Showing papers by "Collège de France published in 2001"

Human hypertension caused by mutations in WNK kinases

Abstract: Hypertension is a major public health problem of largely unknown cause. Here, we identify two genes causing pseudohypoaldosteronism type II, a Mendelian trait featuring hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Both genes encode members of the WNK family of serine-threonine kinases. Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein. Both proteins localize to the distal nephron, a kidney segment involved in salt, K+, and pH homeostasis. WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions. The WNK kinases and their associated signaling pathway(s) may offer new targets for the development of antihypertensive drugs.

The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain.

Abstract: Most connective tissues in the head develop from neural crest cells (NCCs), an embryonic cell population present only in vertebrates. We show that NCC-derived pericytes and smooth muscle cells are distributed in a sharply circumscribed sector of the vasculature of the avian embryo. As NCCs detach from the neural folds that correspond to the future posterior diencephalon, mesencephalon and rhombencephalon, they migrate between the ectoderm and the neuroepithelium into the anterior/ventral head, encountering mesoderm-derived endothelial precursors. Together, these two cell populations build a vascular tree rooted at the departure of the aorta from the heart and ramified into the capillary plexi that irrigate the forebrain meninges, retinal choroids and all facial structures, before returning to the heart. NCCs ensheath each aortic arch-derived vessel, providing every component except the endothelial cells. Within the meninges, capillaries with pericytes of diencephalic and mesencephalic neural fold origin supply the forebrain, while capillaries with pericytes of mesodermal origin supply the rest of the central nervous system, in a mutually exclusive manner. The two types of head vasculature contact at a few defined points, including the anastomotic vessels of the circle of Willis, immediately ventral to the forebrain/midbrain boundary. Over the course of evolution, the vertebrate subphylum may have exploited the exceptionally broad range of developmental potentialities and the plasticity of NCCs in head remodelling that resulted in the growth of the forebrain.

Coherent Control of an Atomic Collision in a Cavity

Abstract: Following a recent proposal by S. B. Zheng and G. C. Guo [Phys. Rev. Lett. 85, 2392 (2000)], we report an experiment in which two Rydberg atoms crossing a nonresonant cavity are entangled by coherent energy exchange. The process, mediated by the virtual emission and absorption of a microwave photon, is characterized by a collision mixing angle 4 orders of magnitude larger than for atoms colliding in free space with the same impact parameter. The final entangled state is controlled by adjusting the atom-cavity detuning. This procedure, essentially insensitive to thermal fields and to photon decay, opens promising perspectives for complex entanglement manipulations.

First hominid from the Miocene (Lukeino Formation, Kenya)

Abstract: Remains of an early hominid have been recovered from four localities in the Lukeino Formation, Tugen Hills, Kenya, in sediments aged ca 6 Ma. 13 fossils are known, belonging to at least five individuals. The femora indicate that the Lukeino hominid was a biped when on the ground, whilst its humerus and manual phalanx show that it possessed some arboreal adaptations. The upper central incisor is large and robust, the upper canine is large for a hominid and retains a narrow and shallow anterior groove, the lower fourth premolar is ape-like, with offset roots and oblique crown, and the molars are relatively small, with thick enamel. A new genus and species is erected for the remains.

Cosmology from MAXIMA-1, BOOMERANG, and COBE DMR cosmic microwave background observations.

Abstract: Recent results from BOOMERANG-98 and MAXIMA-1, taken together with COBE DMR, provide consistent and high signal-to-noise measurements of the cosmic microwave background power spectrum at spherical harmonic multipole bands over 2

Résolution d'EDP par un schéma en temps « pararéel »

Abstract: Resume On propose dans cette Note un schema permettant de profiter d'une architecture parallele pour la discretisation en temps d'une equation d'evolution aux derivees partielles. Cette methode, basee sur un schema d'Euler, combine des resolutions grossieres et des resolutions fines et independantes en temps en s'inspirant de ce qui est classique en espace. La parallelisation qui en resulte se fait dans la direction temporelle ce qui est en revanche non classique. Elle a pour principale motivation les problemes en temps reel, d'ou la terminologie proposee de «parareel ».

Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators

Abstract: The circadian timing system in mammals is composed of a master pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and slave clocks in most peripheral cell types. The phase of peripheral clocks can be completely uncoupled from the SCN pacemaker by restricted feeding. Thus, feeding time, while not affecting the phase of the SCN pacemaker, is a dominant Zeitgeber for peripheral circadian oscillators. Here we show that the phase resetting in peripheral clocks of nocturnal mice is slow when feeding time is changed from night to day and rapid when switched back from day to night. Unexpectedly, the inertia in daytime feeding-induced phase resetting of circadian gene expression in liver and kidney is not an intrinsic property of peripheral oscillators, but is caused by glucocorticoid signaling. Thus, glucocorticoid hormones inhibit the uncoupling of peripheral and central circadian oscillators by altered feeding time.

