[Structural variations of heptacaine. 2. Preparation and antiarrhythmic activity of N-2-(2-heptyloxyphenylcarbamoyloxy)ethyl-n-benzylpiperidiniu+ ++ m chloride].
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Animals↗
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Results for “Structural variation”
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Isolation of chicken-bek and a related gene; identification of structural variation in the ligand-binding domains of the FGF-receptor family.
cDNA clones carrying the chicken-bek gene and a related gene were isolated. Deducing the amino acid sequence of chicken-bek allowed us to predict that it encodes for a receptor tyrosine kinase related to the fibroblast growth factor (FGF) receptor, and that the chicken-bek gene and Cek3 are closely related. However, a significant structural difference was identified between chicken-bek and Cek3 within the putative extracellular region, in such a manner that the structure of the immunoglobulin-like domain was conserved. A probe specific to the altered structure detected mRNA in the tissues as did a probe common to bek and Cek3, indicating heterogeneity in the FGF-receptor family in a novel manner. Furthermore, another bek-like gene was isolated and the expressions of its mRNA and protein product were analysed in tissues and cultured cells.
Amino Acid Sequence↗
Investigation of mechanistic consequences of natural structural variation within the cysteine proteinases by knowledge-based modelling and kinetic methods.
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Amino Acid Sequence↗
Promoter helical structure variation at the Escherichia coli polymerase interaction sites.
There is evidence that the Escherichia coli polymerase recognizes and binds to three sites on the promoter DNA: the -10, -35, and -16 regions. Sequence homology was noted among the -10 sites (Pribnow box) and among the -35s with consensus sequences, TATAAT and TTGACA , respectively. Weak nucleotide sequence homology was detected at -16. Since the polymerase recognizes these sites in a multitude of promoters, one expects similarities in the three-dimensional structures. To date, no data directly bearing on such structures exist. Recently, Calladine ( Calladine , C.R. (1982) J. Mol. Biol. 161, 343-352) and, subsequently, Dickerson ( Dickerson , R.E. (1983) J. Mol. Biol. 166, 419-441) suggested "rules" for doublestranded DNA structures which were tested against data from several known crystals. Using these rules, I compare the deviations from "ideal" B-DNA of the twist angles, base pair roll, sideways shift, and propeller suppression in 56 promoters at the three sites. I also appended to these the twist angle computations on additional 77 promoters from the recently published compilation of promoter sequences. For the latter, additional nucleotides from the spacer regions were added. The results display similarities at the -10 site. Equally strong similarities were obtained for the -35 and the -16 contact regions. The existence of structural differences for some sites is likely to account for the different degrees of efficiency of the polymerase recognition and transcriptional regulation.
Base Sequence↗
Structural variations of different oral basement membranes revealed by cationic dyes and detergent added to aldehyde fixative solution.
The ultrastructural appearance of different types of basement membrane was studied using histochemical methods for visualizing glycosaminoglycans. Samples of rat gingiva and mouse molar germ tissue were fixed either with glutaraldehyde, glutaraldehyde-ruthenium hexammine trichloride (RHT), glutaraldehyde-Cuprolinic Blue (CB) or cetylpyridinium chloride-glutaraldehyde (CPC). Ultrathin sections were stained with uranyl acetate and lead citrate. The results showed that the conventional trilaminar structure of the basement membrane was observed after glutaraldehyde and CB fixation. In contrast, after CPC or RHT fixation, the appearance of the basement membrane was homogeneous without any evidence of a lamina lucida. Furthermore, after single fixation with CPC, the ultrastructure of different basement membranes from oral tissues showed some differences in appearance which were related to their localizations, functions, or both.
Animals↗
Constituents of Mammea americana L. 8. Novel structural variations on the mammein theme and antitumor activity of mammein and related coumarin and phloroglucinol derivatives.
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Alkenes↗
Ligand-dependent structural variations in Escherichia coli F1 ATPase revealed by cryoelectron microscopy.
The Escherichia coli F1 ATPase, ECF1, has been examined by cryoelectron microscopy after reaction with Fab' fragments generated from monoclonal antibodies to the alpha and epsilon subunits. The enzyme-antibody complexes appeared triangular due to the superposition of three anti-alpha Fab' fragments on alternating densities of the hexagonally arranged alpha and beta subunits. The Fab' to the epsilon subunit superimposed on a beta subunit. A density was observed near the center of the structure in the internal cavity. The position of this central density with respect to peripheral sites was not fixed. Sorting of images of ECF1 labeled with the combination of three anti-alpha Fab' fragments plus an Fab' directed to the epsilon subunit gave three classes in each of which the central density was closest to a different beta subunit. The distribution of the central density among the three classes was measured for different ligand-binding conditions. When ATP was present in catalytic sites under conditions where there was no enzyme turnover (i.e., without Mg2+ present), there were approximately equal numbers of images in each of three classes. When ATP and Mg2+ were added and ATP hydrolysis was allowed to proceed, almost two-thirds of the images were in the class in which the central density was closest to the beta subunit superimposed by the epsilon subunit. We conclude that domains within the ECF1 structure, either the central mass or a domain including the epsilon subunit, move in the enzyme in response to ligand binding. We suggest that this movement is involved in coupling catalytic sites to the proton channel in the F0 part of the ATP synthase.
