Showing papers by "Collège de France published in 1995"
TL;DR: The crystal structure of the human retinoid-X receptor RXR-α ligand-binding domain reveals a previously undiscovered fold of an antiparallel α-helical sandwich, packed as dimeric units.
Abstract: The crystal structure of the human retinoid-X receptor RXR-alpha ligand-binding domain reveals a previously undiscovered fold of an antiparallel alpha-helical sandwich, packed as dimeric units. Two helices and one loop form the homodimerization surface, and hydrophobic heptad repeats participate in stabilizing the fold. The existence of a ligand-binding pocket is proposed that would allow 9-cis retinoic acid to interact with different functional modules, including the AF-2 activating domain. Several lines of evidence indicate that the overall structure is a prototype fold of ligand-binding domains of nuclear receptors.
1,176 citations
TL;DR: In this paper, a mouse trap mechanism was proposed to reposition the amphi-pathic α-helix of the AF-2 activating domain and form a transcriptionally active receptor.
Abstract: The 2.0-A crystal structure of the ligand-binding domain (LBD) of the human retinoic acid receptor (RAR)-γ bound to all-trans retinoic acid reveals the ligand-binding interactions and suggests an electrostatic guidance mechanism. The overall fold is similar to that of the human RXR-α apo-LBD, except for the carboxy-terminal part which folds back towards the LBD core, contributing to the hydrophobic ligand pocket and 'sealing' its entry site. We propose a 'mouse trap' mechanism whereby a ligand-induced conformational transition repositions the amphi-pathic α-helix of the AF-2 activating domain and forms a transcriptionally active receptor.
1,056 citations
TL;DR: It is proposed that TIF1, which contains several conserved domains found in transcriptional regulatory proteins, is a mediator of ligand‐dependent AF‐2, and the N‐terminal moiety is fused to B‐raf in the mouse oncoprotein T18.
Abstract: Nuclear receptors (NRs) bound to response elements mediate the effects of cognate ligands on gene expression. Their ligand-dependent activation function, AF-2, presumably acts on the basal transcription machinery through intermediary proteins/mediators. We have isolated a mouse nuclear protein, TIF1, which enhances RXR and RAR AF-2 in yeast and interacts in a ligand-dependent manner with several NRs in yeast and mammalian cells, as well as in vitro. Remarkably, these interactions require the amino acids constituting the AF-2 activating domain conserved in all active NRs. Moreover, the oestrogen receptor (ER) AF-2 antagonist hydroxytamoxifen cannot promote ER-TIF1 interaction. We propose that TIF1, which contains several conserved domains found in transcriptional regulatory proteins, is a mediator of ligand-dependent AF-2. Interestingly, the TIF1 N-terminal moiety is fused to B-raf in the mouse oncoprotein T18.
634 citations
TL;DR: Combining this conditional site-specific recombination system with tissue-specific expression of Cre-ER may allow modification of the mammalian genome in vivo in a spatiotemporally regulated manner.
Abstract: We have developed a strategy to generate mutant genes in mammalian cells in a conditional manner by employing a fusion protein, Cre-ER, consisting of the loxP site-specific Cre recombinase linked to the ligand-binding domain of the human estrogen receptor. We have established homozygous retinoid X receptor alpha-negative (RXR alpha-/-) F9 embryonal carcinoma cells constitutively expressing Cre-ER and have shown that estradiol or the estrogen agonist/antagonist 4-hydroxytamoxifen efficiently induced the recombinase activity, whereas no activity was detected in the absence of ligand or in the presence of the antiestrogen ICI 164,384. Furthermore, using a targeting vector containing a selection marker flanked by loxP sites, we have inactivated one retinoic acid receptor alpha allele in such a line, demonstrating that the presence of the recombinase does not inhibit homologous recombination. Combining this conditional site-specific recombination system with tissue-specific expression of Cre-ER may allow modification of the mammalian genome in vivo in a spatiotemporally regulated manner.
611 citations
TL;DR: In this paper, high statistics measurements of neutrino energy spectra carried out at 15, 40 and 95 meters from a 2800 Megawatt reactor, using detection modules filled with 6 Li-loaded liquid scintillator.
523 citations
TL;DR: In this paper, it was demonstrated that reversible photochemical interconversion between the two photochromic states could be used to effectively switch a number of physical properties, such as electron conduction and push-pull interaction.
