cells stimulated by VEGF in combination with PF-4, but not in response to VEGF alone. EphA2 is largely considered to promote angiogenesis and endothelial sprouting, but it also influences cell–cell interactions, leading Hang et al. to speculate that PF-4 might draw on this regulatory role of EphA2 to confer angiostatic effects. While the data indicate the complexity of EphA2’s involvement in angiogenesis, they also highlight the potential widespread application of this methodology for the more physiologically relevant study of angiogenesis and inflammation.

 

 

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Centrosome Contributions To Chromosome Instability And Genome Remodeling In Cancer

Centrosomes are minute cellular organelles essential for the organization of the cell cytoskeleton. Their unmatched ability to nucleate and organize microtubule networks makes centrosomes the unrivaled conductors of important interphase processes such as cell polarity and shape, cell locomotion, and organization of the immunologic synapse. But it is in mitosis that centrosomes gain the highest notoriety. Mitotic centrosomes orchestrate, with clockmaker’s precision, the construction and operation of the mitotic spindle, ensuring the equal partition of the replicated genome to daughter cells. Dysfunction of centrosomes is inextricably linked to chromosome missegregation and aneuploidy, which are hallmarks of cancer cells. During the last two decades, numerous intrinsic and extrinsic centrosome defects in cancer have been characterized molecularly, enhancing our mechanistic understanding of centrosome biology and unraveling an unsuspected level of complexity for this tiny organelle. Nevertheless, it appears unlikely that intrinsic centrosome defects alone can cause cancer. Rather, the accumulated evidence strongly suggests that dysfunctional centrosomes accelerate the Darwinian evolution of the cancer genome caused by chromosome fragmentation and misrepair, by misallocating whole chromosomes to daughter cells or interfering with the completion of mitosis. Centrosome dysfunction appears particularly relevant in carcinomas and sarcomas in which the genome typically has undergone extensive fragmentation and reshuffling, which changes the genomic coordinates of thousands of genes, facilitating the gain/loss of certain chromosome segments. Finally, manipulation of molecular networks participating in centrosome biology may soon become a viable target for specific therapeutic intervention in cancer with defective centrosomes, particularly since normal cells, which lack such alterations, may be spared the lethality associated with centrosome directed therapies.

 

 

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Ciliary membrane inheritance directs ciliogenesis

Ciliary membrane inheritance directs ciliogenesis | Cell Biology | Scoop.it

Primary cilia are microtubule-based sensory organelles that are surrounded by a ciliary membrane. They are nucleated at their base by the mother centriole, and an accepted model is that primary cilia are disassembled prior to mitosis so that the centrosomes can function at mitotic spindle poles.

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Cells in Action: Why Cancer Cells Leave the Tumors?

Cells in Action: Why Cancer Cells Leave the Tumors? | Cell Biology | Scoop.it

Invading cancer cells leave the tumor to form distant metastases and are ultimately responsible for 90% of deaths in cancer. Reducing the ability of cancer cells to invade and metastasize could extend the life of cancer patients. However, our current understanding of the conditions that trigger and guide the invasion of cancer cells is insufficient and our abilities to interfere with these processes are limited. By using novel microfluidic tools, we uncovered an unexpected ability of cancer cells to navigate and exit microscopic mazes along the shortest path. To explain this behavior, we propose a novel mechanism that guides cancer cell migration. This mechanism depends on the generation of spatial chemical gradients by the cancer cell themselves, through the competition between epidermal growth factor (EGF) uptake by the cells and the restricted diffusion of EGF from surrounding microenvironment to the cells. Employing this strategy when placed in uniform but confined environments, cancer cells can self-generate spatial gradients of EGF, effectively mapping the environment, and guiding their own escape from the confinement. Better understanding of the cancer cell guidance strategy by self-generated gradients could lead to approaches for restricting the migration of malignant cells to delay local invasion and distant metastases.