Adenosine Diphosphate↗
[Morphological and structural variations of the human inguinal region (author's transl)].
In the inguinal region, numerous muscular and fibrous alterations are described. They are related to the unconstant position of the pubic tubercle in relation io the interspinous diameter (linea bi-spinalis). The pubic tubercle can be observed in two different locations: either high or low. The high location is characterized by the presence of the pubic tubercle at a distance of 5 to 7.5 cm below the interspinous diameter. It must be considered as normal and is found in 65% of the subjects. In the low locations, the distance between spinous tubercle and interspinous diameter reaches 7,5 to 12 cm. It is an important abnormality which interests 35% of the subjects. The lower the pubic tubercle are located, the more often morphological alterations are to be found in the following structures: obliquus externus, obliquus internus, transversus and cremaster muscles as well as fascia transversalis. Nevertheless, the pyramidalis muscle as well as the inguinal ligamentary formation, Hesselbach's interfoveolar ligament and Thompson's iliopubic tract do not follow that rule, since the important morphological variations of these deep fibrous components can never be related to the distance between pubic tubercle and interspinous diameter. The functional signification of the inguinal region and especially of the inguinal canal is modified by those ostelogical, muscular and ligamentary variations.
Humans↗
Correlation between structural variation and activity of murine kidney beta-galactosidase: implications for genetic control.
Two closely linked regulatory genes have been reported to control activity levels of beta-galactosidases in murine tissues. The specific effects of these genes on murine glycolipid metabolism have not been elucidated. A/HeJ kidney 4-methylumbelliferyl-beta-galactosidase exhibited lower thermostability than the corresponding C57BL/6J and SWR/J enzymes. This altered response to heat segregated with the Bgsh allele among progeny derived from backcrosses of F1 (A/HeJ; SWR/J) mice to the respective parental strains. Restriction of the heat-sensitive A/HeJ beta-galactosidase to kidney tissue suggests that it is not determined by the Bgs locus, since the latter appears to be expressed in all tissues. More likely, the Bgs region of chromosome 9 contains a gene cluster consisting of a number of regulatory and structural loci. The proposed structural genes share affinity for the artificial substrates commonly employed for their assay but may differ in their relative affinities for glycosphingolipid substrates. Presence of the Bgsh allele results in an increase of kidney GM1-ganglioside-beta-galactosidase; however, galactosylceramide-beta-galactosidase appears unaffected by this allele.
Animals↗
Structural variations of blood group A antigens in human normal colon and carcinomas.
The blood group A determinant is carried by four basic carrier carbohydrate chains. This paper reports the expression of blood group A variants, as determined by immunohistology with highly specific monoclonal anti-A antibodies, in 18 adenocarcinomas of the distal colon, 4 specimens of normal proximal mucosa from group A persons, and 5 specimens of fetal colonic mucosa. Monoclonal antibodies directed to type 1 chain A, type 1 chain ALeb, type 2 chain A, type 2 chain ALey, and type 3 chain A (repetitive A) were used. In normal mucosa, type 1 chain A and ALeb were expressed in proximal regions. Type 1 chain A was expressed in columnar cells, whereas type 1 chain ALeb was found in goblet cells. Type 2 and type 3 chain A structures were not found in normal adult mucosa. All types of A antigens were detected in adenocarcinomas from the distal colon as well as in normal fetal mucosa. In fetal mucosa, type 1 chain A and ALeb antigens and type 3 chain A antigens were expressed in columnar cells, whereas type 2 chain A and Ley and type 1 chain ALeb antigens were found in goblet cells. The results indicate that blood group A antigens with type 1, 2, and 3 carriers are present in fetal mucosa and adenocarcinomas of distal colon, while epithelial mucosa of normal adult colon is characterized by the exclusive expression of type 1 chain A antigens.
ABO Blood-Group System↗
Sequence-dependent structural variation in single-helical DNA. Proton NMR studies of d(T-A-T-A) and d(A-T-A-T) in aqueous solution.
