Showing papers by "Rhône-Poulenc published in 1994"
TL;DR: It is proposed that heparin causes oligomerization of aFGF such that its binding to FGFR results in dimerization and activation, which represents a novel mechanism for transmembrane signaling and may account for the action of many heParin-bound growth factors.
657 citations
TL;DR: A series of 63 3-substituted quinoline derivatives has been prepared and tested for inhibition of cell-free platelet derived growth factor receptor tyrosine kinase activity and the presence of 6,7-dimethoxy groups on the quin Caroline ring was found to be advantageous although not essential for potent inhibition of PDGF-RTK.
Abstract: A series of 63 3-substituted quinoline derivatives has been prepared and tested for inhibition of cell-free platelet derived growth factor receptor tyrosine kinase (PDGF-RTK) activity. The compounds were generally prepared either by a Friedlander condensation between an arylacetaldehyde and an o-aminobenzaldehyde or by a palladium-catalyzed coupling between an aryl bromide or triflate and an organostannane or organozinc chloride. The presence of 6,7-dimethoxy groups on the quinoline ring was found to be advantageous although not essential for potent inhibition of PDGF-RTK. A lipophilic group attached to the quinoline 3-position contributed substantially to activity. The lipophilic groups generally consisted of monocyclic aromatics or small alkynyl, alkenyl, and alkyl groups. Optimum activity of ca. 120 nM (ICm) was observed when 6,7-dimethoxyquinoline was substituted in the 3-position with 4-methoxyphenyl (15d), 3-fluoro-4-methoxyphenyl(17m), 3-fluorophenyl(17b), 4-hydroxyphenyl (24), 6-methoxypyridin3-y1(150), B-pyridin-2(1H)-one (23), trans-@-styryl(15e), thiophene-3-y1(2e), 5-chlorothiophene2-yl (150, or cyclopentenyl (17x1) groups. Most of the compounds in the series were tested for inhibition of cell-free epidermal growth factor receptor tyrosine kinase activity and found to be inactive. Platelet-derived growth factor (PDGF) receptors are integral, transmembrane glycoproteins whose expression is generally limited to cells of mesodermal 0rigin.l Abnormal expression of PDGF and/or PDGF receptors has been linked to a number of pathophysiological processes which include various forms of neoplasia, atherosclerosis, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, and abnormal wound healing.2 Upon ligand binding, the intrinsic tyrosine kinase activity of the PDGF receptor is activated. This leads to tyrosine phosphorylation of numerous proteins, including the receptor itself. Receptor autophosphorylation is essential for all subsequent steps of signal transduction. Importantly, the signaling cascade that follows from the action of PDGF on smooth muscle cell (SMC) PDGF receptors is believed to result in a significant contribution to the process of SMC proliferation and chem~taxis.~ This process is a crucial component of the sequence of events leading to restenosis after percutaneous transluminal coronary angioplasty procedure^.^ An inhibitor of the PDGF receptor tyrosine kinase activity would block its action. Such an inhibitor could potentially be utilized in the treatment of proliferative disorders linked to PDGF receptors, including postangioplasty restenosis. A series of 2,3-diarylacrylonitrile compounds has been prepared in our laboratories as epidermal growth factor receptor tyrosine kinase (EGF-RTK) inhibitors.5 I With several exceptions, these compounds were generally poor PDGF-RTK inhibitors. Compound 1 (RG13022): however, displayed modest inhibitory activity in both the EGFRTK' and PDGF-RTK cell-free assays (IC50 = 0.5-3 and 0.7-4 pM, respectively). As part of an effort to identify lead structures as PDGF-RTK inhibitors, we decided to
437 citations
TL;DR: An FGFR2 mutation in the conserved region of the immunoglobulin Illc domain in the Jackson-Weiss syndrome family is reported, and in four of 12 Crouzon syndrome cases, two new mutations are identified and two previously described mutations are found.
Abstract: Jackson-Weiss syndrome is an autosomal dominant condition characterized by craniosynostosis, foot anomalies and great phenotypic variability. Recently mutations in fibroblast growth factor receptor 2 (FGFR2) have been found in patients with another craniosynostotic syndrome, Crouzon syndrome. FGFR2 is a member of the tyrosine kinase receptor superfamily, having a high affinity for peptides that signal the transduction pathways for mitogenesis, cellular differentiation and embryogenesis. We now report an FGFR2 mutation in the conserved region of the immunoglobulin IIIc domain in the Jackson-Weiss syndrome family in which the syndrome was originally described. In addition, in four of 12 Crouzon syndrome cases, we identified two new mutations and found two previously described mutations in the same region.
