Showing papers by "Collège de France published in 2005"

Action Observation and Acquired Motor Skills: An fMRI Study with Expert Dancers

Abstract: When we observe someone performing an action, do our brains simulate making that action? Acquired motor skills offer a unique way to test this question, since people differ widely in the actions they have learned to perform. We used functional magnetic resonance imaging to study differences in brain activity between watching an action that one has learned to do and an action that one has not, in order to assess whether the brain processes of action observation are modulated by the expertise and motor repertoire of the observer. Experts in classical ballet, experts in capoeira and inexpert control subjects viewed videos of ballet or capoeira actions. Comparing the brain activity when dancers watched their own dance style versus the other style therefore reveals the influence of motor expertise on action observation. We found greater bilateral activations in premotor cortex and intraparietal sulcus, right superior parietal lobe and left posterior superior temporal sulcus when expert dancers viewed movements that they had been trained to perform compared to movements they had not. Our results show that this 'mirror system' integrates observed actions of others with an individual's personal motor repertoire, and suggest that the human brain understands actions by motor simulation.

Non-sticking drops

Abstract: While the behaviour of large amounts of liquid is dictated by gravity, surface forces become dominant at small scales. They have for example the remarkable ability to make droplets stick to their substrates (even if they are inclined), which is a practical issue in many cases (windshields, window panes, greenhouses, or microfluidic devices). Here we describe how this problem can be overcome with super-hydrophobic materials. These materials are often developed thanks to micro-textures, which decorate a solid surface, and we describe the way such textures modify the wettability of that solid. We conclude by showing the unusual dynamics of drops in a super-hydrophobic situation.

Notch signals control the fate of immature progenitor cells in the intestine

Abstract: The Notch signalling pathway plays a crucial role in specifying cellular fates in metazoan development by regulating communication between adjacent cells. Correlative studies suggested an involvement of Notch in intestinal development. Here, by modulating Notch activity in the mouse intestine, we directly implicate Notch signals in intestinal cell lineage specification. We also show that Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. We conclude that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium.

On water repellency

Abstract: Water-repellency is a property of some materials, either natural or synthetic, which makes water hardly stick to them: drops roll very easily off these solids, and bounce back upon impacting them. Here we discuss recent advances in this field, which has been particularly lively in recent years. We first examine the physical causes for this effect. Then we discuss the loss of adherence of the drops in such a state, and stress their remarkable dynamic behaviour. We finally suggest several remaining challenges in the field.

On water repellency

Abstract: Water-repellency is a property of some materials, either natural or synthetic, which makes water hardly stick to them: drops roll very easily off these solids, and bounce back upon impacting them. Here we discuss recent advances in this field, which has been particularly lively in recent years. We first examine the physical causes for this effect. Then we discuss the loss of adherence of the drops in such a state, and stress their remarkable dynamic behaviour. We finally suggest several remaining challenges in the field.

Mutations in dynamin 2 cause dominant centronuclear myopathy.

Abstract: Autosomal dominant centronuclear myopathy is a rare congenital myopathy characterized by delayed motor milestones and muscular weakness. In 11 families affected by centronuclear myopathy, we identified recurrent and de novo missense mutations in the gene dynamin 2 (DNM2, 19p13.2), which encodes a protein involved in endocytosis and membrane trafficking, actin assembly and centrosome cohesion. The transfected mutants showed reduced labeling in the centrosome, suggesting that DNM2 mutations might cause centronuclear myopathy by interfering with centrosome function.

Popper, Karl R

Abstract: Born 1902; died 1994. Famous as a philosopher of science, Popper maintained that scientific truth is not manifest, but that indeed that scientific theories are conjectures open to refutation or falsification. Popper controversially denounced inductive reasoning—validity of a scientific theory from empirical observations to general regularities—insisting instead that scientific theories should be open to testing. As a theory passes more severe tests, it becomes more highly “corroborated”. He called this approach hypothetico-deductive. ‘Realism and the Aim of Science’ (1982) is his work most relevant to biostatistics, re-examining in detail problems of truth, corroboration, and probability. Keywords: conjecture; refutation; induction; inference; epistemology; probability; propensity; indeterminism

