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PubMed2006

Structural and functional variations in human apolipoprotein E3 and E4.

There are three major apolipoprotein E (apoE) isoforms. Although APOE-epsilon3 is considered a longevity gene, APOE-epsilon4 is a dual risk factor to atherosclerosis and Alzheimer disease. We have expressed full-length and N- and C-terminal truncated apoE3 and apoE4 tailored to eliminate helix and domain interactions to unveil structural and functional disturbances. The N-terminal truncated apoE4-(72-299) and C-terminal truncated apoE4-(1-231) showed more complicated or aggregated species than those of the corresponding apoE3 counterparts. This isoformic structural variation did not exist in the presence of dihexanoylphosphatidylcholine. The C-terminal truncated apoE-(1-191) and apoE-(1-231) proteins greatly lost lipid binding ability as illustrated by the dimyristoylphosphatidylcholine turbidity clearance. The low density lipoprotein (LDL) receptor binding ability, determined by a competition binding assay of 3H-LDL to the LDL receptor of HepG2 cells, showed that apoE4 proteins with N-terminal (apoE4-(72-299)), C-terminal (apoE4-(1-231)), or complete C-terminal truncation (apoE4-(1-191)) maintained greater receptor binding abilities than their apoE3 counterparts. The cholesterol-lowering abilities of apoE3-(72-299) and apoE3-(1-231) in apoE-deficient mice were decreased significantly. The structural preference of apoE4 to remain functional in solution may explain the enhanced opportunity of apoE4 isoform to display its pathophysiologic functions in atherosclerosis and Alzheimer disease.

Animals↗
PubMed1996

High-resolution random mesh algorithms for creating a probabilistic 3D surface atlas of the human brain.

Striking variations exist, across individuals, in the internal and external geometry of the brain. Such normal variations in the size, orientation, topology, and geometric complexity of cortical and subcortical structures have complicated the problem of quantifying deviations from normal anatomy and of developing standardized neuroanatomical atlases. This paper describes the design, implementation, and results of a technique for creating a three-dimensional (3D) probabilistic surface atlas of the human brain. We have developed, implemented, and tested a new 3D statistical method for assessing structural variations in a data-base of anatomic images. The algorithm enables the internal surface anatomy of new subjects to be analyzed at an extremely local level. The goal was to quantify subtle and distributed patterns of deviation from normal anatomy by automatically generating detailed probability maps of the anatomy of new subjects. Connected systems of parametric meshes were used to model the internal course of the following structures in both hemispheres: the parieto-occipital sulcus, the anterior and posterior rami of the calcarine sulcus, the cingulate and marginal sulci, and the supracallosal sulcus. These sulci penetrate sufficiently deeply into the brain to introduce an obvious topological decomposition of its volume architecture. A family of surface maps was constructed, encoding statistical properties of local anatomical variation within individual sulci. A probability space of random transformations, based on the theory of Gaussian random fields, was developed to reflect the observed variability in stereotaxic space of the connected system of anatomic surfaces. A complete system of probability density functions was computed, yielding confidence limits on surface variation. The ultimate goal of brain mapping is to provide a framework for integrating functional and anatomical data across many subjects and modalities. This task requires precise quantitative knowledge of the variations in geometry and location of intracerebral structures and critical functional interfaces. The surface mapping and probabilistic techniques presented here provide a basis for the generation of anatomical templates and expert diagnostic systems which retain quantitative information on intersubject variations in brain architecture.

Algorithms↗
PubMed2006

Nanoscale heterogeneity in ceria zirconia with low-temperature redox properties.

We have investigated nanoscale compositional and structural variations in Ce(0.5)Zr(0.5)O(2) samples with different redox properties. Different samples were prepared using a spray freezing technique, and the synthesis conditions were varied to yield materials with reduction temperatures in the range of 400-750 degrees C. X-ray diffraction and thermal gravimetric analysis were used to characterize the average structures and redox properties of these materials. The nanoscale structural and compositional variations in individual nanoparticles of high activity were determined with atomic-scale electron imaging and nanometer-resolution electron energy loss spectroscopy. During the early stage of particle formation, the crystallization process is initiated via the nucleation of ceria-rich nanodomains. This results in the formation of high-surface-area materials that exhibit nanoscale compositional heterogeneity consisting of Ce-rich cores surrounded by Zr-rich shells. The effect of high-temperature redox cycling on the nanoscale structure, composition, and low-temperature redox properties was also determined. Our analysis suggests that our most active material exhibits significant compositional and structural heterogeneity at the nanometer level.

