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PubMed2002

Human IgG monoclonal anti-alpha(IIb)beta(3)-binding fragments derived from immunized donors using phage display.

Previous studies of the immune response in polytransfused Glanzmann thrombasthenia (GT) patients and in autoimmune thrombocytopenic purpura (AITP) have relied on serum analysis and have shown the frequent development of Abs directed against the alpha(IIb)beta(3) integrin. However, little is known about the molecular diversity of the humoral immune response to alpha(IIb)beta(3) due to the paucity of mAbs issuing from these pathologies. We have isolated human IgG anti-alpha(IIb)beta(3) binding fragments using combinatorial libraries of single-chain IgG created from the B cells of a GT and an AITP patient, both with serum Abs. Ab screening was performed using activated platelets or activated alpha(IIb)beta(3)-expressing Chinese hamster ovary cells. Sequencing of selected phage Abs showed that a broad selection of genes from virtually all V gene families had been used, indicating the diversity of the immune response. About one-half of the V(H) and V(L) segments of our IgG anti-alpha(IIb)beta(3) fragments displayed extensive hypermutations in the complementarity-determining region, supporting the idea that an Ag-driven immune response was occurring in both patients. The H chain complementarity-determining region 3 analysis of phage Abs revealed motifs other than the well-known RGD and KQAGDV integrin-binding sequences. To our knowledge, our study is the first to illustrate multiple human IgG anti-alpha(IIb)beta(3) reactivities and structural variations linked to the anti-platelet human immune response. Human alpha(IIb)beta(3) Abs preferentially directed against the activated form of the integrin were further characterized because platelet alpha(IIb)beta(3) inhibitors are potential therapeutic reagents for treating acute coronary syndromes. Currently available alpha(IIb)beta(3) antagonists do not specifically recognize the activated form of the integrin.

Aged↗
PubMed2005

The immunomodulatory effects of novel beta-oxa, beta-thia, and gamma-thia polyunsaturated fatty acids on human T lymphocyte proliferation, cytokine production, and activation of protein kinase C and MAPKs.

We have recently demonstrated that a novel n-3 long chain polyunsaturated fatty acid (PUFA) (beta-oxa 21:3n-3) was a more potent and more selective anti-inflammatory agent than n-3 PUFA. To gain further insights into this technology, we synthesized other novel PUFA consisting of beta-oxa, beta-thia, and gamma-thia compounds. All three types displayed anti-inflammatory activity. Each of the unsaturated beta-oxa fatty acids showed similar inhibition of PHA-PMA-induced T cell proliferation with a parallel inhibition of TNF-beta production. However, beta-oxa 25:6n-3 and beta-oxa 21:4n-3 displayed lower inhibitory action on IFN-gamma production. Surprisingly, beta-oxa 23:4n-6 and beta-oxa 21:3n-6 had marginal effect on IL-2 production. Thus, structural variation can generate selectivity for different immunological parameters. The beta-thia compounds 23:4n-6, 21:3n-6, and 21:3n-3 were highly effective in inhibiting all immunological responses. Of the two gamma-thia PUFA tested, gamma-thia 24:4n-6 was a strong inhibitor of all responses apart from IL-2, but gamma-thia 22:3n-6 had very little inhibitory effect. Two of the most active compounds, beta-thia 23:4n-6 and beta-thia 21:3n-6, were studied in more detail and shown to have an IC(50) of 1-2 muM under optimal conditions. Thus, these PUFA retain the immunosuppressive properties of the n-3 PUFAs, 20:5n-3 and 22:6n-3, but not the neutrophil-stimulating properties. Their action on T lymphocytes is independent of cyclooxygenase or lipoxygenase activity, and they act at a postreceptor-binding level by inhibiting the activation of protein kinase C and ERK1/ERK2 kinases.

Cell Proliferation↗
PubMed1986

Ultrastructure of erythrocytic stages of Plasmodium ovale in humans.