Detection of a non‐Gaussian spot in WMAP

Abstract: An extremely cold and big spot in the Wilkinson Microwave Anisotropy Probe (WMAP) 1-yr data is analysed. Our work is a continuation of a previous paper by Vielva et al. that reported the detection of non-Gaussianity, with a method based on the spherical Mexican hat wavelet (SMHW) technique. We study the spots at different thresholds on the SMHW coefficient maps, considering six estimators, namely the number of maxima, the number of minima, the numbers of hot and cold spots, and the number of pixels of those spots. At SMHW scales around 4° (10° on the sky), the data deviate from Gaussianity. The analysis is performed on all of the sky, the Northern and Southern hemispheres, and on four regions covering all of the sky. A cold spot at (b = -57°,l = 209°) is found to be the source of this non-Gaussian signature. We compare the spots of our data with 10 000 Gaussian simulations, and conclude that only around 0.2 per cent of them present such a cold spot. Excluding this spot, the remaining map is compatible with Gaussianity, and even the excess of kurtosis in the paper by Vielva et al. is found to be due exclusively to this spot. Finally, we study whether the spot causing the observed deviation from Gaussianity could be generated by systematics or foregrounds. None of them seem to be responsible for the non-Gaussian detection.

A new population of very high energy gamma-ray sources in the Milky Way.

Abstract: Very high energy gamma-rays probe the long-standing mystery of the origin of cosmic rays. Produced in the interactions of accelerated particles in astrophysical objects, they can be used to image cosmic particle accelerators. A first sensitive survey of the inner part of the Milky Way with the High Energy Stereoscopic System (HESS) reveals a population of eight previously unknown firmly detected sources of very high energy gamma-rays. At least two have no known radio or x-ray counterpart and may be representative of a new class of "dark" nucleonic cosmic ray sources.

Residual stresses in thin polymer films cause rupture and dominate early stages of dewetting.

Abstract: Residual stresses in thin polymer films cause rupture and dominate early stages of dewetting

The design of cationic lipids for gene delivery.

Abstract: Synthetic gene delivery vectors are gaining increasing importance in gene therapy as an alternative to recombinant viruses. Among the various types of non-viral vectors, cationic lipids are especially attractive as they can be prepared with relative ease and extensively characterised. Further, each of their constituent parts can be modified, thereby facilitating the elucidation of structure-activity relationships. In this forward-looking review, cationic lipid-mediated gene delivery will mainly be discussed in terms of the structure of the three basic constituent parts of any cationic lipid: the polar headgroup, hydrophobic moiety and linker. Particular emphasis will be placed on recent advances in the field as well as on our own original contributions. In addition to reviewing critical physicochemical features (such as headgroup hydration) of monovalent lipids, the use of headgroups with known nucleic-acid binding modes, such as linear and branched polyamines, aminoglycosides and guanidinium functions, will be comprehensively assessed. A particularly exciting innovation in linker design is the incorporation of environment-sensitive groups, the intracellular hydrolysis of which may lead to more controlled DNA delivery. Examples of pH-, redox- and enzyme-sensitive functional groups integrated into the linker are highlighted and the benefits of such degradable vectors can be evaluated in terms of transfection efficiency and cationic lipid-associated cytotoxicity. Finally, possible correlations between the length and type of hydrophobic moiety and transfection efficiency will be discussed. In conclusion it may be foreseen that in order to be successful, the future of cationic lipid-based gene delivery will probably require the development of sophisticated virus-like systems, which can be viewed as "programmed supramolecular systems" incorporating the various functions required to perform in a chronological order the different steps involved in gene transfection.

Conditional Mineralocorticoid Receptor Expression in the Heart Leads to Life-Threatening Arrhythmias

Abstract: Background— Life-threatening cardiac arrhythmia is a major source of mortality worldwide. Besides rare inherited monogenic diseases such as long-QT or Brugada syndromes, which reflect abnormalities in ion fluxes across cardiac ion channels as a final common pathway, arrhythmias are most frequently acquired and associated with heart disease. The mineralocorticoid hormone aldosterone is an important contributor to morbidity and mortality in heart failure, but its mechanisms of action are incompletely understood. Methods and Results— To specifically assess the role of the mineralocorticoid receptor (MR) in the heart, in the absence of changes in aldosteronemia, we generated a transgenic mouse model with conditional cardiac-specific overexpression of the human MR. Mice exhibit a high rate of death prevented by spironolactone, an MR antagonist used in human therapy. Cardiac MR overexpression led to ion channel remodeling, resulting in prolonged ventricular repolarization at both the cellular and integrated lev...