Abstract: Organic photochromic systems represent a starting point for the elaboration of light-triggered molecular switching devices. The novel bispyridinium and bispyridine compounds 12+ and 6 were synthesized as their uncyclized isomers from 3,5-dibromo-2-methylthiophene in overall yields of 43 and 44%, respectively. The diarylethene photochromes 2 and 10–13, substituted with electron donors and acceptors, were prepared from 5-methylthiophene-2-carboxaldehyde in 21–32% overall yield. All of the compounds were found to exhibit pronounced photochromic properties. Irradiation with UV light resulted in essentially complete photocyclization of the open forms to the intensely coloured closed isomers which could, in turn, be reconverted back to the open state with visible light of γ>600 nm. The absorption maxima of the described compounds in their closed forms are shifted far towards, and even into, the near-IR region. Whereas no thermochromic properties were observed for the open isomers, the rates of thermal decolouration of the cyclized forms was found to be highly dependent on the nature of the substituents on the thiophene rings. It was demonstrated that reversible photochemical interconversion between the two photochromic states could be used to effectively switch a number of physical properties. Thus, the molecules 12+ and 12 represent two kinds of redox switches, the former in reduction and the latter in oxidation, in which electron conduction is switched on in the closed state and off in the open state. Compound 12 may also be considered to be a photoswitchable analogue of tetrathiafulvalene type substances. On the other hand, compound 2 displays a marked increase in nonlinear optical activity on conversion from the open to the closed form. Such systems are prototypes of photoswitchable molecular wires where electron conduction and push-pull interaction can be reversibly modulated by an external stimulus, namely, irradiation by light.
494 citations
TL;DR: It is demonstrated that progesterone is not simply a sex steroid, and a new therapeutic approach is suggested to promote myelin repair in male mice after cryolesion of the sciatic nerve.
Abstract: Progesterone is shown here to be produced from pregnenolone by Schwann cells in peripheral nerves. After cryolesion of the sciatic nerve in male mice, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impaired remyelination. Administration of progesterone or its precursor, pregnenolone, to the lesion site increased the extent of myelin sheath formation. Myelination of axons was also increased when progesterone was added to cultures of rat dorsal root ganglia. These observations indicate a role for locally produced progesterone in myelination, demonstrate that progesterone is not simply a sex steroid, and suggest a new therapeutic approach to promote myelin repair.
446 citations
Journal Article•
403 citations
TL;DR: It is shown that anandamide is a potent inhibitor of gap-junction conductance and dye permeability in striatal astrocytes and may control intercellular communication in astroCytes and therefore neuron–glial interactions.
Abstract: Anandamide, an endogenous arachidonic acid derivative that is released from neurons and activates cannabinoid receptors, may act as a transcellular cannabimimetic messenger in the central nervous system. The biological actions of anandamide and the identity of its target cells are, however, still poorly documented. Here we show that anandamide is a potent inhibitor of gap-junction conductance and dye permeability in striatal astrocytes. This inhibitory effect is specific for anandamide as compared to co-released congeners or structural analogues, is sensitive to pertussis toxin and to protein-alkylating agents, and is neither mimicked by cannabinoid-receptor agonists nor prevented by a cannabinoid-receptor antagonist. Glutamate released from neurons evokes calcium waves in astrocytes that propagate via gap junctions, and may, in turn, activate neurons distant from their initiation sites in astrocytes. We find that anandamide blocks the propagation of astrocyte calcium waves generated by either mechanical stimulation or local glutamate application. Thus, by regulating gap-junction permeability, anandamide may control intercellular communication in astrocytes and therefore neuron-glial interactions.
351 citations
TL;DR: A detailed study of an original spreading behavior observed with nonvolatile droplets containing surface-active agents, where the droplet moves spontaneously on the surface with velocities on the order of a few centimeters per second.
Abstract: We present a detailed study of an original spreading behavior observed with nonvolatile droplets containing surface-active agents: The droplet moves spontaneously on the surface with velocities on the order of a few centimeters per second. For small droplets, this self-supported motion may be interpreted in terms of capillary models, which gives precise information about the reaction mechanism that occurs at the surface. For large droplets, gravity intervenes and we observed an important change in the profile of the droplets and different spreading regimes.
