SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
By inserting an oxygen link between the 3-fluorophenyl and the lactone ring of 5,5-dimethyl-3-(3fluorophenyl)-4-(4-methanesulfonylphenyl)-2 (5H)-furanone 1 (DFU), analogs with enhanced in vitro COX-2 inhibitory potency as well as in vivo potency in models of inflammation were obtained.
The T lineage repertoire is shaped by opposing processes of positive and negative selection. To probe the specificity of selection, N15 TCR-transgenic (tg) recombinase-activating gene (RAG)-2(- / -) H-2(b) mice recognizing the VSV8 octapeptide RGYVYQGL bound to K(b) were utilized in conjunction with VSV8 variants differing only at the central p4 position. The V4I mutant octamer, like VSV8, induces negative selection of immature double-positive thymocytes on the beta(2)-microglobulin (beta(2)M)(+ / +) background and is a strong agonist for mature N15 T cells. In contrast, V4L or V4norvaline octamers promote positive selection in N15tg RAG-2(-/-) beta(2)M(-/-) H-2(b) fetal thymic organ culture and are weak agonists for N15 T cells. Hence, the absence of a p4 side chain Cbeta-methyl group results in positive selection of the N15 TCR. Hydrophobicity of the p4 residues also modulates thymocyte fate: the positively selecting norvaline and leucine variants have one and two Cgamma-methyl groups, respectively, while the weakly selecting gamma-methylleucine p4 contains three Cgamma-methyl groups. Moreover, the most hydrophobic octamer containing p4 cyclohexylglycine substitution fails to select. Thus, for N15 and presumably other MHC class I-restricted TCR, there is a high degree of structural specificity to peptide-dependent thymic selection processes.
The resonance coherent anti-Stokes Raman scattering (CARS) spectra for a number of flavoproteins are found to be fingerprints for the particular type of flavoprotein. One group studied were the bacterial flavodoxins: Desulfovibrio vulgaris, Desulfovibrio desulfuricans, Azotobacter vinelandii, Megasphaera elsdenii, Clostridium kluyverii and Clostridium formicoaceticum. The other examples were the enzymes lactate monooxygenase and glucose oxidase. FMN complexed to Vibrio harveyi luciferase, and a partially characterized non-fluorescent flavoprotein from Photobacterium leiognathi. In the frequency range 1700-1100 cm-1, differences in the frequency positions and relative intensities of the prominent bands are reflections of the interactions of the isoalloxazine ring with the protein. Based on tentative assignment of the vibrational modes in flavin models, the spectra are interpreted in terms of hydrogen bonding between the amino acid residues of the binding site and particular atoms of the isoalloxazine ring.
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.
The modulation of substrate selectivity of human plasma LTP reaction is the subject of the present investigation. The moderate selectivity by a factor of 5 to 6 was observed in the LTP-catalyzed transfer of cholesteryl ester over triacylglycerol between plasma lipoproteins. On the other hand, the transfer of cholesteryl ester by LTP was highly selective over the negligible transfer of triacylglycerol, by a factor of 60 to 500, between the microemulsions with LDL size, regardless of the activators such as human and pig apolipoprotein (apo) A-I, human apo C-III and apo E that bound to the surface of the emulsion in equilibrium. The presence of free cholesterol in these microemulsions reduced slightly the rate of cholesteryl ester transfer but had no effect on triacylglycerol transfer. Other surface-active reagents such as cholic acid, Triton X-100 and Tween-20, did not have an effect on the triacylglycerol transfer either. Triacylglycerol transfer by LTP became measurable between such lipid particles as prepared by co-sonication of lipid with pig apo A-I and isolated as the mixed-microemulsions in the density of LDL and HDL. In these conditions, the substrate selectivity for cholesteryl ester over triacylglycerol was a factor of 6 to 16 mimicking the ratio in plasma lipoproteins. The conformation of pig apo A-I estimated by circular dichroism showed that its apparent helical content was further more induced when apo A-I was integrated into the mixed-microemulsion by co-sonication than the lipid-bound apo A-I in equilibrium. Apo A-I, thus integrated into lipid particles, was highly resistant to the denaturation by guanidine hydrochloride while the lipid-bound apo A-I in equilibrium was denatured as readily as the lipid-free protein. Thus, triacylglycerol transfer by LTP was induced by structural modulation of substrate-carrying lipid particles such as higher integration of apolipoproteins.
Free electron laser (FEL) have been developed as tunable lasers over a wide range of wavelenths. Equipment in the region of 6-16 microns (1,660-630 cm-1) is available in the Beijing free electron laser erected by Institute of High Energy Physics, CAS. In this study we report first measurements of infrared-induced molecular change under irradiation by FEL of 9.414 microns and 6.228 microns, respectively. Taking o-amino-benzoic acid as an example, FTIR characterization indicates that the peak positions of both N-H and C=O stretching vibrations shift before and after the irradiation of FEL. It demonstrates that FEL induces the re-arrangement of H-bonds between COOH and NH2 by stimulating the vibration of carboxyl groups. It suggests that the presence of stable/metastable phases in the title compound.
