Sequence distribution in Acrylonitrile-methylacrylate random copolymers by N.M.R spectroscopy

The sequence distribution studies on the acrylonitrile-methylmethacrylate copolymer of high methylmethacrylate (M) content (30%

Aspects of tautomerism. 6. Base-catalyzed hydrolysis of pseudo esters of .gamma.-keto acids

The rates of base-catalyzed hydrolysis of pseudo esters derived from y-keto acids show strikingly poor sensitivity to the nature of the leaving group.la The rates vary in the narrow range of about 12-fold as contrasted to a 103-fold spread of the corresponding benzoate esters. The results presented are consistent with a rate-determining formation of a tetrahedral intermediate (11) and i t s rapid collapse, by the cleavage of the lactone ring in a fast step.

Conformational Choices for the Stereochemically Constrained gamma-Amino Acid Residue Gabapentin: Theoretical Studies and Correlation With Experimental Results

Gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn) is an achiral, conformationally constrained gamma amino acid residue. A survey of available crystal structures of Gpn peptides reveals that the torsion angles about the C-gamma-C-beta (theta(1)) and C-beta-C-alpha(theta(2)) bonds are overwhelmingly limited to gauche, gauche (g(+)g(+)/g(-)g(-)) conformations. The Gpn residue forms C-7 and C-9 hydrogen bonds in which the donor and acceptor atoms come from the flanking peptide units. In combination with alpha amino acid residues alpha gamma and gamma alpha segments can adopt C-12 hydrogen bonded structures. The conformational choices available to the Gpn residue have been probed using energy calculations, adopting a grid search strategy. Ramachandran phi-psi maps have been constructed for fixed values of theta(1) and theta(2), corresponding to the gauche and trans conformations. The sterically allowed and energetically favorable regions of conformational space have been defined and experimental observations compared. C-7 and C-9 hydrogen bonded conformational families have been identified using a grid search approach in which theta(1) and theta(2) values are varied over a range of +/- 10 degrees about ideal values at 1 degrees intervals. The theoretical analysis together with experimental observations for 59 Gpn residues from 35 crystal structures permits definition of the limited range of conformational possibilities at this gamma amino acid residue. .

Study of transition-metal monosulphides by photoelectron spectroscopy

Monosulphides of the first-row transition metals have been studied by X-ray and UV photoelectron spectroscopy. Systematics in the valence bands as well as metal and sulphur core levels across the series have been discussed. Exchange splittings and spin-orbit splittings in these compounds have been examined. CuS is found to show features of both S2 and S22.

A study of the nature of coordination in metal monothiocarbamates based on infrared spectroscopy and the HSAB concept

The nature of coordination in metal monothiocarbamates is shown to depend on the hardness or softness of the metal ton. Thus, the monothiocarbamate ion acts as a monodentate ligand with metal-sulphur bending when the metal ion is a soft acid while it acts as a bidentate ligand when the metal ion is a hard acid; it can exhibit either behaviour when the metal ion is a borderline acid. In dialkyltin and dialkylmonocholorotin complexes, the monothiocarbamate ion acts as a bidentate ligand with strong Sn-S bonding while in trialkyl-or triaryl-tin complexes it acts essentially as a monodentate ligand. Thus, R3Sn(I) seems to be a soft or borderline acid while R2Sn(II) is a hard acid.

Study of As2(Se,Te)3 glasses by X-ray absorption and photoelectron spectroscopy

Arsenic selenide-telluride glasses have been investigated by X-ray absorption and photoelectron spectroscopy. The core electron energy shifts and chemical shifts in K-absorption edge measurements associated with the glass-crystal transitions of pure As2Se3 and As2Te3 have been studied. The effect of composition on the core level energy and valence bands of As2(Se,Te)3 glasses, has been discussed. Mixed-composition glasses are found to be considerably ionic.