Embryonic retinoic acid synthesis is essential for heart morphogenesis in the mouse.

Abstract: Retinoic acid (RA), the active derivative of vitamin A, has been implicated in various steps of cardiovascular development, but its contribution to early heart morphogenesis has not been clearly established in a mammalian system. To block endogenous RA synthesis, we have disrupted the gene encoding RALDH2, the first retinaldehyde dehydrogenase whose expression has been detected during early mouse post-implantation development. We describe here the heart abnormalities of the RA-deficient Raldh2 mutants that die in utero at gestational day 10.5. The embryonic heart tube forms properly, but fails to undergo rightward looping and, instead, forms a medial distended cavity. Expression of early heart determination factors is not altered in mutants, and the defect in heart looping does not appear to involve the Nodal/Lefty/Pitx2 pathway. Histological and molecular analysis reveal distinct anteroposterior components in the mutant heart tube, although posterior chamber (atria and sinus venosus) development is severely impaired. Instead of forming trabeculae, the developing ventricular myocardium consists of a thick layer of loosely attached cells. Ultrastructural analysis shows that most of the ventricular wall consists of prematurely differentiated cardiomyocytes, whereas undifferentiated cells remain clustered rostrally. We conclude that embryonic RA synthesis is required for realization of heart looping, development of posterior chambers and proper differentiation of ventricular cardiomyocytes. Nevertheless, the precise location of this synthesis may not be crucial, as these defects can mostly be rescued by systemic (maternal) RA administration. However, cardiac neural crest cells cannot be properly rescued in Raldh2(-/- )embryos, leading to outflow tract septation defects.

Noncommutative Manifolds, the Instanton Algebra and Isospectral Deformations

Abstract: We give new examples of noncommutative manifolds that are less standard than the NC-torus or Moyal deformations of ℝn. They arise naturally from basic considerations of noncommutative differential topology and have non-trivial global features.

Does the brain model Newton's laws?

Abstract: How does the nervous system synchronize movements to catch a falling ball? According to one theory, only sensory information is used to estimate time-to-contact (TTC) with an approaching object1,2; alternatively, implicit knowledge about physics may come into play3,4. Here we show that astronauts initiated catching movements earlier in 0 g than in 1 g, which demonstrates that the brain uses an internal model of gravity to supplement sensory information when estimating TTC.

The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway.

Abstract: Hereditary paragangliomas are usually benign tumors of the autonomic nervous system that are composed of cells derived from the primitive neural crest. Even though three genes (SDHD, SDHC, and SDHB), which encode three protein subunits of cytochrome b of complex II in the mitochondrial respiratory chain, have been identified, the molecular mechanisms leading to tumorigenesis are unknown. We studied a family in which the father and his eldest son had bilateral neck paragangliomas, whereas the second son had a left carotid-body paraganglioma and an ectopic mediastinal pheochromocytoma. A nonsense mutation (R22X) in the SDHD gene was found in these three affected subjects. Loss of heterozygosity was observed for the maternal chromosome 11q21-q25 within the tumor but not in peripheral leukocytes. Assessment of the activity of respiratory-chain enzymes showed a complete and selective loss of complex II enzymatic activity in the inherited pheochromocytoma, that was not detected in six sporadic pheochromocytomas. In situ hybridization and immunohistochemistry experiments showed a high level of expression of markers of the angiogenic pathway. Real-time quantitative reverse transcriptase (RT)-PCR measurements confirmed that vascular endothelial growth factor and endothelial PAS domain protein 1 mRNA levels were significantly higher (three- and sixfold, respectively) than those observed in three sporadic benign pheochromocytomas. Thus, inactivation of the SDHD gene in hereditary paraganglioma is associated with a complete loss of mitochondrial complex II activity and with a high expression of angiogenic factors.

Neurosteroids: Beginning of the story

Abstract: Neurosteroids are synthetisized in the central and the peripheral nervous system, in glial cells, and also in neurons, from cholesterol or steroidal precursors imported from peripheral sources. They include 3 beta-hydroxy-delta 5-compounds, such as pregnenolone (PREG) and dehydroepiandrosterone, their sulfate esters, and compounds known as reduced metabolites of steroid hormones, such as the tetrahydroderivative of progesterone 3 alpha-hydroxy-5 alpha-pregnan-20-one. These neurosteroids can act as modulators of neurotransmitter receptors, such as GABAA, NMDA, and sigma 1 receptors. Progesterone itself is also a neurosteroid, and a progesterone receptor has been detected in peripheral and central glial cells. At different sites in the brain, neurosteroid concentrations vary according to environmental and behavioral circumstances, such as stress, sex recognition, or aggressiveness. A physiological function of neurosteroids in the central nervous system is strongly suggested by the role of hippocampal PREGS with respect to memory performance, observed in aging rats. In the peripheral nervous system, a role for PROG synthesized in Schwann cells has been demonstrated in remyelination after cryolesion of the sciatic nerve in vivo and in cultures of dorsal root ganglia. A new mechanism of PREG action discovered in the brain involves specific steroid binding to microtubule associated protein and increased tubulin polymerization for assembling microtubules. It may be important to study the effects of abnormal neurosteroid concentration/metabolism in view of the possible treatment of functional and trophic disturbances of the nervous system.