The orientation of cellulose microfibrils in the cell wall and the shape and the dimensions of the cells of earlywood of four Norway spruce (Picea abies [L.] Karst.) stems grown in Finland were studied by X-ray diffraction and optical microscopy. The average microfibril angle (MFA) decreased and the diameter of the cell increased rapidly up to rings 5-10 from the pith and remained at the same level after that. The average MFA close to the pith was over 20 degrees and decreased to about 8 degrees after ring 10 from the pith. The average diameter of the cells was 35 microm in the outer rings. The shape of the cross section of the lumen changed from circular to rectangular from the pith to the bark. The tracheid length increased also as a function of the distance from the pith. The thickness of the cell wall varied between 2.8 and 3.5 microm. Automatic cell lumen and cell wall recognition procedures were developed for the analysis of the images of the cross sections of the cells.
Two series of analogues of 9-propionyl-10-cinnamyl-9,10-diazatricyclo[4.2.1.1(2,5)]decane (1a) and 2-propionyl-7-cinnamyl-2,7-diazatricyclo[4.4.0.0(3,8)]decane (2a), in which the cinnamyl moiety was replaced by various aralkenyl chains, 1b-l and 2b-l, respectively, have been synthesized and evaluated for their ability to bind to the opioid mu-, delta- and kappa-receptors. The binding data indicated that compounds 1b,d,e,h and 2b,d,e,f,h,i showed a mu-affinity in the low nanomolar range with moderate or negligible affinity towards delta- and kappa-receptors. Selected DTDs, the pairs 1,2b, 1,2e and 1,2h, were also evaluated for analgesic effect. In the hot plate test, only 1b given ip was found to have similar opioid antinociception and chronic tolerance as morphine.
Three manganese(II) complexes, [Mn(II)(2)L(1)(2)(H(2)O)(4)](ClO(4))(2).H(2)O (1, L(1)H = (bis(2-pyridylmethyl)amino)acetic acid), [Mn(II)(2)L(2)(2)(H(2)O)(2)](BPh(4))(2).2EtOH.2H(2)O (2, L(2)H = 3-(bis(2-pyridylmethyl)amino)propionic acid), {[Mn(II)(2)L(2)(2)(H(2)O)(MeCN)](BPh(4))(2).2MeCN}(infinity) (3), and a manganese(IV) complex [Mn(IV)(2)O(2)L(2)(2)](ClO(4))(2).4H(2)O (4) were synthesized and characterized by X-ray crystallography. The compound 1 was a dinuclear Mn(II)(2) complex which crystallized in the monoclinic crystal system, space group P2(1)/n, with Z = 4, a = 12.19(1) Å, b = 14.623(8) Å, c = 21.72(1) Å, beta = 96.29(6) degrees, V = 3849(4) Å(3). The complex cation had an approximate C(2) symmtery. The two manganeses were both seven-coordinate and doubly bridged by one oxygen atom of carboxylate groups in &mgr;(2),eta(1)-mode. The compound 2 was also a dinuclear Mn(II)(2) complex which crystallized in the monoclinic crystal system, space group P2(1)/n, with Z = 2, a = 16.760(2) Å, b = 9.643(2) Å, c = 23.533(2) Å, beta = 92.984(8) degrees, V = 3798.4(7) Å(3). The complex cation of 2 also had two seven-coordinate manganese ions, but unlike 1 the nonbridging carboxylate oxygens weakly coordinate to the manganese ions. The compound 3 crystallized in the orthorhombic crystal system, space group P2(1)2(1)2(1), with Z = 4, a = 27.888(3) Å, b = 29.054(2) Å, c = 9.428(2) Å, V = 7638(2) Å(3). The cationic portion of 3 consisted of infinite chains of Mn(II) (two Mn(II) ions per an asymmetric unit) bridged by carboxylates in bidentate syn/anti mode. The compound 4 was a dinuclear bis(&mgr;-oxo) Mn(IV)(2) complex which crystallized in the trigonal crystal system, space group R&thremacr;, with Z = 8, a = 23.962(4) Å, c = 17.190(3) Å, V = 8547(3) Å(3). All these structures are made up from a common fragment "L(n)()Mn" assembling in various topologies. Variable-temperature magnetic susceptibility measurements revealed that the Mn(II) ions in 1-3 were weakly antiferromagnetically coupled (J = -0.631(6), -0.655(5), and -0.20(1) cm(-)(1) for 1-3), and that the Mn(IV) ions in 4 were strongly antiferromagnetically coupled (J = -97.5(5) cm(-)(1)). The cyclic voltammogram of 4 showed two reduction waves with E(1/2) values of -0.52 and 0.28 V (vs ferrocene). These E(1/2) values are more negative by 0.1 V than those of the closely related complex [Mn(III)Mn(IV)O(2)L(1)(2)](ClO(4)).
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.