Journal Article↗
PubMed2006

A chromosomal rearrangement hotspot can be identified from population genetic variation and is coincident with a hotspot for allelic recombination.

Insights into the origins of structural variation and the mutational mechanisms underlying genomic disorders would be greatly improved by a genomewide map of hotspots of nonallelic homologous recombination (NAHR). Moreover, our understanding of sequence variation within the duplicated sequences that are substrates for NAHR lags far behind that of sequence variation within the single-copy portion of the genome. Perhaps the best-characterized NAHR hotspot lies within the 24-kb-long Charcot-Marie-Tooth disease type 1A (CMT1A)-repeats (REPs) that sponsor deletions and duplications that cause peripheral neuropathies. We investigated structural and sequence diversity within the CMT1A-REPs, both within and between species. We discovered a high frequency of retroelement insertions, accelerated sequence evolution after duplication, extensive paralogous gene conversion, and a greater than twofold enrichment of SNPs in humans relative to the genome average. We identified an allelic recombination hotspot underlying the known NAHR hotspot, which suggests that the two processes are intimately related. Finally, we used our data to develop a novel method for inferring the location of an NAHR hotspot from sequence variation within segmental duplications and applied it to identify a putative NAHR hotspot within the LCR22 repeats that sponsor velocardiofacial syndrome deletions. We propose that a large-scale project to map sequence variation within segmental duplications would reveal a wealth of novel chromosomal-rearrangement hotspots.

Alleles↗
PubMed1989

The direct examination of three-dimensional bone architecture in vitro by computed tomography.

We describe a new method for the direct examination of three-dimensional bone structure in vitro based on high-resolution computed tomography (CT). Unlike clinical CT, a three-dimensional reconstruction array is created directly, rather than a series of two-dimensional slices. All structural indices commonly determined from two-dimensional histologic sections can be obtained nondestructively from a large number of slices in each of three orthogonal directions. This permits a comprehensive description of structural variation within a specimen and greatly facilitates the study of structural anisotropy. A measure of three-dimensional connectivity (Euler number/tissue volume) has been determined for the first time in human cancellous bone and shown to correlate with several two-dimensional histomorphometric indices. The method has the potential for overcoming many of the limitations of current approaches to the study of bone architecture at the microscopic level.

Bone and Bones↗
PubMed1980

A relationship between plasmid structure, structural lability, and sensitivity to site-specific endonucleases in Neisseria gonorrhoeae.

Nearly all gonococcal strains carry a small "phenotypically cryptic" plasmid of approximately 4,200 basepairs. A detailed physical map of this plasmid has been constructed, revealing the presence of numerous putative inverted repeats. These studies also revealed the presence on the plasmid of recognition sequences for several site-specific endonucleases (particularly HpaII, MspI and AluI) that are particularly resistant to cleavage, and confirmed previous reports of structural lability. Both the sites that are resistant to cleavage, and the observed structural variation are associated with the inverted repetitive sequences.

Base Composition↗
PubMed1997

The importance of cellular environment to function of the CD44 matrix receptor.

Much has been learned recently by experimental manipulation of the structure of CD44 and assessment of the resulting functions. However, even greater structural variation is naturally introduced by CD44-bearing cells. A structural model is now available for the portion of CD44 that recognizes hyaluronan, but it is clear that all domains of the molecule influence CD44 functions.

Animals↗
PubMed1997

Tyramine-containing poly(4-nitrophenylacrylate) as iodinatable ligand carrier in biodistribution analysis.

PURPOSE: Targeted label or drug delivery requires access to convenient carrier systems and methods for efficient ligand conjugation. The main purpose of this study is to design an iodinatable synthetic polymer, whose application in vivo in tumor-bearing mice is tested with several related carbohydrate ligands, namely ABH and Lewis blood group epitopes. METHODS: Tyramine and aminopropyl derivatives of the synthetic oligosaccharides were attached to poly(4-nitrophenylacrylate). Following iodination, the biodistribution of the sugar-free and the substituted polymers was determined in tumor-bearing mice. Flow cytofluorimetric analysis assessed tumor cell binding of further ligand types to human tumor cells in vitro. RESULTS: Quantitative ligand incorporation was achieved under mild conditions. Whereas the ligand-free poly[N-(2-hydroxyethyl)acrylamide] (MW 30 kDa) showed preferential accumulation in kidney, neoglycopolymers were found in substantial amounts in liver, kidney or spleen. The nature of the carbohydrate structure quantitatively influenced the distribution pattern. Tumor cell binding of blood group determinants and three further ligand types revealed non-uniform intensity in labeling and percentage of positive cells even in comparison between lines with identical histogenetic origin. CONCLUSIONS: Carbohydrate-exposing poly[N-(2-hydroxyethyl)acrylamide] polymers with tyramine as an iodine acceptor distribute in mice with a profile which is quantitatively influenced by small structural variations of the ligand part. Further refinement of the ligand structure may increase the level of selectivity for organ and tumor accumulation.