Nuclear receptors coordinate the activities of chromatin remodeling complexes and coactivators to facilitate initiation of transcription

Abstract: Recent advances in the field of in vitro chromatin assembly have led to in vitro transcription systems which reproduce in the test tube, in vivo characteristics of ligand-dependent transcriptional activation by nuclear receptors. Dissection of these systems has begun to provide us with information concerning the underlying molecular mechanisms. Through recruitment of coactivator proteins, nuclear receptors act first to remodel chromatin within the promoter region and then to recruit the transcriptional machinery to the promoter region in order to initiate transcription. Here we present a possible sequential mechanism for ligand-dependent transcriptional activation by nuclear receptors and discuss the in vitro and in vivo data that support this model.

Role of Lateral Acceleration in Curve Driving: Driver Model and Experiments on a Real Vehicle and a Driving Simulator

Abstract: Experimental studies show that automobile drivers adjust their speed in curves so that maximum vehicle lateral accelerations decrease at high speeds. This pattern of lateral accelerations is described by a new driver model, assuming drivers control a variable safety margin of perceived lateral acceleration according to their anticipated steering deviations. Compared with a minimum time-to-lane-crossing (H. Godthelp, 1986) speed modulation strategy, this model, based on nonvisual cues, predicts that extreme values of lateral acceleration in curves decrease quadratically with speed, in accordance with experimental data obtained in a vehicle driven on a test track and in a motion-based driving simulator. Variations of model parameters can characterize "normal" or "fast" driving styles on the test track. On the simulator, it was found that the upper limits of lateral acceleration decreased less steeply when the motion cuing system was deactivated, although drivers maintained a consistent driving style. This is interpreted per the model as an underestimation of curvilinear speed due to the lack of inertial stimuli. Actual or potential applications of this research include a method to assess driving simulators as well as to identify driving styles for on-board driver aid systems.

Estradiol Accelerates Reendothelialization in Mouse Carotid Artery Through Estrogen Receptor-α but Not Estrogen Receptor-β

Abstract: Background—The atheroprotective effect of 17β-estradiol (E2) has been suggested in women and clearly demonstrated in animals through both an effect on lipid metabolism and a direct effect on the cells of the arterial wall It has been shown, for example, that E2 promotes endothelium-dependent relaxation and accelerates reendothelialization in rats Similar studies have been undertaken in mice to appreciate the molecular mechanism of this process Methods and Results—We report here a model of electric carotid injury adapted from that described by Carmeliet et al (1997) that allows us to precisely evaluate the reendothelialization process We demonstrate that E2 accelerates endothelial regeneration in castrated female wild-type mice In ovariectomized transgenic mice in which either the estrogen receptor (ER)-α or ERβ gene has been disrupted, E2 accelerated reendothelialization in female ERβ knockout mice, whereas this effect was abolished in female ERα knockout mice Conclusions—This study demonstrates tha

Dinosaurian growth rates and bird origins

Abstract: Dinosaurs, like other tetrapods, grew more quickly just after hatching than later in life. However, they did not grow like most other non-avian reptiles, which grow slowly and gradually through life. Rather, microscopic analyses of the long-bone tissues show that dinosaurs grew to their adult size relatively quickly, much as large birds and mammals do today. The first birds reduced their adult body size by shortening the phase of rapid growth common to their larger theropod dinosaur relatives. These changes in timing were primarily related not to physiological differences but to differences in growth strategy.

Representation of the visual field in the lateral intraparietal area of macaque monkeys: a quantitative receptive field analysis

