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PubMed2006

The nicholas approach to natural product hybrids.

The intermolecular Nicholas reaction of terpene-based scaffolds is an excellent access to natural product hybrid compounds. These intermolecular reactions have a low selectivity and are scarcely efficient for non-conjugated cations, but they are highly efficient to produce new terpene structures through an intramolecular reaction pathway. The use of cations derived from natural product derived [Co(2)(CO)(6)]-enyne complexes is, in contrast, a highly efficient regio- and stereoselective procedure to prepare very complex structures, incorporating diverse densely functionalized or labile moieties. Thus, beta-pinene-diterpene-alkaloid or homohybrids can be accessed in totally stereo-, regio- and siteselective fashion. This approach efficiently discriminates between different propargylic positions by selecting the nature of the alcohol, being the enyne-derived cations the most reactive. The chimera 38 with a steroid-terpene-indole skeleton was prepared in this way.

Alkynes↗
PubMed1996

Evaluation of gene structure prediction programs.

We evaluate a number of computer programs designed to predict the structure of protein coding genes in genomic DNA sequences. Computational gene identification is set to play an increasingly important role in the development of the genome projects, as emphasis turns from mapping to large-scale sequencing. The evaluation presented here serves both to assess the current status of the problem and to identify the most promising approaches to ensure further progress. The programs analyzed were uniformly tested on a large set of vertebrate sequences with simple gene structure, and several measures of predictive accuracy were computed at the nucleotide, exon, and protein product levels. The results indicated that the predictive accuracy of the programs analyzed was lower than originally found. The accuracy was even lower when considering only those sequences that had recently been entered and that did not show any similarity to previously entered sequences. This indicates that the programs are overly dependent on the particularities of the examples they learn from. For most of the programs, accuracy in this test set ranged from 0.60 to 0.70 as measured by the Correlation Coefficient (where 1.0 corresponds to a perfect prediction and 0.0 is the value expected for a random prediction), and the average percentage of exons exactly identified was less than 50%. Only those programs including protein sequence database searches showed substantially greater accuracy. The accuracy of the programs was severely affected by relatively high rates of sequence errors. Since the set on which the programs were tested included only relatively short sequences with simple gene structure, the accuracy of the programs is likely to be even lower when used for large uncharacterized genomic sequences with complex structure. While in such cases, programs currently available may still be of great use in pinpointing the regions likely to contain exons, they are far from being powerful enough to elucidate its genomic structure completely.

Alternative Splicing↗
PubMed1987

Bacillus cereus phospholipase C: carboxylic acid ester specificity and stereoselectivity.

Thiophosphate analogs of phosphatidylcholine have been synthesized with varying structural complexity. These analogs have been used in a continuous spectrophotometric assay for phospholipase C (Bacillus cereus) to estimate the minimal structural requirements associated with the non-polar portion of the substrate phospholipid. The analogs were of three types containing zero, one or two carboxylic acid ester functionalities. The analogs with one or two ester groups acted as substrates for phospholipase C, while those without an ester functionality were not hydrolyzed. The rac-phosphatidylcholine analog with two ester functionalities gave biphasic time-course results, and was subsequently resolved into enantiomers by selective hydrolysis with a sterospecific phospholipase A2 (Crotalus atrox). The enantiomer with R absolute configuration was rapidly hydrolyzed by the phospholipase C while the enantiomer with the S configuration was slowly hydrolyzed after a long induction period. The results suggest that the B. cereus phospholipase C is specific for an ester functionality and is stereoselective for the R absolute configuration at glycerol C-2.

Bacillus cereus↗
PubMed2004

A hydroxyethylated cholesterol-based cationic lipid for DNA delivery: effect of conditioning.