436 citations
TL;DR: It is proposed that DNA topoisomerase IV is a primary target of fluoroquinolones in S. aureus.
Abstract: A 4.6 kb Staphylococcus aureus DNA fragment containing DNA gyrase-like genes (grlA and grlB) was cloned and sequenced. The proteins GrlA and GrlB exhibit more than 30% identity with E. coli DNA topoisomerase IV subunits and with the gyrase subunits from S. aureus and Escherichia coli. The combined E. coli cell extracts of GrlA and GrlB overproducing strains catalysed ATP-dependent relaxation and decatenation specific to DNA topoisomerase IV. The temperature-sensitive phenotype of Salmonella typhimurium parC and parE mutants was complemented by the S. aureus grlA and grlB genes, when the two genes were co-expressed. These results show that GrlA and GrlB are the subunits of S. aureus DNA topoisomerase IV. The GyrA subunit of DNA gyrase has been previously defined as a primary target of quinolones based on genetic and biochemical experiments essentially carried out in E. coli. Single-point mutations occurring in the 'quinolone resistance-determining region' (QRDR) of GyrA were found in bacteria exhibiting quinolone resistance, the most common mutation being a substitution of Ser-83 on the E. coli GyrA sequence. We analysed eight S. aureus fluoroquinolone-resistant clinical isolates and observed that mutations in the QRDR of GyrA are not present in the low-quinolone-resistant isolates. In contrast, Ser-80 of GrlA, which corresponds to Ser-83 of E. coli GyrA, is substituted to Phe or Tyr in both high- and low-quinolone-resistant isolates. We propose that DNA topoisomerase IV is a primary target of fluoroquinolones in S. aureus.
380 citations
TL;DR: The isolation of a cDNA coding for a human galanin receptor from a Bowes melanoma cell line cDNA expression library is reported here by using a radioligand binding strategy and the nucleotide sequence of the cloned receptor reveals an open reading frame encoding a 349-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the guanine nucleotide binding protein-coupled neuropeptide receptor family.
Abstract: The ubiquitous neuropeptide galanin controls numerous functions such as endocrine secretions, intestinal motility, and behavioral activities. These regulatory effects of galanin are mediated through the interaction with specific membrane receptors and involve the pertussis toxin-sensitive guanine nucleotide binding proteins Gi/Go as transducing elements. We report here the isolation of a cDNA coding for a human galanin receptor from a Bowes melanoma cell line cDNA expression library, by using a radioligand binding strategy. The nucleotide sequence of the cloned receptor reveals an open reading frame encoding a 349-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the guanine nucleotide binding protein-coupled neuropeptide receptor family. The cloned receptor expressed in COS cells specifically binds human, porcine, and rat galanin with high affinity (Kd in the nanomolar range) and mediates the galanin inhibition of adenylate cyclase. A 2.8-kb galanin receptor transcript was identified in several human tissues. Cloning of this galanin receptor should enhance our knowledge of its distribution, structure, and function in human physiology and pathophysiology.
369 citations
TL;DR: Docetaxel is an active drug in patients with advanced squamous cell carcinoma of the head and neck with a response rate of 32% (95% confidence interval 17%-47%).
255 citations
Patent•
09 May 1994TL;DR: In this article, a chimeric gene for conferring to plants an increased tolerance to a herbicide was proposed, where the gene comprises a promoter region, a transit peptide region and a sequence encoding glyphosate tolerance and a polyadenylation signal region.
Abstract: The present invention relates to a chimeric gene for conferring to plants an increased tolerance to a herbicide. This chimeric gene comprises, in the direction of transcription, a promoter region, a transit peptide region, a sequence encoding glyphosate tolerance and a polyadenylation signal region, wherein the promoter region consists of at least one promoter of a plant histone gene enabling the expression of the herbicide tolerance protein in the regions of glyphosate accumulation. The present invention further provides vectors containing the present chimeric genes, as well as plant cells and plants transformed with such vectors which permit production of glyphosate-tolerant plants.