278 citations
TL;DR: This new find from Chad documents the presence of an early hominid a considerable distance, 2,500 km, west of the Rift Valley, which is most similar in morphology to Australopithecus afarensis.
Abstract: THE first sites with Pliocene and Pleistocene mammals west of the Rift Valley in Central Africa in northern Chad were reported in 1959 (ref. 1), and documented the presence of mixed savannah and woodland habitats. Further sites2 and a probable Homo erectus cranio-facial fragment3 were subsequently discovered. In 1993 a survey of Pliocene and Pleistocene formations in the Borkou-Ennedi-Tibesti Province of Chad (B.E.T.) led to the discovery of 17 new sites in the region of Bahr el Ghazal (classical Arabic for River of the Gazelles) near Koro Toro. One site, KT12 (15°58'10" N, 18°52'46" E) yielded an australopithecine mandible associated with a fauna biochronologically estimated to be 3.0-3.5 Myr old. Australopithecine species described since 1925 are known from southern Africa and from sites spread along the eastern Rift Valley from Tanzania to Ethiopia (Fig. 1). This new find from Chad, which is most similar in morphology to Australopithecus afarensis4, documents the presence of an early hominid a considerable distance, 2,500 km, west of the Rift Valley.
TL;DR: In this paper, the bisphenolic dithienylethene molecules 1a and 1b were synthesized in overall yields of 45% from 4-bromoanisole and 44% from 2.6-di-tert-butyl-4-iodophenol, respectively.
Abstract: The bisphenolic dithienylethene molecules 1a and 1b were synthesized in overall yields of 45% from 4-bromoanisole and 44% from 2.6-di-tert-butyl-4-iodophenol, respectively. The corresponding extended quinones 3a and 3b were also prepared. Photochemical studies showed that compounds 1 are photochromic; the open forms 1 could be converted with UV light of 312nm to the closed coloured forms 2 with photostationary states lying at essentially complete conversion (> 98%). The 1a-2a system was found to exhibit good resistance to photofatigue and thermal stability for both photoisomers. Cyclic voltammetry studies involving the 2/3 couples showed that whereas 2b undergoes irreversible oxidation at + 0.85 V (vs. SCE in THF), the hydroquinone 2a is reversibly oxidized at an E1/2 of + 0.72V (in MeCN, quasi-reversibly in THF at + 0.81 V); this reflects the differences in deprotonation behaviour of the generated QH2/2+ species. The large difference in oxidation potential between 1a and 2a allows the photochemical switching of redox properties. In a complementary fashion, redox switching of the photochromic properties within the 2a-3a pair is possible since 3a is stable to visible light. Owing to this unique behaviour, the triad consisting of 1-3a represents a novel molecular device with mutually regulating photo- and electrochromic behaviour. In addition, the ability to interconvert between the three stable states makes the system well-suited as the basis for an optical memory system with multiple storage and nondestructive readout capacity through a write-lock-read-unlock-erase cycle.
TL;DR: It is shown that in animal cells the “independent” activity of AF-1 is embodied in a rather hydrophobic proline-rich 99-amino acid activating domain (amino acids 51-149), whereas in yeast, three discrete activating domains are almost as active on their own as the whole A/B region, indicating that multiple activating domains can operate independently in yeast.
TL;DR: In this article, the authors found that intra-arterial hemopoietic cells aggregates are present in the omphalomesenteric and umbilical arteries and to a lesser degree in the dorsal aorta.
Abstract: In the course of a previous experimental study on the early development of the mouse embryo hemopoietic system, we found that, at the 10–25 pairs of somite stages, the para-aortic splanchnopleure contains hemopoietic progenitors. Trying to discover a structural basis for this potentiality, we have looked for cytological signs of hemopoiesis in the embryo proper between 8.5 and 12 days post-coitum, i.e. prior to full-blown fetal liver hemopoiesis. Two suggestive findings are reported: (1) intra-arterial hemopoietic cells aggregates are present in the omphalomesenteric and umbilical arteries and to a lesser degree in the dorsal aorta; (2) cells groups resembling yolk sac blood islands are observed in the mesentery. The intra-arterial aggregates are strikingly similar to the intra-aortic clusters of avian embryos. These cytological aspects provide the anatomical basis underlying recent functional data that revealed the hemogenic capacity of the para-aortic splanchnopleure.