 

 

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Cell cycle-dependent SUMO-1 conjugation to nuclear mitotic apparatus protein (NuMA)

Cell cycle-dependent SUMO-1 conjugation to nuclear mitotic apparatus protein (NuMA) | Cell Biology | Scoop.it

Covalent conjugation of proteins with small ubiquitin-like modifier 1 (SUMO-1) plays a critical role in a variety of cellular functions including cell cycle control, replication, and transcriptional regulation. Nuclear mitotic apparatus protein (NuMA) localizes to spindle poles during mitosis, and is an essential component in the formation and maintenance of mitotic spindle poles. Here we show that NuMA is a target for covalent conjugation to SUMO-1. We find that the lysine 1766 residue is the primary NuMA acceptor site for SUMO-1 conjugation. Interestingly, SUMO modification of endogenous NuMA occurs at the entry into mitosis and this modification is reversed after exiting from mitosis. Knockdown of Ubc9 or forced expression of SENP1 results in impairment of the localization of NuMA to mitotic spindle poles during mitosis. The SUMOylation-deficient NuMA mutant is defective in microtubule bundling, and multiple spindles are induced during mitosis. The mitosis-dependent dynamic SUMO-1 modification of NuMA might contribute to NuMA-mediated formation and maintenance of mitotic spindle poles during mitosis.

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Malignant cells adopt a different pathway for genome duplication

Malignant cells adopt a different pathway for genome duplication | Cell Biology | Scoop.it

Researchers at the University of Geneva, Switzerland, discover how tumour cells solve the problems linked to the replication of their unstable DNA

 

 

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New study identifies the signal that guides the migration and differentiation of enteric neuron precursors

New study identifies the signal that guides the migration and differentiation of enteric neuron precursors | Cell Biology | Scoop.it

Neural development involves the proliferation and migration of immature neurons, followed by their differentiation into the multiple cell types that make up the nervous system. These processes are poorly understood but are known to require the coordinated activity of dozens of transcription factors and signaling molecules. Hideki Enomoto, Toshihiro Uesaka and colleagues from the RIKEN Center for Developmental Biology have now identified a molecule that controls the migration and differentiation of a large population of neurons in the gut, known as the enteric nervous system (ENS).

 

 

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The Cell Biology of Dendrite Differentiation

The Cell Biology of Dendrite Differentiation | Cell Biology | Scoop.it

The morphology of neuronal dendrites defines the position and extent of input connections that a neuron receives and influences computational aspects of input processing. Establishing appropriate dendrite morphology thus underscores proper neuronal function. Indeed, inappropriate patterning of dendrites is a common feature of conditions that lead to mental retardation. Here, we explore the basic mechanisms that lead to the formation of branched dendrites and the cell biological aspects that underlie this complex process. We summarize some of the major steps that from developmental transcriptional regulation and environmental information modulate the neuron’s cytoskeleton to obtain the arborized structures that have fascinated neuroscientists for more than a century.

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Quand les cellules tumorales apprennent à vivre sur du tissu mou

Quand les cellules tumorales apprennent à vivre sur du tissu mou | Cell Biology | Scoop.it
Quand les cellules tumorales apprennent à vivre sur du tissu mou

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Meeting report: mitosis and nuclear structure

Meeting report: mitosis and nuclear structure | Cell Biology | Scoop.it

The Company of Biologists Workshop entitled ‘Mitosis and Nuclear Structure’ was held at Wiston House, West Sussex in June 2013. It provided a unique and timely opportunity for leading experts from different fields to discuss not only their own work but also its broader context. Here we present the proceedings of this meeting and several major themes that emerged from the crosstalk between the two, as it turns out, not so disparate fields of mitosis and nuclear structure. Co-chaired by Katherine Wilson (Johns Hopkins School of Medicine, Baltimore, MD), Timothy Mitchison (Harvard University, Cambridge, MA) and Michael Rout (Rockefeller University, New York, NY), this workshop brought together a small group of scientists from a range of disciplines to discuss recent advances and connections between the areas of mitosis and nuclear structure research. Several early-career researchers (students, postdoctoral researchers, junior faculty) participated along with 20 senior scientists, including the venerable and affable Nobel Laureate Tim Hunt. Participants were encouraged to embrace unconventional thinking in the ‘scientific sandbox’ created by this unusual combination of researchers in the inspiring, isolated setting of the 16th-century Wiston House.

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Insight on cell migration, movement of cancer cells

Insight on cell migration, movement of cancer cells | Cell Biology | Scoop.it

Nov. 21, 2013 — The migration of groups of cells in order to form tissues is common during the development of an organism. Discovering how these multiple movements are achieved is not only crucial to understand the basic principles of development but provides new information and insights for further research into processes associated with the spread of cancer.