232 citations
TL;DR: In this article, the authors present a review of the literature dealing with reduction of nitriles, which is mostly published in patents and is mostly focused on the reduction of primary diamines.
Abstract: Primary or alkylated amines are important chemicals and intermedi-ates. N-Alkylamines are used without further transformation as surface-active agents. Aliphatic primary diamines polymerize with aliphatic diacids to give linear polyamides which have conquered a large place in textile and mechanical industry [11. Mono- and polyamines are produced by catalytic hydrogenation of the corresponding nitriles [2]. In particular this pathway to hexamethylenediamine has been made easier since the synthesis of adi-ponitrile by hydrocyanation of butadiene was made possible [3]. The spec-ifications for production of amines are often very drastic from the point of view of purity, in particular for the diamines used in the textile industry. Thus the stress is put on selectivity of the reaction and most of industrial processes have a yield approaching stoichiometry. It exists few reviews on reduction of nitriles [4, 51, the literature dealing with this type of reaction being mostly published in patents [6–91, an...
212 citations
TL;DR: At the International Workshop on the Standardisation of Genotoxicity Test Procedures, in Melbourne (27-28 February 1993), the current international guidelines for the correct conduct of bacterial mutation assays were considered, and the major differences between them were examined.
Abstract: At the International Workshop on the Standardisation of Genotoxicity Test Procedures, in Melbourne (27-28 February 1993), the current international guidelines for the correct conduct of bacterial mutation assays were considered, and the major differences between them were examined. An attempt was made to construct a scientifically based, internationally harmonized protocol. The main points of agreement were as follows. The consensus opinion was that there are currently insufficient data to justify a preference for either the preincubation or plate-incorporation methodologies as the initial test. Whichever method is used there was consensus agreement that the bacterial test battery should consist of S. typhimurium TA1537, TA1535, TA98 and TA100. There was also consensus that the 3 strains TA97a, TA97 and TA1537 could be used interchangeably. Although it was not possible to achieve a consensus, the majority of the working group members agreed that strains for the detection of mutagens acting specifically on AT base pairs should be routinely included within the test battery. These strains may be S. typhimurium TA102 or E. coli WP2 strains (WP2 pKM101 and WP2 uvrA or WP2 uvrA pkM101). With regard to study design it was universally agreed that 5 doses of test compound should be used in each experiment, and a majority agreement was obtained for 3 plates per dose. The use of 2 plates per dose is acceptable ONLY if the experiment is repeated. It is recommended that the negative controls may consist of solvent control alone provided that historical data are available to demonstrate lack of effect of the solvent in question. Positive control compounds should be included in all experiments, although the nature of these control compounds need not be specified in the guidelines. There was consensus agreement that for non-toxic freely soluble test agents, an upper limit of 5 mg/plate should be tested (5 microliters per plate for liquids). For insoluble or toxic compounds, the recommendations were the same as those for other in vitro tests (see appropriate paper). A consensus agreement was reached on the need to carry out further tests if equivocal results are obtained in the initial test, although it was generally agreed that the design of the repeat study should be left flexible. As there are little or no data to support the use of an exact repeat assay, a majority of the group recommended that negative results in the first test should be further investigated by either conducting a modified repeat (e.g. S9 titration) or by conducting the alternative methodology.(ABSTRACT TRUNCATED AT 400 WORDS)
201 citations
TL;DR: In patients undergoing autologous or allogeneic BMT for neoplastic disease, lenograstim significantly reduced duration of neutropenia and led to earlier hospital discharge and there was no significant toxicity ascribed to lenogsrastim.
167 citations
TL;DR: These compounds did not significantly inhibit the in vitro activities of several purified HIV-1 enzymes, but appeared to block virus infection at a postbinding, envelope-dependent step involved in the fusion of the virus to the cell membrane.
Abstract: A series of triterpene compounds characterized by a stringent structure-activity relationship were identified as potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Currently studied botulinic derivatives have 50% inhibitory concentrations (IC50) against HIV-1 strain IIIB/LAI in the 10 nM range in several cellular infection assays but are inactive against HIV-2. These compounds did not significantly inhibit the in vitro activities of several purified HIV-1 enzymes. Rather, they appeared to block virus infection at a postbinding, envelope-dependent step involved in the fusion of the virus to the cell membrane.