We have synthesised a novel cholesterol-based cationic lipid to promote DNA transfer in cells. This lipid, dimethyl hydroxyethyl aminopropane carbamoyl cholesterol iodide (DMHAPC-Chol) contains a biodegradable carbamoyl linker and a hydroxyethyl group in the polar amino head moiety and is characterised by NMR. Liposomes prepared from this lipid and dioleoyl phosphatidyl ethanolamine (DOPE) in equimolar proportion showed a weak cytotoxicity as revealed by MTT assays and are efficient to deliver plasmids DNA evaluated by the expression of reporter genes in vitro and in vivo. In this paper, we present an original method to determine the lipid concentration based on the colorimetric detection of the colipid DOPE and the measure of the molar ratio DOPE/cationic lipid in the liposome by FTIR spectroscopy. The liposomes and lipid/DNA complexes structures were characterized by transmission electron microscopy (TEM) and by quasi-elastic light scattering (QLS). TEM indicated that the complexes correspond to aggregates containing globular substructures with liposomes size. The method of immuno-gold labelling was used to detect plasmid in the complex and reveals the presence of DNA inside the aggregates. Transfection results showed efficient DNA transfer depending on the charge ratio and liposomes conditioning. Gel retardation results indicated that at a molar charge ratio between X = 1.5 and X = 2.5 (depending on the liposome conditioning), all DNA was taken by liposomes. We showed that conditioning by freeze-drying (lyophilization) facilitates storage and improves transfection efficiency. When the liposomes were lyophilized prior to DNA addition or when the complexes were subjected to freeze-thawing cycles, the obtained complexes showed a transfection with levels enhanced up to four and five-fold respectively for the lyophilized liposomes and freeze-thawed complexes. NMR was used to characterize the modifications under freezing which showed an effect on 31P spectra.

Animals↗
PubMed1993

An ultrastructural study of experimentally induced microliths in rat proximal and distal tubules.

Calcium oxalate stone formation was induced in rats by oral application of ethylene glycol and ammonium chloride for 4, 8 and 24 days. After each induction period, light-microscopically, birefringent crystals were seen in the tubular lumen and, intracellularly, in proximal and distal tubular cells. After a postfixation which partially removed the crystalline material crystal ghosts were seen by electron microscopy. In the lumen, crystal ghosts were observed ranging from single crystals to crystal agglomerates. The large intraluminal agglomerates were surrounded by epithelial cells and cellular debris. Both crystal types had an organic interior. In the cytoplasm of ultrastructurally changed proximal tubular cells, small (200 to 600 nm. in diameter) single crystal ghosts were present in the terminal web at the basis of the microvilli. Others were present in large vacuolar structures, with a fine granular matrix. After the prolonged microlith induction periods, such vacuolar structures were seen throughout the cell. The organic matrix of the crystal ghosts therein had acquired a more aggregated and complex structure.

Ammonium Chloride↗
PubMed1984

Polarization optical analysis of blood cell membranes.

The present study deals with investigations of membrane structure using polarization topo-optical reactions. Polarization microscopy is a special field of biological submicroscopic morphology. It represents a powerful tool well able to reveal the features of organization of biological structures, and the regularity of macromolecules building cells and tissues - properties that cannot directly be studied by other approaches to complex biological systems. Only in "pure" systems can X-ray diffraction, or the analysis of circular dichroism and the dispersion of optical rotability provide data equivalent to those obtained by polarization microscopy in complex systems. One of the main drawbacks of molecular biology is that most information is relevant to isolated, purified particles or macromolecules. Thus, no conclusions can be drawn concerning the original arrangement of molecules. The gap between biochemical-biophysical and morphological approaches to molecular arrangement in complex structures is bridged by the polarization optical technique. As was pointed out in the introduction, polarization microscopy became a routine biological research method following the pioneering work of Romhányi. His enlightening topo-optical reactions (Romhányi 1960, 1963, 1966) were based on the oriented dye binding of the original charge carriers of regularly arranged tissue constituents. The second group of Romhányi's topo-optical reactions comprised procedures such as sulfation (Romhányi et al. 1973, 1974), the aldehyde-bisulfite-toluidine blue (ABT) reaction (Romhányi et al. 1974, 1975), the permanganate-bisulfite-toluidine blue (PBT) reaction (Fischer 1979, 1979a), and the sialic acid-specific reaction (Makovitzky 1980) all of which operate with induced dye-binding groups; i.e. dye-binding moieties on biological macromolecules are produced by specific chemical reactions.