 

 

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Researchers at National Heart Lung and Blood Institute Target Cell Biology

By a News Reporter-Staff News Editor at Life Science Weekly -- Research findings on Life Science Research are discussed in a new report. According to news originating from Bethesda, Maryland, by NewsRx correspondents, research stated, "The ability of cells to move directionally toward areas of stiffer extracellular matrix (ECM) via a process known as 'durotaxis' is thought to be critical for development and wound healing, but durotaxis can also drive cancer metastasis. Migration is driven by integrin-mediated focal adhesions (FAs), protein assemblies that couple contractile actomyosin bundles to the plasma membrane, transmit force generated by the cytoskeleton to the ECM, and convert the mechanical properties of the microenvironment into biochemical signals."

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Carl-Philipp Heisenberg group detects mechanism in cell division relevant for closing wounds

Spreading of the epithelial cell layer is fundamental for epithelial closure and wound healing, as well as for embryonic development. The challenge presented here is that the cell layer needs to increase in surface area, but nevertheless maintain its integrity. For their research, the Heisenberg's team used the process of epiboly in zebrafish development to model cell spreading. Epiboly is a step in the embryonic development of zebrafish during which a thin epithelial cell layer spreads over the entire cell sphere within a space of only 6 hours. This fast cell spreading comes along with a rapid increase of the epithelium's surface area, and a build-up of tension in the cell layer.

 

 

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SIRT2 regulates ciliogenesis and contributes to abnormal centrosome amplification caused by loss of polycystin-1

SIRT2 regulates ciliogenesis and contributes to abnormal centrosome amplification caused by loss of polycystin-1 | Cell Biology | Scoop.it

The mechanisms underlying many of the human disease phenotypes associated with ciliary dysfunction and abnormal centrosome amplification have yet to be fully elucidated. Here, we present for the first time that SIRT2, a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, regulates ciliogenesis and centrosome amplification. Overexpression of SIRT2 in renal epithelial cells appeared to disrupt cilia formation, causing decreased numbers of cells with cilia and decreased cilia length, while inhibition of SIRT2 activity by nicotinamide treatment or knockdown of SIRT2 with siRNA was shown to block cilia disassembly during the cell cycle. Overexpression of SIRT2 in zebrafish decreased cilia numbers in Kupffer's vesicle, while morpholino knock down of SIRT2 increased cilia length. Aberrant centrosome amplification and polyploidy were seen with overexpression of SIRT2 in mouse IMCD3 cells, similar to that observed following Pkd1 knockdown. SIRT2 was upregulated in both Pkd1 mutant and knockdown cells. Depletion of SIRT2 prevented the abnormal centrosome amplification and polyploidy associated with loss of polycystin-1 (PC1) alone. Thus, we conclude that the aberrant centrosome amplification and polyploidy in Pkd1 mutant or depleted cells was mediated through overexpression of SIRT2. Our results suggest a novel function of SIRT2 in cilia dynamics and centrosome function, and in ciliopathy-associated disease progression.

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Researchers gain new insights into brain neuronal networks

A paper published in a special edition of the journal Science proposes a novel understanding of brain architecture using a network representation of connections within the primate cortex. Zoltán Toroczkai, professor of physics at the University of Notre Dame and co-director of the Interdisciplinary Center for Network Science and Applications, is a co-author of the paper "Cortical High-Density Counterstream Architectures."

 

 

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Pas à pas, la migration cellulaire se dévoile

Pas à pas, la migration cellulaire se dévoile | Cell Biology | Scoop.it

Comment les cellules parviennent-elles à se déplacer ? Le mécanisme qui leur permet d'effectuer leurs « premiers pas », qu'ils soient à bon ou mauvais escient pour l'organisme, vient d'être décrit par Guillaume Montagnac et ses collègues de l'équipe de Philippe Chavrier au laboratoire Compartimentation et dynamique cellulaires (CDC, CNRS/Institut Curie). Ces travaux publiés dans la revue Nature ont été réalisés en collaboration avec d'autres chercheurs, associés au CNRS, à l'Institut Pasteur, à l'Inserm, à l'Université Paris Descartes, à l'Université Nice Sophia Antipolis et à l'Ecole de médecine de l'Université de Stanford.

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