Previously, GABA(A) receptor epsilon and theta subunits have been identified only in human. Here, we describe properties of the epsilon and theta subunit genes from mouse and rat that reveal an unusually high level of divergence from their human homologs. In addition to a low level of amino acid sequence conservation ( approximately 70%), the rodent epsilon subunit cDNAs encode a unique Pro/Glx motif of approximately 400 residues within the N-terminal extracellular domain of the subunits. Transcripts of the rat epsilon subunit were detected in brain and heart, whereas the mouse theta subunit mRNA was detectable in brain, lung, and spleen by Northern blot analysis. In situ hybridization revealed a particularly strong signal for both subunit mRNAs in rat locus ceruleus in which expression was detectable from the first postnatal day. Lower levels of coexpression were also detected in other brainstem nuclei and in the hypothalamus. However, the expression pattern of theta subunit mRNA was more widespread than that of epsilon subunit, being found also in the cerebral cortex of rat pups. In contrast to primate brain, neither subunit was expressed in the hippocampus or substantia nigra. The results indicate that GABA(A) receptor epsilon and theta subunits are evolving at a much faster rate than other known GABA(A) receptor subunits and that their expression patterns and functional properties may differ significantly between species.
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).
A diversity of sensilla has been described in crustaceans, both across species and within a given species. However, few homologous setal types have been identified in crustaceans. In this study we examined setae with features of the hooded sensillum, which is a class of bimodal chemomechanosensilla first identified on antennules of the Caribbean spiny lobster Panulirus argus. We examined the antennules of 13 species representing seven families of malacostracan crustaceans, and most body surfaces of P. argus, and compared the sensillar morphology from different species and from different body regions to identify interspecific and intraspecific homologues of hooded sensilla. Our results show that sensilla with morphological characteristics of antennular hooded sensilla are present and have a similar pattern of distribution on the antennules of reptantian species representing three families (Palinuridae and Scyllaridae of the Achelata and Nephropidae of the Homarida). Furthermore, hooded sensillar homologues are present on most body surfaces of P. argus. However, there are intraspecific and interspecific variations in the morphology of these sensilla. We present evidence that supports the idea that postembryonic changes in individual sensilla may be responsible for some of these morphological variations. Despite these variations, we conclude that the sensilla are homologues, because they have several common characteristics, similar positions on the body surface, similar substructures, a continuum to their morphological variations, and morphological variation that is correlated with phylogenetic similarity. Taken together these results support the idea that the hooded sensillum is a singular and biologically important sensillar type that has a broad distribution.
Explore the source record for details and available documents.
The electrophoresis of linear, kilobase-sized DNA molecules with permuted sequences has been studied in polyacrylamide and agarose gels. Plasmid pBR322, bacteriophage phi X174, and the SV40 minichromosome were each digested with a series of single-cut restriction enzymes. The linearized, permuted isomers of all three DNAs exhibit different mobilities in large-pore polyacrylamide gels, suggesting that all three DNAs contain sites of anisotropic, sequence-dependent curvature. Various experimental parameters such as acrylamide concentration, crosslinker ratio and buffer composition affect the magnitude of the observed differential mobilities. Band sharpness appears to be optimal in polyacrylamide gels containing 6.9-8.1%T and 0.5-1%C. Only small mobility differences are observed for the linearized, permuted sequence isomers in agarose gels.
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.
Addition of sterically different substrates to CYP2B4 suggests perturbation of the environment of the haem ring and differing degrees of 6cls-5chs conversion. Strain on the ring, by implication induced by changes in the surrounding protein environment, is demonstrated by the emergence of the v29 band upon laurate binding. Furthermore, intensity differences and frequency shifts for non-Raman active (Eu) modes appear to be substrate dependent and are sensitive to haem/substrate interactions. The likelihood is that substrate induced distortion of the haem will have an effect on catalytic activities and attention needs to be directed towards substrate pocket interactions. SERRS (Surface enhanced resonance Raman scattering) provides a unique and sensitive spectroscopic probe of these interactions.
The extracellular giant hemoglobin from the earthworm Lumbricus terrestris was reconstructed at 14.9-A resolution from cryo-electron microscope images, using a new procedure for estimating parameters of the contrast transfer (CTF) function. In this approach, two important CTF parameters, defocus and amplitude contrast ratio, can be refined iteratively within the framework of 3D projection alignment procedure, using minimization of sign disagreement between theoretical CTF and cross-resolution curves. The 3D cryo-EM map is in overall good agreement with the recent X-ray crystallography map of Royer et al. (2000, Proc. Natl. Acad. Sci. USA 97, 7107-7111), and it reveals the local threefold arrangement of the three linker chains present within each 1/12 of the complex. The 144 globin chains and 36 linker chains within the complex are clearly visible, and the interdigitation of the 12 coiled-coil helical spokes forming the central toroidal piece is confirmed. Based on these findings, two mechanisms of the dodecameric unit assembly are proposed and termed "zigzag" and "pairwise" polymerizations. However, the detection by cryo-EM of 12 additional rod-like bodies within the toroid raises the possibility that the architecture of the toroid is more complex than previously thought or that yet unknown ligands or allosteric effectors for this oxygen carrier are present.