Palladium(II) and platinum(II) complexes of beta-functionalized ethyl selenolates: Effect of substitution on synthesis, reactivity, spectroscopy, structures and thermal behavior

Sodium ethylselenolates with functional groups X (where X = -OH, -COOH, -COOMe and -COOEt) at beta-carbon were prepared in situ by reductive cleavage of corresponding diselenide with NaBH4 either in methanol or aqueous ammonia. Treatment of these selenolates with [M2Cl2(mu-Cl)(2)(PR'(3))(2)] (M = Pd or Pt; PR'(3) = PMePh2, PnPr(3)) in different stoichiometry yielded various bi- and tri-nuclear complexes. The homoleptic hexanuclear complexes [Pd(mu-SeCH2CH2X)(2)](6) (X = OH, COOH, COOEt), were obtained by reacting Na2PdCl4 with NaSeCH2CH2X. All these complexes have been fully characterized. Molecular structures of ethylselenolates containing hydroxyl and carboxylic acid groups revealed solid state associated structures through inter-molecular hydrogen bond interactions. Trinuclear complex, [Pd3Cl2(mu-SeCH2CH2COOH)(4)(PnPr(3))(2)] (3a), was disposed in a boat form unlike chair conformation observed for the corresponding methylester complex. The effect of beta-functionality in ethylselenolate ligands towards reactivity, structures and thermal properties of palladium and platinum complexes has been extensively Studied.

Gabapentin: A Stereochemically Constrained gamma Amino Acid Residue in Hybrid Peptide Design

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino adds, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino adds with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino add residue that contains a cyclohexyl ring at the C-beta carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C-7 and C-9 hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alpha gamma sequences, district C-12 hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones.

Contribution from unresolved discrete sources to the extragalactic gamma-ray background (EGRB)

The origin of the extragalactic gamma-ray background (EGRB) is still an open question, even nearly forty years after its discovery. The emission could originate either from truly diffuse processes or from unresolved point sources. Although the majority of the 271 point sources detected by EGRET (Energetic Gamma Ray Experiment Telescope) are unidentified, of the identified sources, blazars are the dominant candidates. Therefore, unresolved blazars may be considered the main contributor to the EGRB, and many studies have been carried out to understand their distribution, evolution and contribution to the EGRB. Considering that gamma-ray emission comes mostly from jets of blazars and that the jet emission decreases rapidly with increasing jet to line-of-sight angle, it is not surprising that EGRET was not able to detect many large inclination angle active galactic nuclei (AGNs). Though Fermi could only detect a few large inclination angle AGNs during the first three months of its survey, it is expected to detect many such sources in the near future. Since non-blazar AGNs are expected to have higher density as compared to blazars, these could also contribute significantly to the EGRB. In this paper, we discuss contributions from unresolved discrete sources including normal galaxies, starburst galaxies, blazars and off-axis AGNs to the EGRB.

Growth inhibition of human promonocytic leukaemic U937 cells by interferon gamma is irreversible and not cell cycle phase-specific.

Growth of human promonocytic leukaemic U937 cells was found arrested within 24 h upon exposure to interferon gamma (IFN-gamma). Removal of the interferon did not result in the resumption of growth, as is evident from the absence of doubling of viable cell count and(3)H-thymidine incorporation. 5-Bromo-2'-deoxyuridine-based flow cytometric analysis of the growth-arrested cells, 24 h subsequent to the removal of IFN-gamma, showed absence of DNA synthesis, confirming the irreversible nature of the growth inhibition. Propidium iodide-based flow cytometric analysis of the growth-arrested cells showed a distribution which is typical of a growth inhibition without resulting in the accumulation of cells in any specific phase of the cell cycle. These results indicated that IFN-gamma arrested growth of U937 cells in an irreversible and cell cycle phase-independent manner. These observations were in contrast to our earlier report on the reversible and cell cycle phase-specific growth inhibition of human amniotic (fetal epithelial) WISH cells by the interferon. Copyright 1999 Academic Press.

Alveolar macrophages as accessory cells for human gamma delta T cells activated by Mycobacterium tuberculosis.