The two deoxyribotetranucleoside triphosphates d(T-A-T-A) and d(A-T-A-T) were investigated in aqueous solution by one- and two-dimensional proton NMR at 300 and 500 MHz. It is demonstrated that both compounds occur predominantly in the single-helical form. Accurate coupling constants are obtained by computer simulation of several 500-MHz spectra. The data are interpreted in terms of N and S pseudorotational ranges. The geometry of the major S-type conformers displays a clear sequence dependence, as expressed by variation of the endocyclic backbone angle delta (C5'-C4'-C3'-O3'). A simple sum rule is proposed to predict delta variation in single-helical DNA fragments. Comparisons are made with other sequence-dependent geometries as observed in a double-helical B-DNA fragment in the crystalline state. Furthermore, one- and two-dimensional nuclear Overhauser effect (NOE) spectroscopy was carried out on d(T-A-T-A). An inventory is made of the observed intra- and inter-residue NOEs. The NOE data confirm the presence of a highly stacked single-helical conformation of d(T-A-T-A) in solution. No indications are found for the formation of a bulge-out structure as observed for analogous alternating purine-pyrimidine oligoribonucleotides.
Base Sequence↗
Extramembraneous particles and structural variations of tubular myelin figures in rat lung surfactant.
Tubular myelin figures of pulmonary surfactant were examined by electron microscopy after fixation in glutaraldehyde and postfixation in an osmium tetroxide-ferrocyanide mixture. Bilayered membranes were seen as parallel arrays or as lattices with spacings varying from about 36 to 50 nm. This method also produced good visualization of drumstick-like particles, 5 nm in diameter and about 15 nm in length. The particles were regularly spaced at intervals of 16 nm in rows along the rectangular angles of myelin membranes. Depending on the size of the tubules the particles contacted each other in the center of the tubules at low diameters (tubular diameter less than 40 nm) and formed a continuous filamentous central core, or they were separated from one another (tubular diameter greater than 40 nm). In the latter case the central core had a hollow appearance. Based on further findings employing tannic acid, lipid extraction with 2,2-dimethoxypropane, and a ruthenium red-osmium tetroxide technique for the demonstration of polyanionic proteins it is suggested that these particles are protein in nature and that they are involved in the formation and maintenance of the structure of tubular myelin. A new concept of the ultrastructure of tubular myelin figures is proposed.
Animals↗
Effects of structural variations on non-ionic surfactants on micellar properties and solubilization: surfactants containing very long hydrocarbon chains.
Polyoxyethylene mono-ethers of dotriacontanol (C32E41) and 4,9-dimethyltritriacontanol (C35E40) have been synthesized. The micellar weights in water at 298K were 4.82 x 10(5) and 5.90 x 10(5), the aggregation numbers 212 and 260, and the levels of hydration 290 and 283 mol water mol-1 surfactant, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants. The presence of large micelles did not result in increased solubilization; C32E41 and C35E40 had a lower solubilizing capacity than that of cetomacrogol.
Colloids↗
Effects of structural variations of non-ionic surfactants on micellar properties and solubilization: surfactants based on erucyl and behenyl (C22) alcohols.
Studies on erucyl alcohol ethoxylated with 24 units and on behenyl alcohol ethoxylated with 21 ethylene oxide units gave values of 10.2 x 10(3) and 25.4 x 10(3) for the micellar weights, 74 and 203 for the aggregation number, and 134 and 106 moles water mole-1 surfactant for the micellar hydration, respectively. The solubilization of azobenzene, cortisone acetate, griseofulvin, sulphadiazine, phenylbutazone, betamethasone, tolbutamide, and menaphthone was studied in 2% solutions of the above surfactants, and in cetomacrogol. Excluding sulphadiazine, a linear relationship was found between moles solubilized/mole surfactant, and (log P)/molar volume of solubilizate.
Colloids↗
Effects of structural variation in beta-monoglycerides and other lipids on ordering in synthetic membranes.
Studies of beta-monoglyceride multilayers were carried out using a variety of spin probes. Effects of variables such as chain length, unsaturation, and branching on organization of acyl chains in lipids of model membranes were assessed. In addition, effects of added cholesterol on membrane order were determined. Results indicated that pure beta-monolaurin yields highly ordered films, whereas, unsaturated glycerides such as beta-monoolein, beta-monolinolein, and analogous lecithins yield fluid films. Branched monoglycerides behaved similarly to beta-monoolein, suggesting that branching in acyl chains is an effective substitute for unsaturation in maintaining membrane integrity. Multilayers of beta-monoglycerides exhibited similar properties to those of more complex lipids such as phospholipids. beta-Monoglycerides, by virtue of the presence of a single acyl chain, provided a relatively simple and effective alternative to the use of phospholipids in studies of membrane architecture.