An electron microscopic study of Plasmodium ovale in humans supplied information on the fine structure of erythrocytic trophozoites, presegmenting schizonts and gametocytes. Ultrastructural features of P. ovale appeared quite similar to those described in other mammalian malarial parasites. However, some minor structural variations were observed. The parasite was a fairly compact cell of an oval shape. However, occasionally trophozoites had slender cytoplasmic protrusions. Ingestion of host cell cytoplasm occurred cytostomally. Nucleus contained a nucleolus-like dense region. The asexual parasites possessed acristate mitochrondria and were surrounded by a single-membraned pellicle in addition to a parasitophorous vacuole membrane. The gametocytes, however, possessed cristate mitochondria and were surrounded by a three-membraned pellicle in addition to a parasitophorous vacuole membrane.

Adult↗
PubMed2006

Carotenoid biosynthesis in cyanobacteria: structural and evolutionary scenarios based on comparative genomics.

Carotenoids are widely distributed pigments in nature and their biosynthetic pathway has been extensively studied in various organisms. The recent access to the overwhelming amount genomic data of cyanobacteria has given birth to a novel approach called comparative genomics. The putative enzymes involved in the carotenoid biosynthesis among the cyanobacteria were determined by similarity-based tools. The reconstruction of biosynthetic pathway was based on the related enzymes. It is interesting to find that nearly all the cyanobacteria share quite similar pathway to synthesize beta-carotene except for Gloeobacter violaceus PCC 7421. The enzymes, crtE-B-P-Qb-L, involved in the upstream pathway are more conserved than the subsequent ones (crtW-R). In addition, many carotenoid synthesis enzymes exhibit diversity in structure and function. Such examples in the families of zeta -carotene desaturase, lycopene cylases and carotene ketolases were described in this article. When we mapped these crt genes to the cyanobacterial genomes, the crt genes showed great structural variation among species. All of them are dispersed on the whole chromosome in contrast to the linear adjacent distribution of the crt gene cluster in other eubacteria. Moreover, in unicellular cyanobacteria, each step of the carotenogenic pathway is usually catalyzed by one gene product, whereas multiple ketolase genes are found in filamentous cyanobacteria. Such increased numbers of crt genes and their correlation to the ecological adaptation were carefully discussed.

Bacteria↗
PubMed1987

Tiacumicins, a novel complex of 18-membered macrolides. II. Isolation and structure determination.

A novel complex of Gram-positive antibiotics has been isolated from the fermentation broth and mycelium of Dactylosporangium aurantiacum subsp. hamdenesis subsp. nov. The structures of these six compounds were deduced employing UV, MS, IR, and extensive 1D and 2D homonuclear and heteronuclear NMR experiments. Each component contained a highly unsaturated 18-membered macrolide ring. Components differed from one another by minor structural variations in the macrolide ring and by the number and esterification pattern of glycosidically bound sugars.

Actinomycetales↗
PubMed1997

The synthesis and antifungal activity of N-alkylated analogs of echinocandin B.

The synthesis and biological activity of a series of N-alkylated derivatives of echinocandin B are described and compared with the N-acylated analogs. The linear, rigid geometry of the side chain that was essential to improve the antifungal potency of the N-acylated series gave similar in vitro results with the N-alkylated derivatives. However the slight structural variation forfeited all in vivo activity.

Animals↗
PubMed1999

Total Synthesis of the Marine Natural Product 7-Deoxy-okadaic Acid: A Potent Inhibitor of Serine/Threonine-Specific Protein Phosphatases.

A small change to the structure of okadaic acid (1), the omission of the single hydroxy group at C7, facilitated substantially the first total synthesis of the derivative 7-deoxyokadaic acid (2). The conformation of 2 is in agreement with that of 1 and this minimal structural variation has been reported previously to have little effect on the inhibitory activity towards the serine/threonine-specific protein phosphatases PP-1 and PP-2A.

Journal Article↗
PubMed1999

Dendrites of classes of hippocampal neurons differ in structural complexity and branching patterns.