Abstract: The representation of the visual field in the primate lateral intraparietal area (LIP) was examined, using a rapid, computer-driven receptive field (RF) mapping procedure. RF characteristics of single LIP neurons could thus be measured repeatedly under different behavioral conditions. Here we report data obtained using a standard ocular fixation task during which the animals were required to monitor small changes in color of the fixated target. In a first step, statistical analyses were conducted in order to establish the experimental limits of the mapping procedure on 171 LIP neurons recorded from three hemispheres of two macaque monkeys. The characteristics of the receptive fields of LIP neurons were analyzed at the single cell and at the population level. Although for many neurons the assumption of a simple two-dimensional gaussian profile with a central area of maximal excitability at the center and progressively decreasing response strength at the periphery can represent relatively accurately the spatial structure of the RF, about 19% of the cells had a markedly asymmetrical shape. At the population level, we observed, in agreement with prior studies, a systematic relation between RF size and eccentricity. However, we also found a more accentuated overrepresentation of the central visual field than had been previously reported and no marked differences between the upper and lower visual representation of space. This observation correlates with an extension of the definition of LIP from the posterior third of the lateral intraparietal sulcus to most of the middle and posterior thirds. Detailed histological analyses of the recorded hemispheres suggest that there exists, in this newly defined unitary functional cortical area, a coarse but systematic topographical organization in area LIP that supports the distinction between its dorsal and ventral regions, LIPd and LIPv, respectively. Paralleling the physiological data, the central visual field is mostly represented in the middle dorsal region and the visual periphery more ventral and posterior. An anteroposterior gradient from the lower to the upper visual field representations can also be identified. In conclusion, this study provides the basis for a reliable mapping method in awake monkeys and a reference for the organization of the properties of the visual space representation in an area LIP extended with respect to the previously described LIP and showing a relative emphasis of central visual field.

Galpha(olf) is necessary for coupling D1 and A2a receptors to adenylyl cyclase in the striatum.

Abstract: In the brain, dopamine and adenosine stimulate cyclic AMP (cAMP) production through D1 and A2a receptors, respectively. Using mutant mice deficient in the olfactory isoform of the stimulatory GTP-binding protein alpha subunit, Galpha(olf), we demonstrate here the obligatory role of this protein in the adenylyl cyclase responses to dopamine and adenosine in the caudate putamen. Responses to dopamine were also dramatically decreased in the nucleus accumbens but remained unaffected in the prefrontal cortex. Moreover, in the caudate putamen of mice heterozygous for the mutation, the amounts of Galpha(olf) were half of the normal levels, and the efficacy of dopamine- and CGS 21680 A(2) agonist-stimulated cAMP production was decreased. Together, these results identify Galpha(olf) as a critical parameter in the responses to dopamine and adenosine in the basal ganglia.

RXR-alpha ablation in skin keratinocytes results in alopecia and epidermal alterations.

Abstract: RXR-alpha is the most abundant of the three retinoid X receptors (RXRs) in the epidermis. In this study, we have used Cre-mediated recombination to selectively disrupt the mouse gene for RXR-alpha in epidermal and hair follicle keratinocytes. We show that RXR-alpha is apparently dispensable for prenatal epidermal development, while it is involved in postnatal skin maturation. After the first hair pelage, mutant mice develop a progressive alopecia, histologically characterised by the destruction of hair follicle architecture and the formation of utriculi and dermal cysts in adult mice. Our results demonstrate that RXR-alpha plays a key role in anagen initiation during the hair follicle cycle. In addition, RXR-alpha ablation results in epidermal interfollicular hyperplasia with keratinocyte hyperproliferation and aberrant terminal differentiation, accompanied by an inflammatory reaction of the skin. Our data not only provide genetic evidence that RXR-alpha/VDR heterodimers play a major role in controlling hair cycling, but also suggest that additional signalling pathways mediated by RXR-alpha heterodimerised with other nuclear receptors are involved in postnatal hair follicle growth, and homeostasis of proliferation/differentiation of epidermal keratinocytes and of the skin's immune system.

Comparative osteohistology of some embryonic and perinatal archosaurs: developmental and behavioral implications for dinosaurs

Abstract: Histologic studies of embryonic and perinatal longbones of living birds, non-avian dinosaurs, and other reptiles show a strong phylogenetic signal in the distribution of tissues and patterns of vascularization in both the shafts and the bone ends. The embryonic bones of basal archosaurs and other reptiles have thin-walled cortices and large marrow cavities that are sometimes subdivided by erosion rooms in early stages of growth. The cortices of basal reptiles are poorly vascularized, and osteocyte lacunae are common but randomly organized. Additionally, there is no evidence of fibrolamellar tissue organization around the vascular spaces. Compared with turtles, basal archosaurs show an increase in vascularization, better organized osteocytes, and some fibrolamellar tissue organization. In dinosaurs, including birds, vascularization is greater than in basal archosaurs, as is cortical thickness, and the osteocyte lacunae are more abundant and less randomly organized. Fibrolamellar tissues are eviden...

Why is nacre strong? Elastic theory and fracture mechanics for biocomposites with stratified structures

Abstract: Nacre, stratified ceramic layers surrounded by organic matrix, is a tough material found inside certain seashells. We construct a coarse-grained elastic energy for such an anisotropic system and present an analytic solution for a notch crack normal to the stratified sheets. This analysis proves the reduction in stress concentration which was announced in our earlier work (P. G. de Gennes and K. Okumura, C. R. Acad. Sci. Paris 1, Ser. IV, 257 (2000)) and the related increase in toughness.