Submarine fault scarps in the Sea of Marmara pull-apart (North Anatolian Fault): Implications for seismic hazard in Istanbul

Abstract: Earthquake scarps associated with recent historical events have been found on the floor of the Sea of Marmara, along the North Anatolian Fault (NAF). The MARMARASCARPS cruise using an unmanned submersible (ROV) provides direct observations to study the fine-scale morphology and geology of those scarps, their distribution, and geometry. The observations are consistent with the diversity of fault mechanisms and the fault segmentation within the north Marmara extensional step-over, between the strike-slip Ganos and Izmit faults. Smaller strike-slip segments and pull-apart basins alternate within the main step-over, commonly combining strike-slip and extension. Rapid sedimentation rates of 1?3 mm/yr appear to compete with normal faulting components of up to 6 mm/yr at the pull-apart margins. In spite of the fast sedimentation rates the submarine scarps are preserved and accumulate relief. Sets of youthful earthquake scarps extend offshore from the Ganos and Izmit faults on land into the Sea of Marmara. Our observations suggest that they correspond to the submarine ruptures of the 1999 Izmit (Mw 7.4) and the 1912 Ganos (Ms 7.4) earthquakes. While the 1999 rupture ends at the immediate eastern entrance of the extensional Cinarcik Basin, the 1912 rupture appears to have crossed the Ganos restraining bend into the Sea of Marmara floor for 60 km with a right-lateral slip of 5 m, ending in the Central Basin step-over. From the Gulf of Saros to Marmara the total 1912 rupture length is probably about 140 km, not 50 km as previously thought. The direct observations of submarine scarps in Marmara are critical to defining barriers that have arrested past earthquakes as well as defining a possible segmentation of the contemporary state of loading. Incorporating the submarine scarp evidence modifies substantially our understanding of the current state of loading along the NAF next to Istanbul. Coulomb stress modeling shows a zone of maximum loading with at least 4?5 m of slip deficit encompassing the strike-slip segment 70 km long between the Cinarcik and Central Basins. That segment alone would be capable of generating a large-magnitude earthquake (Mw 7.2). Other segments in Marmara appear less loaded.

Retinoic acid-dependent eye morphogenesis is orchestrated by neural crest cells

Abstract: Using genetic approaches in the mouse, we show that the primary target tissue of retinoic acid (RA) action during eye morphogenesis is not the retina nor the corneal ectoderm, which both express RA-synthesizing retinaldehyde dehydrogenases (RALDH1 and RALDH3), but the neural crest cell-derived periocular mesenchyme (POM), which is devoid of RALDH. In POM, the effects of the paracrine RA signal are mediated by the nuclear RA receptors heterodimers RXRalpha/RARbeta and RXRalpha/RARgamma. These heterodimers appear to control: (1) the remodeling of the POM through activation of Eya2-related apoptosis; (2) the expression of Foxc1 and Pitx2, which play crucial roles in anterior eye segment development; and (3) the growth of the ventral retina. We additionally show that RALDH1 and RALDH3 are the only enzymes that are required for RA synthesis in the eye region from E10.5 to E13.5, and that patterning of the dorsoventral axis of the retina does not require RA.

Regulation of Notch signalling by non-visual beta-arrestin.

Abstract: Signalling activity of the Notch receptor, which plays a fundamental role in metazoan cell fate determination, is controlled at multiple levels. We uncovered a Notch signal-controlling mechanism that depends on the ability of the non-visual beta-arrestin, Kurtz (Krz), to influence the degradation and, consequently, the function of the Notch receptor. We identified Krz as a binding partner of a known Notch-pathway modulator, Deltex (Dx), and demonstrated the existence of a trimeric Notch-Dx-Krz protein complex. This complex mediates the degradation of the Notch receptor through a ubiquitination-dependent pathway. Our results establish a novel mode of regulation of Notch signalling and define a new function for non-visual beta-arrestins.

Retinoic Acid Controls the Bilateral Symmetry of Somite Formation in the Mouse Embryo

Abstract: A striking characteristic of vertebrate embryos is their bilaterally symmetric body plan, which is particularly obvious at the level of the somites and their derivatives such as the vertebral column. Segmentation of the presomitic mesoderm must therefore be tightly coordinated along the left and right embryonic sides. We show that mutant mice defective for retinoic acid synthesis exhibit delayed somite formation on the right side. Asymmetric somite formation correlates with a left-right desynchronization of the segmentation clock oscillations. These data implicate retinoic acid as an endogenous signal that maintains the bilateral synchrony of mesoderm segmentation, and therefore controls bilateral symmetry, in vertebrate embryos.