Blood Platelets↗
PubMed1996

Imaging of cervical spine trauma.

The cervical spine, supporting such critical structures as the medulla, spinal cord, and cervical nerve roots, can be very challenging to image properly because of its complex structural anatomy and superimposition of bony and soft tissue parts. In this article, the use and value of the various modalities that image the cervical spine are discussed. Plain radiography remains the best screening tool in the initial evaluation of the cervical spine after trauma. Additional views, such as swimmer's, pillar and lateral flexion, and extension, often are helpful in certain circumstances.

Adult↗
PubMedDate not supplied

Pharmacophore identification, in silico screening, and virtual library design for inhibitors of the human factor Xa.

Factor Xa inhibitors are innovative anticoagulant agents that provide a better safety/efficacy profile compared to other anticoagulative drugs. A chemical feature-based modeling approach was applied to identify crucial pharmacophore patterns from 3D crystal structures of inhibitors bound to human factor Xa (Pdb entries 1fjs, 1kns, 1eqz) using the software LIGANDSCOUT and CATALYST. The complex structures were selected regarding the criteria of high inhibitory potency (i.e. all ligands show K(i) values against factor Xa in the subnanomolar range) and good resolution (i.e. at least 2.2 A) in order to generate selective and high quality pharmacophore models. The resulting chemical-feature based hypotheses were used for virtual screening of commercial molecular databases such as the WDI database. Furthermore, a ligand-based molecular modeling approach was performed to obtain common-feature hypotheses that represent the relevant chemical interactions between 10 bioactive factor Xa inhibitors and the protein, respectively. In a next step a virtual combinatorial library was designed in order to generate new compounds with similar chemical and spatial properties as known inhibitors. The software tool ILIB DIVERSE was used for this procedure in order to provide new scaffolds of this group of anticoagulants. Finally we present the combination of these two techniques, hence virtual screening was performed with selective pharmacophore models in a focused virtual combinatorial database. De novo derived molecular scaffolds that were able to adequately satisfy the pharmacophore criteria are revealed and are promising templates for candidates for further development.

Anticoagulants↗
PubMed2002

The X-ray crystallographic structure of Escherichia coli branching enzyme.

Branching enzyme catalyzes the formation of alpha-1,6 branch points in either glycogen or starch. We report the 2.3-A crystal structure of glycogen branching enzyme from Escherichia coli. The enzyme consists of three major domains, an NH(2)-terminal seven-stranded beta-sandwich domain, a COOH-terminal domain, and a central alpha/beta-barrel domain containing the enzyme active site. While the central domain is similar to that of all the other amylase family enzymes, branching enzyme shares the structure of all three domains only with isoamylase. Oligosaccharide binding was modeled for branching enzyme using the enzyme-oligosaccharide complex structures of various alpha-amylases and cyclodextrin glucanotransferase and residues were implicated in oligosaccharide binding. While most of the oligosaccharides modeled well in the branching enzyme structure, an approximate 50 degrees rotation between two of the glucose units was required to avoid steric clashes with Trp(298) of branching enzyme. A similar rotation was observed in the mammalian alpha-amylase structure caused by an equivalent tryptophan residue in this structure. It appears that there are two binding modes for oligosaccharides in these structures depending on the identity and location of this aromatic residue.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2003

Functional insights revealed by the crystal structures of Escherichia coli glucose-1-phosphatase.