TL;DR: In this paper, the geometric data is encoded by a triple (A. H. D) of an algebra, represented in a Hilbert space, with selfadjoint operator D. This point of view is dictated by the general framework of noncommutative geometry and allows us to use geometric ideas in many situations beyond Riemannian geometry.
Abstract: In this Letter, we develop geometry from a spectral point of view, the geometric data being encoded by a triple (A. H. D.) of an algebraA represented in a Hilbert spaceH with selfadjoint operatorD. This point of view is dictated by the general framework of noncommutative geometry and allows us to use geometric ideas in many situations beyond Riemannian geometry.
TL;DR: It is shown that the movements of invagination and divergence which characterize gastrulation are still going on in the tail bud after the 25-somite stage, and points to the unity in the development mechanisms within the Vertebrate phylum.
TL;DR: Results demonstrate that induction of LTP in the hippocampal‐prefrontal cortex pathway is an NMDA receptor‐dependent process.
Abstract: This study investigated the role of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor in the induction of long-term potentiation (LTP) in the hippocampal-prefrontal cortex pathway in vivo. Field potentials evoked by electrical stimulation of the CA1/subicular region were recorded in the prelimbic area of the prefrontal cortex under continuous perfusion of artificial cerebrospinal fluid in anaesthetized rats. High-frequency stimulation of the CA1/subicular region induced LTP of the evoked response in the prelimbic area of the prefrontal cortex. LTP was completely blocked when the selective NMDA receptor antagonist D-(-)2-amino-5-phosphonopentanoic acid (D-AP5; 200 microM), was perfused during the tetanus. Perfusion of D-AP5 did not affect normal transmission or pre-established LTP. These results demonstrate that induction of LTP in the hippocampal-prefrontal cortex pathway is an NMDA receptor-dependent process.
TL;DR: An efficient differential subtractive hybridization cloning strategy was used to identify additional RA-responsive genes in P19 cells and describes the sequence and expression pattern in mouse embryos and adult tissues of one of these novel RA-inducible genes, Stra1, and shows that it corresponds to the mouse ligand for the Cek5 receptor protein-tyrosine kinase.
TL;DR: A protocol has been developed for the purification of the cytochrome b6f complex from the unicellular alga Chlamydomonas reinhardtii that comprises only three steps: selective solubilization from thylakoid membranes, sucrose gradient sedimentation, and hydroxylapatite chromatography.
TL;DR: The case of an apraxic patient who was impaired in all aspects of gestural behavior following bilateral posterior parietal cortex lesions is reported, and the existence of specialized cortical mechanisms for the representation and activation of the postural schemata of the hand required for complex actions is proposed.
TL;DR: It is suggested that the AT1 gene is involved in the development of aortic stiffness in hypertensive patients and could modulate the effects of lipids on large arteries.
Abstract: Several clinical and experimental studies have suggested a significant role of angiotensin II in the development of alterations of small and large arteries. The present study was designed to assess the contribution of polymorphism (corresponding to an A1166-->C transversion) of the angiotensin II type 1 receptor (AT1) gene to aortic stiffness. One hundred thirty-four never-treated hypertensive patients were included in the study. Aortic distensibility was evaluated by measuring carotid-femoral pulse wave velocity. Age, systolic and diastolic pressure, and metabolic parameters were similar in the three genotypes. Pulse wave velocity was 11.4 +/- 2.5 m/s in AT1 AA homozygotes, 12.5 +/- 3.2 m/s in AC heterozygotes, and 14.7 +/- 4.0 m/s in CC homozygotes (P = .003, P < .001 after adjustment for age, blood pressure, and body mass index). Moreover, an interaction was found between AT1 genotype and the ratio of total to high-density lipoprotein cholesterol in terms of the development of aortic stiffness. Thus, a positive correlation was observed between the ratio of total to high-density lipoprotein cholesterol and pulse wave velocity in AC and CC (r = .42, P < .001) but not AA patients. These results suggest that the AT1 gene is involved in the development of aortic stiffness in hypertensive patients and could modulate the effects of lipids on large arteries.
TL;DR: Findings do not suggest that common molecular variants of the endothelial nitric oxide synthase gene are involved in essential hypertension.