Journal Article•
TL;DR: The results show that an octanol/buffer distribution coefficient value around 3000 corresponds to an optimal transepithelial passage of drugs and that too high a lipophilicity can result in low intestinal epithelial permeability and in low oral absorption.
Abstract: It is generally admitted in drug research that the passage of molecules across cellular barriers increases with lipophilicity and that the most lipophilic compounds will have the highest intestinal absorption. Using two in vitro models of intestinal epithelium, we presently demonstrate that this concept is not always valid and that highly lipophilic compounds display a low transepithelial permeability. We used epithelial cell lines grown on permeable filters to measure in vitro the transepithelial permeability of various molecules. The octanol/buffer distribution coefficient of the drugs (Do/b) was taken as an index of lipophilicity. When log Do/b values were lower than 3.5, the transepithelial permeability coefficient increased with the lipophilicity. But for log Do/b values ranging from 3.5 to 5.2, the transepithelial permeability coefficient decreased with increasing lipophilicity. Identical results were observed with two differentiated intestinal epithelial cell lines (HT29-18-C1 and Caco-2) and in unstirred or agitated conditions. The results show that an octanol/buffer distribution coefficient value around 3000 corresponds to an optimal transepithelial passage of drugs and that too high a lipophilicity can result in low intestinal epithelial permeability and in low oral absorption.
TL;DR: The anticancer drug docetaxel (Taxotere) was transported in a polarized manner: basolateral to apical permeability was 20-fold higher than in the reverse direction, thus demonstrating that docentaxel is a substrate of P-glycoprotein.
TL;DR: Peptides based upon the 7-amino acid SH3 binding domain core motif displayed strong binding to both the Src and to the Fyn SH3 domains, but failed to bind to the SH3 domain of p21 Ras-GTPase-activating protein (Ras-GAP) and other proteins.
TL;DR: Patients with advanced and/or metastatic breast cancer and bidimensionally measurable disease, were treated with docetaxel every 3 weeks as a 1 hour infusion without any premedication to alleviate the non-hematological toxicities.
TL;DR: The properties of oxygenating and conjugating enzymes in plants are highlighted, with emphasis on the evident narrow substrate specificities, species differences and physiological roles.
Abstract: Plants are able to metabolize agrochemicals and other foreign compounds by a variety of mechanisms and with extraordinary species diversity. Minor structural alterations of these compounds can bring about dramatic and unpredictable changes in the routes of their metabolism. The enzymes responsible for this exist in multiple forms which renders prediction of herbicide metabolism and, therefore, of selectivity, difficult. In some notable instances, pesticides are activated by plant metabolism. In the main, however, mechanisms such as hydroxylation, dealkylation and glutathione conjugation bring about detoxification and form the basis of herbicide selectivity. The properties of oxygenating and conjugating enzymes in plants are highlighted, with emphasis on the evident narrow substrate specificities, species differences and physiological roles. The molecular cloning of the genes specifying these enzymes will permit a much better definition of these mechanisms and will illuminate the natural roles of the enzymes involved. The prospects for utilizing recombinant enzymes as tools for the rational design of new selective herbicides are discussed. Herbicide safeners can protect certain crops from herbicide injury by promoting herbicide metabolism. The precise mechanisms of safener action and the reasons for their specificity are attracting much interest but are at present obscure. Natural variation in detoxification abilities of weed populations has allowed the field selection of some biotypes resistant to repeatedly used herbicides. By analogy, the introduction of microbial detoxification genes into major crops through genetic transformation has created new herbicideresistant crops which will enhance the flexibility of herbicide usage.
TL;DR: Taxotere has activity in adult soft tissue sarcoma in second line, warranting studies on first line efficacy, and this work concludes that taxoids offer a new class of cytostatic drugs.
TL;DR: It is concluded that riluzole has a dual action on cerebellar granule cells, both blocking voltage‐dependent sodium channels and interfering with NMDA receptor‐mediated responses via a pertussis toxin‐sensitive mechanism.