The Escherichia coli periplasmic glucose-1-phosphatase is a member of the histidine acid phosphatase family and acts primarily as a glucose scavenger. Previous substrate profiling studies have demonstrated some of the intriguing properties of the enzyme, including its unique and highly selective inositol phosphatase activity. The enzyme is also potentially involved in pathogenic inositol phosphate signal transduction pathways via type III secretion into the host cell. We have determined the crystal structure of E. coli glucose-1-phosphatase in an effort to unveil the structural mechanism underlying such unique substrate specificity. The structure was determined by the method of multiwavelength anomalous dispersion using a tungstate derivative together with the H18A inactive mutant complex structure with glucose 1-phosphate at 2.4-A resolution. In the active site of glucose-1-phosphatase, there are two unique gating residues, Glu-196 and Leu-24, in addition to the conserved features of histidine acid phosphatases. Together they create steric and electrostatic constraints responsible for the unique selectivity of the enzyme toward phytate and glucose-1-phosphate as well as its unusually high pH optimum for the latter. Based on the structural characterization, we were able to derive simple structural principles that not only precisely explains the substrate specificity of glucose-1-phosphatase and the hydrolysis products of various inositol phosphate substrates but also rationalizes similar general characteristics across the histidine acid phosphatase family.

Binding Sites↗
PubMed2004

An accurate, residue-level, pair potential of mean force for folding and binding based on the distance-scaled, ideal-gas reference state.

Structure prediction on a genomic scale requires a simplified energy function that can efficiently sample the conformational space of polypeptide chains. A good energy function at minimum should discriminate native structures against decoys. Here, we show that a recently developed, residue-specific, all-atom knowledge-based potential (167 atomic types) based on distance-scaled, finite ideal-gas reference state (DFIRE-all-atom) can be substantially simplified to 20 residue types located at side-chain center of mass (DFIRE-SCM) without a significant change in its capability of structure discrimination. Using 96 standard multiple decoy sets, we show that there is only a small reduction (from 80% to 78%) in success rate of ranking native structures as the top 1. The success rate is higher than two previously developed, all-atom distance-dependent statistical pair potentials. Applied to structure selections of 21 docking decoys without modification, the DFIRE-SCM potential is 29% more successful in recognizing native complex structures than an all-atom statistical potential trained by a database of dimeric interfaces. The potential also achieves 92% accuracy in distinguishing true dimeric interfaces from artificial crystal interfaces. In addition, the DFIRE potential with the C(alpha) positions as the interaction centers recognizes 123 native structures out of a comprehensive 125-protein TOUCHSTONE decoy set in which each protein has 24,000 decoys with only C(alpha) positions. Furthermore, the performance by DFIRE-SCM on newly established 25 monomeric and 31 docking Rosetta-decoy sets is comparable to (or better than in the case of monomeric decoy sets) that of a recently developed, all-atom Rosetta energy function enhanced with an orientation-dependent hydrogen bonding potential.

Amino Acids↗
PubMed2004

Tracking optical coherence tomography.

An experimental tracking optical coherence tomography (OCT) system has been clinically tested. The prototype instrument uses a secondary sensing beam and steering mirrors to compensate for eye motion with a closed-loop bandwidth of 1 kHz and tracking accuracy, to within less than the OCT beam diameter. The retinal tracker improved image registration accuracy to <1 transverse pixel (<60 microm). Composite OCT images averaged over multiple scans and visits show a sharp fine structure limited only by transverse pixel size. As the resolution of clinical OCT systems improves, the capability to reproducibly map complex structures in the living eye at high resolution will lead to improved understanding of disease processes and improved sensitivity and specificity of diagnostic procedures.

Eye Movements↗
PubMed1982

Further electron-microscope studies on the human hepatic sinusoidal wall with special reference to the fat-storing cell.

In biopsy specimens from two normal human livers, fat-storing cells and Kupffer cells were observed by electron microscopy with the following results: 1) In the human Ito cells numerous micropinocytotic caveolae and vesicles occurred either scattered beneath the plasma membrane or fused into short tubules. In the cytoplasm abutting on these structures, minute clusters of glycogen beta-particles were revealed which presumably had been synthesized in the local cytoplasm from carbohydrate (glucose) ingested by pinocytosis. 2) Lipid droplets (vacuoles) were formed within the accumulations of the glycogen beta-particles. These findings support the view that the glycogen synthesized in the Ito cells may represent a transitional compound in the process of lipid synthesis from carbohydrate. 3) Among lipid vacuoles, electron-dense droplets equally large were found, often containing electron-lucent areas in their center. On the surface of these dense droplets, compact clusters of glycogen particles adhered as if they might have permeated into the droplets. These droplets may possibly be immature lipid droplets retaining chemical properties of the glycogen in their superficial part; they remained insoluble during the preparation procedures for ultrathin sections. 4) The occurrence of the worm-like structure has for the first time been revealed in the human Kupffer cells. Besides its short tubular profiles, a more complex structure was demonstrated.