Binding Sites↗
Structure-toxicity relationships in the amatoxin series. Structural variations of side chain 3 and inhibition of RNA polymerase II.
The amatoxins, highly toxic components of death cap Amanita mushrooms, bind strongly to RNA polymerase II (or B) in cell nuclei thus preventing the transcription of DNAs to hn-RNAs (Pre-mRNAs), the precursors of messenger RNAs. Three of the binding sites of the bicyclic octapeptides have been identified: an isoleucine side chain in position 6, a trans-4-hydroxyl group at proline in position 2 and a hydroxylated L-isoleucine side chain in position 3. No information exists about the stereochemical conditions at the beta-C-atom (C-atom 3) of this side chain. We have now synthesized the diastereomeric S-deoxo-amaninamides (Fig. 1) containing, in position 3, L-allo-isoleucine (analog 1), (2S, 3R)-2-amino-4-hydroxy-3-methyl butyric acid (analog 2), the diastereomer (2S, 3S)-2-amino-4-hydroxy-3-methylbutyric acid (analog 3) and D-isoleucine (analog 4). In the last synthesis, besides the "normal" bicyclic octapeptide 4, an isomeric Iso-4 was formed. The affinities for Drosophila RNA polymerase II were 100 times weaker as compared to gamma-amanitin for 1, 10 times weaker for 2, 200 times weaker for 3, 100 times weaker for 4, and more than 1000 times weaker for Iso-4. The results point to the importance of a methyl group in (R)-configuration at the beta-C atom of side chain 3.
Amanitins↗
The development of a novel series of (quinolin-2-ylmethoxy)phenyl-containing compounds as high-affinity leukotriene receptor antagonists. 3. Structural variation of the acidic side chain to give antagonists of enhanced potency.
This paper is the third in a series outlining the development of orally active sulfido peptide leukotriene antagonists containing a (quinolin-2-ylmethoxy)phenyl moiety. In this work the systematic variation of the acid side chain substituents led to dramatic and reproducible changes in the oral activity of these compounds, presumably due to alterations in their pharmacokinetic properties. The most potent compound identified, 5-[4-[4-(quinolin-2-yl-methoxy)phenyl]-3-methylbutyl]tetrazole (32), represents a convergence of good in vitro antagonist activity and a 3-10-fold improvement in oral potency over the current clinical candidate 2. The new findings from these optimization studies are as follows: oxygen substitution in the acid side chain was not necessary for antagonist activity, in vitro and in vivo activity was enhanced by alkyl or phenyl substitution on the gamma-carbon of the acid side chain of para-substituted (quinolin-2-ylmethoxy)phenyl derivatives, and free rotation about the side chain carbon atom adjacent to the (quinolin-2-ylmethoxy)phenyl ring was required for activity. The lead compound of this report (32) is a competitive inhibitor of [3H]LTD4 binding to receptor membrane purified from guinea pig lung (Ki = 12 +/- 3 nM) and of the spasmogenic activity of LTC4, LTD4, and LTE4 in guinea pig lung strip. Dosed orally in guinea pigs, this compound blocks LTD4-induced bronchoconstriction (ED50 0.8 mg/kg) and antigen-induced systemic anaphylaxis (ED50 = 1.2 mg/kg).
Animals↗
Cerebral Cortical Structural Variation and General Cognitive Ability: Evidence From Mendelian Randomization.
Understanding the cortical architecture underlying individual differences in general cognitive ability (GCA) remains a central question in cognitive neuroscience. Prior work has established associations between global brain size and GCA, yet the regional effects and directionality of these relationships remain debated. Using a genetically informed cortical parcellation in 11,289 UK Biobank participants, we examined associations between cortical surface area (SA), cortical thickness (CT), and GCA measured via verbal-numerical reasoning. Total SA showed a robust positive association with GCA. At the regional level, dorsolateral prefrontal and superior temporal SA exhibited the strongest positive associations, which persisted after adjustment for global SA. In contrast, CT showed comparatively modest associations. Using Mendelian randomization (MR) with genome-wide significant genetic instruments, we observed evidence consistent with a bidirectional relationship between total SA and GCA. At the regional level, dorsolateral prefrontal and temporal SA demonstrated evidence of MR-inferred directional effects on GCA, while GCA showed evidence of MR-inferred directional effects on total SA and perisylvian thickness. These findings support a polyregional SA architecture underlying GCA, with prominent contributions from prefrontal and temporal association cortices. Our results refine global brain-GCA models and highlight the value of genetically informed parcellation for identifying regional cortical contributions.
Humans↗