Abstract: 1. Intracellular calcium levels were measured in cultured cerebellar granule cells of the rat by use of the fluorescent dye, indo-1/AM. 2. Intracellular calcium levels were increased by depolarizing stimuli such as N-methyl-D-aspartate (NMDA) (100 microM), glutamic acid (20 microM), and veratridine (10 microM). This increase was essentially due to entry of external calcium. 3. Riluzole (10 microM) blocked responses to all the depolarizing agents. 4. Riluzole could still block the increase in intracellular calcium evoked by NMDA or glutamic acid when sodium channels were blocked by tetrodotoxin, suggesting that this effect is not mediated by a direct action of riluzole on the voltage-dependent sodium channel. 5. Pretreatment of the cells with pertussis toxin (0.1 micrograms ml-1) did not modify the increases in intracellular calcium evoked by NMDA, glutamic acid or veratridine. 6. In pertussis toxin-treated cells, riluzole could no longer block responses to excitatory amino acids, but still blocked responses to veratridine. 7. It is concluded that riluzole has a dual action on cerebellar granule cells, both blocking voltage-dependent sodium channels and interfering with NMDA receptor-mediated responses via a pertussis toxin-sensitive mechanism. Furthermore, these two processes have been shown to be independent.
TL;DR: 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma.
Abstract: The syntheses and biological activities of a number of benzamide derivatives, designed from rolipram, which are selective inhibitors of cyclic AMP-specific phosphodiesterase (PDE IV), are described. The effects of changes to the alkoxy groups, amide linkage, and benzamide N-phenyl ring on the inhibition of the cytosolic PDE IV from pig aorta have been investigated. As a result, some highly potent and selective PDE IV inhibitors have been identified. The most potent compounds have been further evaluated for their inhibitory potencies against PDE IV obtained from and superoxide O 2- generation from guinea pig eosinophils in vitro. Selected compounds have also been examined for their activities in inhibiting histamine-induced bronchospasm in anaesthetized guinea pigs. 3-(Cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide (15j) showed exceptional potency in all tests and may have therapeutic potential in the treatment of asthma
TL;DR: In this paper, spray drying of salbutamol sulphate particles using a Buchi 190 mini spray dryer was investigated in relation to particle size and yield of the resultant powder.
TL;DR: Phenytoin, carbamazepine, lamotrigine or RP 66055 may act at sodium channels to prevent depolarization, inhibit release of neurotransmitters such as glutamate and thus protects the cortex against cellular damage induced by focal ischaemia by both pre- and post-synaptic inhibition of abnormal neurotransmission.
TL;DR: The data demonstrate that RP 73401 and rolipram inhibit antigen‐ and mediator‐induced bronchospasm in guinea‐pigs with the same potency and indicate the importance of PDE IV in regulating smooth muscle and inflammatory cell activity.
Abstract: 1. We have investigated the effects of RP 73401, a novel, potent and highly selective cyclic nucleotide phosphodiesterase (PDE) type IV inhibitor, in guinea-pig and rat models of bronchoconstriction and allergic inflammation. In some models, the effects of RP 73401 have been compared with those of the standard PDE type IV inhibitor, rolipram. 2. RP 73401 (0.4-400 micrograms kg-1, intratracheally (i.t.) on lactose) inhibited antigen-induced bronchospasm in previously sensitized conscious guinea-pigs (ID50: 7 +/- 1 micrograms kg-1) and in anaesthetized rats (ID50: 100 +/- 25 micrograms kg-1). Rolipram inhibited the antigen-induced bronchospasm in guinea-pigs with an ID50 of 5 +/- 1 micrograms kg-1. In guinea-pig bronchoalveolar lavage (BAL) fluid, total inflammatory cell and eosinophil numbers were reduced by RP 73401 (ID50s: 3.9 +/- 0.8 micrograms kg-1 and 3.2 +/- 0.7 micrograms kg-1, respectively). In the rat, inflammatory cell numbers are less affected. Only the highest dose of RP 73401 (400 micrograms kg-1) significantly inhibited eosinophil influx (41 +/- 16% inhibition). 3. RP 73401 (0.02-100 micrograms kg-1, i.v.) inhibited PAF-induced bronchial hyperreactivity to bombesin in the anaesthetized guinea-pig (ID50: 0.09 +/- 0.03 micrograms kg-1) and inhibited (0.4-40 micrograms kg-1, i.t.) histamine-induced airway microvascular leakage in the anaesthetized guinea-pig by approximately 60% at all doses. 