Female↗
PubMed2003

"Real" three-dimensional constructive interference in steady-state imaging to discern microneurosurgical anatomy. Technical note.

Three-dimensional (3D) neuroimages are generally considered useful for neurosurgical practice. Nevertheless, neuroimaging modalities such as 3D digital subtraction angiography and 3D computerized tomography angiography are still insufficient because the resulting images fail to delineate neural structures. Complex neurosurgical procedures are mostly performed in the cerebrospinal fluid (CSF) space of the basal cistern, where vessels and neural structures are present along with the lesion. The magnetic resonance (MR) imaging-derived 3D constructive interference in steady-state (CISS) imaging displays the margin between the CSF and neural structures, vessels, and dura mater in detail, in a two-dimensional fashion. The authors know that volume-rendered 3D CISS images would be more useful for surgery than conventional ones. Although the usefulness of "virtual MR image endoscopy" was reported previously, the endoscopic view is different from the operative field because of the perspective being emphasized. Therefore, to simulate surgical views, the authors made 3D neuroimages from a 3D CISS MR sequence by using an advanced computer workstation. After generating volume images, a cutting method was used in the desired plane to visualize the lesion with reference to a multiplanar reformatted image. The authors call these "real" 3D CISS images, and they are more comparable to the operative field. This newly developed method of producing a real 3D CISS image was used in 30 cases and contributed to the understanding of the relationship between a lesion and surrounding structures before attempting neurosurgical procedures, with minimal invasiveness to the patient.

Basilar Artery↗
PubMed1992

[The anatomical characteristics of the root furcations in the molar teeth].

The aim of the present study has been to realize a morphometrical and morphological study on the anatomical characteristics of molar teeth root furcations. Two hundred ninety four molars (147 upper and 147 lower teeth), after extraction and elimination of periodontal ligament residuals by trypsin, have been morphometrically evaluated recording the principal anatomical characters of the furcal and radicular region (root and radicular trunk lengths, mesio-distal and vestibulo-palatal diameters at the cementum-enamel junction, inter-radicular angle width and furcal area extension). By the Pearson's correlation test data such obtained were analyzed to verify the existence of statistically significant correlations among the above mentioned anatomical characteristics. Thirty teeth, selected among the most representatives of the whole sample for their anatomical characters, have been morphologically evaluated: 10 by stereo-microscopical examination, 10 by the observation of non-demineralized histological sections and 10 by scanning electron microscopical examination. Results of the morphometrical evaluation showed that from first to second molar the radicular angle, root length and furcal area width undergo a reduction; differently radicular trunk increases his length. On the basis of this results the Authors try to explain data from recent clinical research testifying that second upper molar is the most frequently extracted tooth. In fact a long radicular trunk is associated with a more apical placement of the furcation entrance and this situation, in conjunction with a narrow inter-radicular angle, can obstruct the insertion of therapeutical instruments, justifying the bad prognosis of the second upper molar involved by periodontal disease. The statistical analysis of anatomical data showed a significant correlation (r = -0.46) among radicular trunk length and inter-radicular angle width (in upper first molars; reverse correlation), root length and inter-radicular angle width (r = 0.51) (lower first molars), vestibular-buccal diameter at the cementum-enamel junction and width of mesial and distal furcal angles (r = 0.43) (upper second molars), the extension of furcal area and the wideness of inter-radicular angle (r = 0.89/0.43). These data are in accord with those from other Authors. Morphological analysis showed the high structural complexity of furcal area in molar teeth with the common observation of cemental crests and pulpal accessory canals orifices; these structures can offer a good receptacle to the subgingival dental plaque and can cause difficulties in debridement and therapeutical treatment of the molar furcal region involved by periodontal disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Histocytological Preparation Techniques↗
PubMed1978

Major histocompatibility complex gene products on macrophages influence T cell activation.