The MAPK pathway and Egr-1 mediate stress-related behavioral effects of glucocorticoids.

Abstract: Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GR(NesCre)) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (DeltaGR) that can be transiently induced. In the hippocampus of the wild-type [corrected] mice after stress, as well as in the cell lines, activation of glucocorticoid receptors greatly increased the expression and enzymatic activity of proteins in the MAPK signaling pathway and led to an increase in the levels of both Egr-1 mRNA and protein. In parallel, inhibition of the MAPK pathway within the hippocampus abolished the increase in contextual fear conditioning induced by glucocorticoids. The present results provide a molecular mechanism for the stress-related effects of glucocorticoids on fear memories.

Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin

Abstract: To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXRalphabeta(ep-/-) somatic mutants in which both RXRalpha and RXRbeta are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXRalphabeta-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXRalphabeta-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.

PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli.

Abstract: The DNA damage-dependent poly(ADP-ribose) polymerases-1 and -2 (PARP-1 and PARP-2) are survival factors that share overlapping functions in the detection, signaling and repair of DNA strand breaks resulting from genotoxic lesions in mammalian cells. Here we show that PARP-1 and PARP-2 subnuclear distributions partially overlap, with both proteins accumulating within the nucleolus independently of each other. PARP-2 is enriched within the whole nucleolus and partially colocalizes with the nucleolar factor nucleophosmin/B23. We have identified a nuclear localization signal and a nucleolar localization signal within the N-terminal domain of PARP-2. PARP-2, like PARP-1, interacts with B23 through its N-terminal DNA binding domain. This association is constitutive and does not depend on either PARP activity or ribosomal transcription, but is prevented by mutation of the nucleolar localization signal of PARP-2. PARP-1 and PARP-2, together with B23, are delocalized from the nucleolus upon RNA polymerase I inhibition whereas the nucleolar accumulation of all three proteins is only moderately affected upon oxidative or alkylated DNA damage. Finally, we show that murine fibroblasts deficient in PARP-1 or PARP-2 are not affected in the transcription of ribosomal RNAs. Taken together, these results suggest that the biological role of PARP-1 and PARP-2 within the nucleolus relies on functional nucleolar transcription, without any obvious implication of either PARP on this major nucleolar process.

FMRP interferes with the Rac1 pathway and controls actin cytoskeleton dynamics in murine fibroblasts

Abstract: Fragile X syndrome, the most common form of inherited mental retardation, is caused by absence of FMRP, an RNA-binding protein implicated in regulation of mRNA translation and/or transport. We have previously shown that dFMR1, the Drosophila ortholog of FMRP, is genetically linked to the dRac1 GTPase, a key player in actin cytoskeleton remodeling. Here, we demonstrate that FMRP and the Rac1 pathway are connected in a model of murine fibroblasts. We show that Rac1 activation induces relocalization of four FMRP partners to actin ring areas. Moreover, Rac1-induced actin remodeling is altered in fibroblasts lacking FMRP or carrying a point-mutation in the KH1 or in the KH2 RNA-binding domain. In absence of wild-type FMRP, we found that phospho-ADF/Cofilin (P-Cofilin) level, a major mediator of Rac1 signaling, is lowered, whereas the level of protein phosphatase 2A catalytic subunit (PP2Ac), a P-Cofilin phosphatase, is increased. We show that FMRP binds with high affinity to the 5'-UTR of pp2acbeta mRNA and is thus a likely negative regulator of its translation. The molecular mechanism unraveled here points to a role for FMRP in modulation of actin dynamics, which is a key process in morphogenesis of dendritic spines, synaptic structures abnormally developed in Fragile X syndrome patient's brain.