4. RP 73401 relaxed guinea-pig isolated trachea under basal tone (EC50: 9 nM) and when precontracted with histamine (IC50: 2 nM), methacholine (IC50: 29 nM) or leukotriene D4 (LTD4, IC50: 4 nM). 5. RP 73401 (0.4-100 microg kg-1, i.t.) inhibited bronchospasm induced by histamine (ID.%: 34 +/- 6 microg kg-1), methacholine (ID50: 66 +/- 12 pg kg-1) and LTD4 (ID50: <4 microg kg-1) in the anaesthetized guinea pig.Against these same bronchoconstrictors, rolipram (i.t.) had ID5o values of 44 +/- 4, 72 +/- 18 and<4 pg kg- respectively. RP 73401 (4 and 40 pg kg-, i.t.) increased the magnitude and duration of bronchodilatation produced by salbutamol in the anaesthetized guinea-pig. At doses producing significant bronchodilatation, RP 73401 was without effect on heart rate or blood pressure in the anaesthetized guinea-pig. RP 73401 (0.01 -0.25 mg kg-1, i.v.) did not affect heart rate and produced only a small fall in blood pressure in the anaesthetized rat.6. These data demonstrate that RP 73401 and rolipram inhibit antigen- and mediator-induced bronchospasmin guinea-pigs with the same potency. Furthermore, RP 73401 administered directly into the airways, protects against allergic airway inflammation. These results indicate the importance of PDE IV in regulating smooth muscle and inflammatory cell activity. At doses suppressing the inflammatory response in the lung, RP 73401 had little effect in the cardiovascular system. RP 73401 may have a role as a bronchodilator and, more importantly, as a prophylactic anti-inflammatory agent in the treatment of asthma.
Patent•
19 Apr 1994
TL;DR: In this paper, the use of mono-and/or bicyclic aryl or heteroaryl quinazoline compounds in inhibiting cell proliferation, including compounds which are useful protein tyrosine kinase (PTK) inhibitors, is described.
Abstract: This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, cell inflammatory response, the control of abnormal cell growth and cell reproduction. More specifically, this invention relates to the use of mono- and/or bicyclic aryl or heteroaryl quinazoline compounds in inhibiting cell proliferation, including compounds which are useful protein tyrosine kinase (PTK) inhibitors. The method of treating cell proliferation using said quinazoline compounds and their use in pharmaceutical compositions is described.
TL;DR: The pKa and log P of 20 compounds, including six substituted phenols, two substituted quinolines, N-methylaniline, five barbiturate derivatives, two phenothiazines, and several other molecules of pharmaceutical interest, were determined by the potentiometric technique at 25 degrees C and ionic strength 0.1 M.
TL;DR: The result of this study showed that the multiplicity and the diversity of crotoxin isoforms result from post-translational modifications occurring on a precursor and from the expression of different messenger RNAs present in an individual snake.
Abstract: Crotoxin, the main toxin from the venom of the South American rattlesnake Crotalus durissus terrificus, is a β-neurotoxin which consists of the non-covalent association of two subunits: a phospholipase A2 subunit B (CB), and a non-enzymic subunit A (CA). We have previously purified and characterized several isoforms of each subunit of crotoxin in the venom collected from numerous snakes. Furthermore, three cDNAs encoding two CB isoforms and the precursor, pro-CA, of subunit A have been isolated from a cDNA library prepared from a single venom gland of Crotalus durissus terrificus.
The aim of this study is to analyse an individual snake venom from an animal that has been used to construct a cDNA library. Several isoforms of subunit A and two isoforms of subunit B were isolated and compared to purified and characterized subunit isoforms from pooled venom. The result of this study showed that the multiplicity and the diversity of crotoxin isoforms result from post-translational modifications occurring on a precursor and from the expression of different messenger RNAs present in an individual snake. It allowed for the identification of the two CB isoforms encoding cDNAs expressed in the individual venom with two isoforms from pooled venom, CBc and probably CBa2, that belong to two classes of crotoxin complexes which can be distinguished biochemically and pharmacologically.
TL;DR: In this paper, a ZrO 2 /CeO 2 mixed oxides are conveniently prepared by intimately admixing a zirconium sol with a cerium sol and calcining the recovered precipitate.