Antigen-pulsed macrophages were used to sensitize or elicit sensitivity from mice of different strains to a variety of antigens. The results indicate that sensitization is directed, not to antigen as such, but to a complex structure on the macrophage surface determined partly by the antigen, and partly by a product coded by the major histocompatibility complex. Delayed type hypersensitivity could be provoked by antigen in responder (R) mice and in the F1 between responder and low responder (LR) strains, but not in LR mice unless pretreated by cyclophosphamide. Sensitivity could be transferred to naive LR-strain mice by lymph node cells taken 5 days after sensitization of cyclophosphamide-pretreated LR mice but not of F1 hybrids between LR and R strains. Sensitivity from these could be transferred only to naive F1 or R-strain mice. The results suggest that low responsiveness cannot be accounted for solely in terms of the operation of a cyclophosphamide-sensitive suppressor mechanism. It is postulated that antigen is less immunogenic when presented by LR-strain cells than by R-strain cells.

Animals↗
PubMed1994

Modulation of human myelopoiesis by human gangliosides.

Cell surface gangliosides are potent modulators of cellular proliferation. We hypothesize that gangliosides shed by tumor cells modulate hematopoiesis and contribute to human tumor-associated suppression of hematopoiesis. To test this hypothesis, we determined the effects on myeloid colony formation by human bone marrow mononuclear cells of total gangliosides isolated from human brain and of seven highly purified individual ganglioside species (GM1, GM2, GD1a, GD1b, GD2, GD3, and GT1b). Total human brain gangliosides and certain individual species, GD1a, GD1b, and GT1b, significantly inhibited myeloid colony formation (number as well as size). The most complex molecules, GD1a, GD1b, and GT1b, were the most inhibitory, suggesting that the degree of inhibition is related to ganglioside structural complexity. To extend these findings, we also investigated certain tumor-derived (neuroblastoma) gangliosides, which we found inhibited both myeloid colony formation and 3H-thymidine incorporation by human bone marrow mononuclear cells. These data suggest a role for gangliosides, which are shed by proliferating cells, in the regulation of human hematopoiesis and may explain the bone marrow hypoplasia observed in association with many human malignancies.

Bone Marrow↗
PubMed1995

The structure of unliganded reverse transcriptase from the human immunodeficiency virus type 1.

The crystal structure of the reverse transcriptase (RT) from the type 1 human immunodeficiency virus has been determined at 3.2-A resolution. Comparison with complexes between RT and the polymerase inhibitor Nevirapine [Kohlstaedt, L.A., Wang, J., Friedman, J.M., Rice, P.A. & Steitz, T.A. (1992) Science 256, 1783-1790] and between RT and an oligonucleotide [Jacobo-Molina, A., Ding, J., Nanni, R., Clark, A. D., Lu, X., Tantillo, C., Williams, R. L., Kamer, G., Ferris, A. L., Clark, P., Hizi, A., Hughes, S. H. & Arnold, E. (1993) Proc. Natl. Acad. Sci. USA 90, 6320-6324] reveals changes associated with ligand binding. The enzyme is a heterodimer (p66/p51), with domains labeled "fingers," "thumb," "palm," and "connection" in both subunits, and a ribonuclease H domain in the larger subunit only. The most striking difference between RT and both complex structures is the change in orientation of the p66 thumb (approximately 33 degrees rotation). Smaller shifts relative to the core of the molecule were also found in other domains, including the p66 fingers and palm, which contain the polymerase active site. Within the polymerase catalytic region itself, there are no rearrangements between RT and the RT/DNA complex. In RT/Nevirapine, the drug binds in the p66 palm near the polymerase active site, a region that is well-packed hydrophobic core in the unliganded enzyme. Room for the drug is provided by movement of a small beta-sheet within the palm domain of the Nevirapine complex. The rearrangement within the palm and thumb, as well as domain shifts relative to the enzyme core, may prevent correct placement of the oligonucleotide substrate when the drug is bound.

Binding Sites↗

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