Why race still matters

Abstract: Daedalus Winter 2005 Why has race mattered in so many times and places? Why does it still matter? Put more precisely, why has there been such a pervasive tendency to apply the category of race and to regard people of different races as essentially different kinds of people? Call this the ‘1⁄2rst question.’ Of course there are many more questions that one must also ask: Why has racial oppression been so ubiquitous? Why racial exploitation? Why racial slavery? Perhaps we tend to think of races as essentially different just because we want to excuse or to justify the domination of one race by another. I shall proceed with the 1⁄2rst question by canvassing 1⁄2ve possible answers to it that variously invoke nature, genealogy (in the sense of Michel Foucault), cognitive science, empire, and pollution rules. One 1⁄2nal preliminary remark is in order. Most parts of this essay could have been written last year or next year, but the discussion of naturalism, medicine, and race could only have been written in November of 2004, and may well be out of date by the time this piece is printed.

Contribution of gap junctional communication between tumor cells and astroglia to the invasion of the brain parenchyma by human glioblastomas.

Abstract: Gliomas are "intraparenchymally metastatic" tumors, invading the brain in a non-destructive way that suggests cooperation between glioma cells and their environment. Recent studies using an engineered rodent C6 tumor cell line have pointed to mechanisms of invasion that involved gap junctional communication (GJC), with connexin 43 as a substrate. We explored whether this concept may have clinical relevance by analyzing the participation of GJC in human glioblastoma invasion. Three complementary in vitro assays were used: (i) seeding on collagen IV, to analyze homocellular interactions between tumor cells (ii) co-cultures with astrocytes, to study glioblastoma/astrocytes relationships and (iii) implantation into organotypic brain slice cultures, that mimic the three-dimensional parenchymal environment. Carbenoxolone, a potent blocker of GJC, inhibited cell migration in the two latter models. It paradoxically increased it in the first one. These results showed that homocellular interaction between tumor cells supports intercellular adhesion, whereas heterocellular glioblastoma/astrocytes interactions through functional GJC conversely support tumor cell migration. As demonstrated for the rodent cell line, connexin 43 may be responsible for this heterocellular functional coupling. Its levels of expression, high in astrocytes, correlated positively with invasiveness in biopsied tumors. our results underscore the potential clinical relevance of the concept put forward by other authors based on experiments with a rodent cell line, that glioblastoma cells use astrocytes as a substrate for their migration by subverting communication through connexin 43-dependent gap junctions.

Vascular development: from precursor cells to branched arterial and venous networks.

Abstract: The adult vascular system is composed of an arterial, a venous and a lymphatic compartment. These different compartments respectively provide oxygen and nutrients to peripheral organs, remove carbon dioxide and waste products and maintain an immune barrier to defend the host against foreign organisms. Malfunctions of the vascular system represent a major cause of mortality and disease in developed countries. Understanding of the molecular mechanisms regulating vascular system development and maintenance is thus crucial for the design of therapies to cure vascular diseases. The molecules implicated in the control of physiological and pathological angiogenesis in the adult already function during embryonic development. Indeed, the survival of the embryo also critically depends on the establishment of a functional circulatory loop. Here we review our current knowledge about the emergence of endothelial precursor cells in the embryo, of their assembly into the primary vascular plexus and of the remodeling of this plexus into arteries and veins. We also focus on the molecular mechanisms controlling the development of arteries, veins and lymphatic vessels.

Control of arterial branching morphogenesis in embryogenesis: go with the flow.

Abstract: Formation of a properly branched vascular system during embryogenesis is crucial for embryo survival. Here we review the regulation of the morphogenesis of the arterial and venous system during embryogenesis. We show that in addition to deterministic patterning mechanisms and plasticity of endothelial cells, arterial-venous differentiation and branching morphogenesis involves a prominent role for blood flow. Based on in vivo observations of developing arteries, we identified a novel morphological event crucial for the morphogenesis of the arterial tree, disconnection of small side branches. This disconnection of side branches occurs exactly at the point of bifurcation. The rate of disconnection of side branches depends on flow velocity and branching angle. The balance between disconnection and maintenance of arterial side branches determines the number of side branches connected to a large artery. Based on these observations, we postulate that the number of pre-existing collaterals connected to a large artery is a function of the disconnection process and can be regulated by hemodynamics. We furthermore show that embryonic arteries already adapt their lumen diameter to the amount of flow carried. Taken together, we suggest that hemodynamics plays a pivotal role in shaping the arterial system. We suggest that flow-evoked remodeling processes determine the number of preexisting collaterals during critical periods of embryo-fetal development. Insight into these basic principles of arterial growth and branching during embryogenesis may aid to understanding the observed variability in the capacity to establish a collateral circulation in patients with ischemic diseases and finding new strategies for therapeutic arteriogenesis.