Abstract: Background The basal release of nitric oxide by the endothelium plays an important role in regulating blood flow and pressure and mediates most of the endothelium-dependent vasodilation. Impairment of nitric oxide production by specific inhibitors increases blood pressure in humans, and several reports suggest that hypertensive subjects have a blunted endothelium-dependent vasodilatation that might be secondary to decreased nitric oxide production from the vessel wall. Methods and Results To determine whether the endothelial nitric oxide synthase gene is involved in human essential hypertension, we identified informative biallelic and multiallelic markers of this locus and performed case-control and linkage studies in hypertensive subjects and normotensive control subjects. We used the affected sib pair method to test for potential linkage in 145 hypertensive pedigrees (269 sib pairs, 346 subjects) with a highly polymorphic marker of the nitric oxide synthase gene (polymorphism information content of 92%). There was no evidence for linkage among affected siblings. The 95% upper confidence limit of this value suggests that at most 1% of alleles in excess of expected are shared. We also identified two informative biallelic markers of this gene to perform a case-control study on white hypertensive and normotensive subjects. Similar genotype distributions between the two groups were noted for both markers. Estimated haplotype frequencies by maximum likelihood methods combining the two biallelic markers were also similar in both groups. Conclusions These findings do not suggest that common molecular variants of the endothelial nitric oxide synthase gene are involved in essential hypertension.
TL;DR: The inductive signal emanates from the neural tube itself, suggesting that planar signalling and predominance of posterior properties are involved in the patterning of the neural primordium.
Abstract: In this study we have analysed the expression of Hoxb-4, Hoxb-1, Hoxa-3, Hoxb-3, Hoxa-4 and Hoxd-4 in the neural tube of chick and quail embryos after rhombomere (r) heterotopic transplantations within the rhombencephalic area. Grafting experiments were carried out at the 5-somite stage, i.e. before rhombomere boundaries are visible. They were preceeded by the establishment of the precise fate map of the rhombencephalon in order to determine the presumptive territory corresponding to each rhombomere. When a rhombomere is transplanted from a caudal to a more rostral position it expresses the same set of Hox genes as in situ. By contrast in many cases, if rhombomeres are transplanted from rostral to caudal their Hox gene expression pattern is modified. They express genes normally activated at the new location of the explant, as evidenced by unilateral grafting. This induction occurs whether transplantation is carried out before or after rhombomere boundary formation. Moreover, the fate of the cells of caudally transplanted rhombomeres is modified: the rhombencephalic nuclei in the graft develop according to the new location as shown for an r5/6 to r8 transplantation. Transplantation of 5 consecutive rhombomeres (i.e. r2 to r6), to the r8 level leads to the induction of Hoxb-4 in the two posteriormost rhombomeres but not in r2,3,4. Transplantations to more caudal regions (posterior to somite 3) result in some cases in the induction of Hoxb-4 in the whole transplant. Neither the mesoderm lateral to the graft nor the notochord is responsible for the induction. Thus, the inductive signal emanates from the neural tube itself, suggesting that planar signalling and predominance of posterior properties are involved in the patterning of the neural primordium.
TL;DR: By combining in vitro and in vivo electrophysiological approaches and the new powerful neuropharmacological techniques developed from the recent advances of molecular biology, the vestibular system can be used as a good model to elucidate some of the basic properties of the brain including learning, neural computation, network reconfiguration and post-lesional plasticity.
TL;DR: Histological analysis revealed essentially all of the defects characteristic of fetal VAD and a number of additional malformations, not described in previous VAD studies, were observed.
Journal Article•
TL;DR: The enhancing effect of the hybridization signal obtained using MW allows shorter autoradiographic exposure times and/or the use of lower concentrations of radioactive probes for the detection of mRNA or the Detection of mRNA expressed at the threshold of detection with usual protocols.
TL;DR: The genomic structure of the human MR is determined and it is indicated that hMR expression is regulated by alternative promoters perhaps in a tissue- or developmental-specific manner.
TL;DR: It is found that the anterior region of the cephalic paraxial mesoderm is largely recruited to provide the forebrain and the upper face with their vasculature, which means that large volumes of tissues are vascularized by a discrete region ofThe cEPhalic Mesoderm.