Dendrites of reconstructed hippocampal neurons were analyzed for morphometric, topologic, and fractal parameters (n = 32 quantities) to investigate neuronal groupings and growth characteristics with a common set of assumptions. The structures studied included CA1 and CA3 pyramidal cells, interneurons, and granule cells from young animals (71 cells in total). Most of the cells showed no characteristic fractal dimension; rather, the scaling relation could be well represented by a two-parameter fit, of which one parameter showed a significant difference between cell classes. Other significant quantities that differentiated cell classes were related to the complexity of the dendritic tree (number of branch points and maximal terminal branch order) and the cell's electrical properties such as the mean attenuation between the soma and terminals. Principal components analysis produced combined measures of only slightly greater discriminative power than the best individual measures, indicating that the elementary quantities capture most of the structural variation between hippocampal cell groups. Another finding was that for all cells the mean segment length increased with dendritic branch order, which is consistent with decreasing branching probability as a function of the path distance from the soma. Analysis of another set of CA1 pyramidal neurons from aged animals (n = 15; 22-24 months) showed only a few significant differences than those from young animals (n = 11; a subset of n = 71) of which the most important was a straightening of the paths between terminals and the soma. The quantities analyzed in these reconstructed hippocampal neurons may reflect both intrinsic neuronal characteristics and extrinsic influences. Hippocampal cell groupings (i.e., pyramidal cells as opposed to dentate granule cells and interneurons) were significantly differentiated by most parameters. These differences and parameter values may be critical for understanding and generating synthetic neuronal populations for modelling studies.

Aging↗
PubMed1998

Isocyanide based multi component reactions in combinatorial chemistry.

Although usually regarded as a recent development, the combinatorial approach to the synthesis of libraries of new drug candidates was first described as early as 1961 using the isocyanide-based one-pot multicomponent Ugi reaction. Isocyanide-based multi component reactions (MCR's) markedly differ from their usual two component counterparts. In the context of combinatorial chemistry, they offer more structural variations, more accessible compounds and more diversity than any other previously known reaction. This review examines the history of isocyanide based MCR's and their applicability in combinatorial chemistry.

Chemistry, Pharmaceutical↗
PubMed1999

Pharmacokinetics of low molecular weight heparins in animal models.

Low molecular weight heparins (LMWHs) are a diverse group of depolymerized heparin preparations with molecular weights ranging from 1800 to 12,000 Da. Due to manufacturing differences, there are marked structural variations between LMWHs that exhibit distinct pharmacologic and biochemical profiles. Pharmacokinetic studies generally use indirect pharmacodynamic measures, particularly anti-Xa activity. Animal models have shown considerable variation between preparations in anti-Xa activity and other pharmacodynamic measures, including bioavailability and release of tissue factor pathway inhibitor (TFPI). Each LMWH has a specific, assay-dependent pharmacokinetic profile, reinforcing the concept that each LMWH is a distinct, noninterchangeable, pharmaceutical product.

Animals↗
PubMedDate not supplied

L-proline analogues of anthraquinone-2-carboxylic acid: cytotoxic activity in breast cancer MCF-7 cells and inhibitory activity against topoisomerase I and II.

A series of proline analogues of anthraquinone-2-carboxylic acid (1-3) were synthesized and evaluated for cytotoxic activity in the cultured breast cancer MCF-7 cells. The concentrations of 1, 2 and 3 needed to inhibit [3H]thymidine incorporation into DNA by 50% (IC50) were found to be 107 +/- 6 microM, 185 +/- 5 microM and 87 +/- 6 microM, respectively. To test whether cytotoxic properties were related to topoisomerase action, the most potent compounds 1 and 3 were evaluated in a cell-free system. Compound 3, which contains a basic substituent at C terminus of the amino acid such as (dimethylamino)propyl inhibited the catalytic activity of both topoisomerases I and II at a concentration of 30 and 60 microM, respectively. However, compound 1 containing an electrostatically neutral moiety, such as methyl ester did not inhibit topoisomerase I or topoisomerase II. In summary, compound 3 is a promising lead compound for a further structural variation in the design of new antitumour drugs.

Anthraquinones↗
PubMed1976

Opiate receptor interactions of benzomorphans in rat brain homogenates.

Minor structural variations of benzomorphans opiates are associated with striking, unpredictable shifts in the relative extent of agonist or antagonist properties in vivo. The relative abilities of a number of benzomorphans in inhibit 3H-naloxone binding in the absence and presence of sodium in vitro show some correlations with their pharmacologic properties in vivo, although distinct exceptions exist. The ability of opiate agonists to inhibit 3H-naloxone binding is greatly reduced by sodium, while pure antagonists are affected very little, if at all, and mixed agonist-antagonist benzomorphans display an intermediate response.