Alveolar macrophages form the first line of defense against inhaled droplets containing Mycobacterium tuberculosis by controlling mycobacterial growth and regulating T cell responses. CD4+ and gamma delta T cells, two major T cell subsets activated by M. tuberculosis, require accessory cells for activation. However, the ability of alveolar macrophages to function as accessory cells for T cell activation remains controversial. We sought to determine the ability of alveolar macrophages to serve as accessory cells for resting (HLA-DR-, IL-2R-) and activated (HLA-DR+, IL-2R+) gamma delta T cells in response to M. tuberculosis and its Ag, and to compare accessory cell function for gamma delta T cells of alveolar macrophages and blood monocytes obtained from the same donor. Alveolar macrophages were found to serve as accessory cells for both resting and activated gamma delta T cells in response to M. tuberculosis Ag. At high alveolar macrophage to T cell ratios (> 3:1), however, expansion of resting gamma delta T cells was inhibited by alveolar macrophages. The inhibition of resting gamma delta T cells by alveolar macrophages was dose-dependent, required their presence during the first 24 h, and was partially overcome by IL-2. Alveolar macrophages did not inhibit activated gamma delta T cells even at high accessory cell to T cell ratios, and alveolar macrophages functioned as well as monocytes as accessory cells. Monocytes were not inhibitory for either resting or activated gamma delta T cells. These findings support the following model. In the normal alveolus the alveolar macrophage to T cell ratio is > or = 9:1, and therefore the threshold for resting gamma delta T cell activation is likely to be high. Once a nonspecific inflammatory response occurs, such as after invasion by M. tuberculosis, this ratio is altered, favoring gamma delta T cell activation by alveolar macrophages.

CD4+ alpha beta T cell and gamma delta T cell responses to Mycobacterium tuberculosis. Similarities and differences in Ag recognition, cytotoxic effector function, and cytokine production.

CD4+ and gamma delta T cells are activated readily by Mycobacterium tuberculosis. To examine their role in the human immune response to M. tuberculosis, CD4+ and gamma delta T cells from healthy tuberculin-positive donor were studied for patterns of Ag recognition, cytotoxicity, and cytokine production in response to M. tuberculosis-infected mononuclear phagocytes. Both T cell subsets responded to intact M. tuberculosis and its cytosolic Ags. However, CD4+ and gamma delta T cells differed in the range of cytosolic Ags recognized: reactivity to a wide m.w. range of Ags for CD4+ T cells, and a restricted pattern for gamma delta T cells, with dominance of Ags of 10 to 15 kDa. Both T cell subsets were equally cytotoxic for M. tuberculosis-infected monocytes. Furthermore, both CD4+ and gamma delta T cells produced large amounts of IFN-gamma: mean pg/ml of IFN-gamma in supernatants was 2458 +/- 213 for CD4+ and 2349 +/- 245 for gamma delta T cells. By filter-spot ELISA (ELISPOT), the frequency of IFN-gamma-secreting gamma delta T cells was one-half of that of CD4+ T cells in response to M. tuberculosis, suggesting that gamma delta T cells on a per cell basis were more efficient producers of IFN-gamma than CD4+ T cells. In contrast, CD4+ T cells produced more IL-2 than gamma delta T cells, which correlated with diminished T cell proliferation of gamma delta T cells compared with CD4+ T cells. These results indicate that CD4+ and gamma delta T cell subsets have similar effector functions (cytotoxicity, IFN-gamma production) in response to M. tuberculosis-infected macrophages, despite differences in the Ags recognized, IL-2 production, and efficiency of IFN-gamma production.

Expanding the Peptide beta-Turn in alpha gamma Hybrid Sequences: 12 Atom Hydrogen Bonded Helical and Hairpin Turns

Hybrid peptide segments containing contiguous alpha and gamma amino acid residues can form C-12 hydrogen bonded turns which may be considered as backbone expanded analogues of C-10 beta-turns) found in alpha alpha segments. Exploration of the regular hydrogen bonded conformations accessible for hybrid alpha gamma sequences is facilitated by the use of a stereochemically constrained gamma amino acid residue gabapentin (1-aminomethylcyclohexaneacetic acid, Gpn), in which the two torsion angles about C-gamma-C-beta (theta(1)) and C-beta-C-alpha (theta(2)) are predominantly restricted to gauche conformations. The crystal structures of the octapeptides Boc-Gpn-Aib-Gpn-Aib-Gpn-Aib-Gpn-Aib-OMe (1) and Boc-Leu-Phe-Val-Aib-Gpn-Leu-Phe-Val-OMe (2) reveal two distinct conformations for the Aib-Gpn segment. Peptide 1 forms a continuous helix over the Aib(2)-Aib(6) segment, while the peptide 2 forms beta-hairpin structure stabilized by four cross-strand hydrogen bonds with the Aib-Gpn segment forming a nonhelical C-12 turn. The robustness of the helix in peptide 1 in solution is demonstrated by NMR methods. Peptide 2 is conformationally fragile in solution with evidence of beta-hairpin conformations being obtained in methanol. Theoretical calculations permit delineation of the various C-12 hydrogen bonded structures which are energetically feasible in alpha gamma and gamma alpha sequences.