Abstract: Zirconium/cerium mixed oxides (optionally including thermally stabilizing dopant values), comprising solid solutions thereof, having contents of zirconium of up to 99% by weight, and having high specific surface areas, are well suited as catalysts and/or catalyst supports, notably for the treatment/conversion of vehicular exhaust gases; such ZrO 2 /CeO 2 mixed oxides are conveniently prepared by (i) intimately admixing a zirconium sol with a cerium sol, the ratio r of the mean diameter r 1 of the particles of the zirconium sol to the diameter r 2 of the particles of the cerium sol being at least 5, (ii) adding a precipitating amount of a base thereto, (iii) recovering the precipitate thus formed, and (iv) calcining the recovered precipitate.
TL;DR: A mechanistic study of the reductive dechlorination of carbon tetrachloride by vitamin B 12 (cyanocobalamin) in the presence of dithiothreitol was conducted as a function of redor potential and pH.
Abstract: A mechanistic study of the reductive dechlorination of carbon tetrachloride by vitamin B 12 (cyanocobalamin) in the presence of dithiothreitol was conducted as a function of redor potential and pH. The solution redor potential decreased both with an increase in the total concentration of dithiothreitol present and with an increase in pH. The pseudo-first-order rate constant of carbon tetrachloride disappearance increased with decreasing redor potential. The predominant cobalt species present under the reaction conditions was cobalamin(II) (vitamin B 12r ), as confirmed by spectrophotometric analysis, suggesting a one-electron reduction of vitamin B 12 and the involvement of two vitamin B 12 molecules per reacting carbon tetrachloride molecule
TL;DR: Analogies between the structure of RP 71955 and some functional domains of gp41, the transmembrane protein of human immunodeficiency virus 1, suggest hypotheses concerning the mode of action of RP71955.
Abstract: The structure of RP 71955, a new tricyclic 21 amino acid peptide active against human immunodeficiency virus 1, was determined. Its amino acid composition was inferred from the results of fast atom bombardment mass spectrometry, nuclear magnetic resonance, Raman spectroscopy, and amino acid analysis. Its sequence could not be determined classically, using Edman degradation, given the lack of a free terminal NH2. It was deduced from the interpretation of interresidue nuclear Overhauser effects and confirmed by the sequencing of peptides obtained by limited chemical hydrolysis. It was found to be CLGIGSCNDFAGCGYAVVCFW. An internal amide bond between the NH2 of C1 and the gamma-COOH of D9 was observed, as well as two disulfide bridges, one between C1 and C13 and one between C7 and C19. The three-dimensional structure of RP 71955 was determined from nuclear magnetic resonance derived constraints using distance geometry, restrained molecular dynamics, nuclear Overhauser effect back calculation, and an iterative refinement using a full relaxation matrix approach. Analogies between the structure of RP 71955 and some functional domains of gp41, the transmembrane protein of human immunodeficiency virus 1, suggest hypotheses concerning the mode of action of RP 71955.
TL;DR: 1H NMR analysis of the complex between the Ser-32-GRB2-N-SH3 domain and the proline-rich peptide VPPPVPPRRR, derived from h-Sos, shows that relative to the SH3 peptide complexes described for PI3K, Fyn and Abl, the prolines in this complex binds in the opposite orientation.
Abstract: GRB2 is a small adaptor protein of 217 amino acids comprising one SH2 domain surrounded by two SH3 domains. GRB2 couples receptor tyrosine kinase activation to Ras signalling by interacting, through its SH3 domains, to the carboxy-terminal proline-rich regions of the guanine nucleotide exchange factor Sos. Here we report the synthesis and solution structure of the amino-terminal SH3 domain of GRB2 and of its more stable Ser 32 mutant. 1H NMR analysis of the complex between the Ser-32-GRB2-N-SH3 domain and the proline-rich peptide VPPPVPPRRR, derived from h-Sos, shows that relative to the SH3 peptide complexes described for PI3K, Fyn and Abl, the proline-rich peptide in this complex binds in the opposite orientation.
TL;DR: Isopropanol and methylbutynol decomposition have been studied under He stream, at 483 K and 453 K, respectively, on different solids to characterize their basicity as discussed by the authors.