Animals↗
PubMed1999

Histological study of parotid, submaxillary and von Ebner salivary glands in chronic alcoholics.

Samples from parotid, submaxillary, and von Ebner salivary glands of six chronic alcoholic individuals who had died of alcoholic hepatic cirrhosis were analyzed by topographic and histochemical routine stains and marked for cytokeratins; two normal adult individuals were used as control. Modifications in the acinar cells were found, but the most evident changes were observed in the ductal system: enlargement of major ducts, heterogeneous expression of cytokeratins and athrophy in epithelial cells, desquamated cells and stasis of content, and ductal hyperplasia in von Ebner glands. The lymphoplasmocytic infiltration does not represent the typical lymphocytic focus on Sjögren's syndrome or other connective tissue pathologies. Our findings indicate that functional and structural variations are produced both in serous acini and ducts parotid, submaxilar and von Ebner glands affected by alcoholic sialosis.

Adult↗
PubMed1992

Developmental anomalies at the thoracic outlet: an analysis of 200 consecutive cases.

Anatomic observations were made during 200 consecutive transaxillary surgical procedures performed in 175 patients because of unremitting signs and symptoms of nerve or vascular compression at the thoracic outlet. There were 160 cases of brachial plexus compression and 40 cases of arterial or venous occlusion. In 132 (66%) of these cases, single or multiple abnormalities were recognized that represented developmental variations previously described in anatomic dissections or in embryologic studies. There were 17 cases of cervical rib or first thoracic rib abnormalities and 20 supernumerary scalene muscles. Developmental variations were identified in 86 scalene and 39 subclavius muscles or their insertions. Comparisons revealed a higher percentage of developmental anomalies in this group of patients than in consecutive anatomic investigations reported in unselected populations. This information was interpreted in light of recent embryologic studies and histochemical and morphometric ultrastructural studies of scalene muscle. The preponderance of evidence suggests that neurovascular compression in the region of the thoracic outlet derives from a combination of these factors: predisposing morphologic variations, structural modifications conditioned by functional requirements, and changes in fiber type or myosin isoform consequent to trauma. The correlation of clinical syndrome with morphologic characteristics alone was significant only for the Paget-Schroetter syndrome.

Adult↗
PubMed2003

[Efficient production of wheat alien translocation lines and characterization by molecular cytogenetics].

The Triticum aestivum-Leymus mollis and T. aestivum-Thinopyrum intermedium translocation lines were induced by gametocidal chromosome 3C derived from Aegilops triuncialis and gamma-ray irradiated pollens of a T. aestivum-Th. intermedium addition line TAI-14 with a lower dosage (10Gy), respectively. By genomic in situ hybridization (GISH) analysis, three T. aestivum-L. mollis translocation lines (WM-10, WM-43 and WM-47) and three deletion lines (WM-18, WM-43 and WM-44) were selected from 59 F2 plants derived from a cross combination of T. aestivum-L. mollis substitution line M8724-8-13 x T. aestivum-Ae. triunicalis 3C chromosome addition line. The frequency of translocation lines produced and total frequency of chromosome structural variation occurred were 5.08% and 8.47%, respectively. Two of the three translocation lines, WM-10 and WM-43 all were heterozygous translocation lines carrying one T. aestivum-L. mollis Robertsonian translocation chromosome, but the translocation chromosome in the two lines were different in morphology. The other one, WM-47 was a double heterozygous translocation with two different translocation chromosomes. By the C-banding, one of the three translocation lines was identified, the translocation chromosome consisted of 7DL of wheat and a chromosome arm of L. mollis. In addition, wheat chromosome deletions were observed in some plants. In another cross combination involved in common wheat and T. aestivum-Th. intermedium addition line, two alien terminal non-Robertsonian translocation lines (WI-21 and WI-68) were identified from 69 F2 plants by C-banding and GISH, and the percentage of translocation line was 2.90%. By C-banding analysis, the translocation chromosomes involved in wheat chromosomes 3A and 4A in the two lines, respectively. These results indicate that inducing wheat alien translocation line by gametocidal chromosome and irradiated pollens all are efficient methods.

Chromosome Banding↗
PubMed2003

Micro-shear bond strengths of adhesive resins to coronal dentin versus the floor of the pulp chamber.

PURPOSE: To evaluate the micro-shear bond strengths to superficial coronal dentin and the floor of the pulp chamber using two dentin bonding systems and to compare the ultrastructure of the resin-dentin interface of the two regions. METHODS: 30 non-carious molars were used to obtain 2 mm thick slabs of coronal dentin and dentin at the pulp chamber. The specimens in each region were divided into three sub-groups to be bonded as follows; Clearfil SE Bond was used according to the manufacturer's instructions, Single Bond was applied to either wet dentin (Blot dry Group) or air-dried dentin (Dry Group) after phosphoric acid etching. A resin composite cylinder 0.5 mm high and 0.75 mm in diameter formed using a vinyl tube was bonded to the dentin. Specimens were stored at 37 degrees C for 24 hours in water and then stressed in shear at a crosshead speed of 1 mm/minute. The data were analyzed with one-way ANOVA and Fisher's PLSD test at the 5% level of significance. In addition, the ultrastructure of cross-sectioned dentin surfaces, the conditioned dentin surface and the resin dentin interfaces were observed by SEM. RESULTS: The bond strengths of Clearfil SE Bond and the Single Bond Blot dry group were approximately 40 MPa in coronal dentin and 30 MPa in the dentin at the floor of the pulp chamber respectively. However, the bond strengths of Single Bond were significantly lower in the Dry condition (MPa) (P < 0.05). SEM observations revealed the thickness of the hybrid layer created by Clearfil SE Bond in coronal dentin and at the floor of the pulp chamber were less than 1.0 microm thick. For Single Bond, a 3-4 microm hybrid layer was created in coronal dentin, while a thinner hybrid layer was observed in the floor of the pulp chamber. Morphological and structural variations in dentin may have influenced the bond strengths of the bonding systems to the floor of the pulp chamber.

Acid Etching, Dental↗
PubMed2004

Assessment of subchondral bone mineral density in equine metacarpophalangeal and stifle joints.

Functional relationships between articular cartilage and underlying subchondral bone have been shown to be associated with the progression of osteoarthritis (OA). However, quantifiable factors substantiating this relationship do not exist. Therefore, the study objective involved quantifying subchondral bone mineral density (BMD) of the equine metacarpophalangeal (MCP) and stifle joints as a step in determining if regional subchondral BMD may be associated with OA changes. BMD was bilaterally quantified using dual energy xray absorptiometry (DEXA) for four subchondral regions: palmer and dorsal aspect of the medial 3rd metacarpal (MC3P, MC3D), medial femoral condyle (MFC), and the medial trochlear ridge (MTR). BMD (g/cm2) was measured using a 5.2 x 5.2 mm region of interest in the subchondral bone area. To account for the differences in thickness, BMD (g/cm2) was divided by sample thickness providing volumetric BMD (g/cm3). No significant effect of side on BMD values was found (p > 0.72). However, there were significant differences in BMD found between all regions (p < 0.05). The volumetric BMD of the MC3P region was significantly greater than the MC3D and the MC3D was greater than the MFC, while the MFC was greater than the MTR (MC3P > MC3D > MFC > MTR). The MCP regions had a higher volumetric BMD than the stifle regions possibly due to higher weight distribution, smaller articular surface area, and joint geometry. The adaptive bone structural variations between the regions studied were shown to be significant. Mechanical properties of the overlying cartilage are currently being analyzed to correlate with these results and provide a possible diagnostic method to investigate OA progression.

Absorptiometry, Photon↗
PubMed2004

[Combination of variance components estimation, regression trees and logistic regression as a concept for exploring associations between animal husbandry conditions and lesions found at slaughter].

Integrated quality control measures have been discussed in farm animal husbandry and veterinary medicine for some time in search of concepts to link information on management factors with disease data gained by veterinary meat inspection at slaughter. Better understanding of relationships between these variables hopefully will help to improve management practices as well as meat quality and safety. In order to analyse data gained on-farm and at slaugherhouses and to investigate relationships between animal husbandry conditions and lesion occurrence at slaughter a biometrical concept has been developed. This concept combines a characterization of variation structures, the generation of regression trees to explore association structures in available animal management and disease data, and logistic regression used to quantify systematic effects of farm management factors. The combination of these three steps is illustrated with an example.

Analysis of Variance↗