Acrylic Resins↗
PubMed2000

Scanning electron microscopic study of the neuromuscular junctions of the cricothyroid and thyroarytenoid muscles in rats.

Neuromuscular junctions were observed in the cricothyroid (CT) and thyroarytenoid (TA) muscles of adult rats by scanning electron microscopy after removing the intramuscular connective tissue components using the HCI hydrolysis method. Morphologically, the junctions were classified into three types in the CT muscle and two types in the TA muscle, based on the structural characteristics of the subneural apparatuses, including junctional folds. In the CT muscle, type 1 junctions (32%) consisted of more than 15 cup-like depressions with slit-like junctional folds. Type 2 junctions (20%) were characterized by approximately 10 cup-like depressions with a small number of pit- or slit-like junctional folds. Type 3 junctions (48%) had irregular labyrinthine gutters with slit-like junctional folds. In the TA muscle, type 1 (82%) and 2 (18%) junctions had similar structures to type 1 and 2 junctions in the CT muscle, respectively. Histochemical studies using myosin adenosine triphosphatase staining showed that both CT and TA muscles predominantly consisted of type II muscle fibers (78% and 82%, respectively), and that the diameter of type II fibers was larger than that of type I fibers. These findings suggest that the type 2 junction belongs to type I muscle fibers, while both type 1 and type 3 junctions belong to type II fibers, and that the type 3 junction is a structural variation of the type 1 junction. The significance of the structural differences of the subneural apparatuses in the intrinsic laryngeal muscles is discussed briefly.

Animals↗
PubMed1991

Level and form of psychopathology and the structure of group therapy.

Drawing upon concepts derived from ego psychological and object relations psychoanalytic theories of individual development and from a depth group psychology, the present empirical study, a naturalistic field investigation, explored hypothesized relationships between aspects of patients' psychological boundaries and structural features of inpatient therapy groups. More specifically, patients were assessed in terms of their level (i.e., psychotic vs. borderline organization) and form (i.e., anaclitic vs. introjective) of psychopathology. Their perceptions of themselves and of their therapy groups were measured following participation in two kinds of small group treatment designed to differ in terms of degree of internal structuring. Findings, generally supporting the hypotheses, showed the anaclitic borderline patients, in particular, to be most sensitive to structural variations and most adversely affected by an impersonal and highly structured treatment climate. Theoretical and practical implications of these findings were discussed.

Adult↗
PubMed2006

Non-canonical base pairs and higher order structures in nucleic acids: crystal structure database analysis.

Non-canonical base pairs, mostly present in the RNA, often play a prominent role towards maintaining their structural diversity. Higher order structures like base triples are also important in defining and stabilizing the tertiary folded structure of RNA. We have developed a new program BPFIND to analyze different types of canonical and non-canonical base pairs and base triples involving at least two direct hydrogen bonds formed between polar atoms of the bases or sugar O2' only. We considered 104 possible types of base pairs, out of which examples of 87 base pair types are found to occur in the available RNA crystal structures. Analysis indicates that approximately 32.7% base pairs in the functional RNA structures are non-canonical, which include different types of GA and GU Wobble base pairs apart from a wide range of base pair possibilities. We further noticed that more than 10.4% of these base pairs are involved in triplet formation, most of which play important role in maintaining long-range tertiary contacts in the three-dimensional folded structure of RNA. Apart from detection, the program also gives a quantitative estimate of the conformational deformation of detected base pairs in comparison to an ideal planar base pair. This helps us to gain insight into the extent of their structural variations and thus assists in understanding their specific role towards structural and functional diversity.

Algorithms↗
PubMed1997

A mutation at the interface between domains causes rearrangement of domains in 3-isopropylmalate dehydrogenase.

The structure of a thermostable Ala172Leu mutant, designated A172L, of 3-isopropylmalate dehydrogenase from Thermus thermophilus was determined. The crystal belongs to space group P2(1), with cell parameters a = 55.5 A, b = 88.1 A, c = 72.0 A and beta = 100.9 degrees. There is one dimer in each asymmetric unit. The final R factor is 17.8% with 69 water molecules at 2.35 A resolution. The mutation is located at the interface between domains and the C alpha trace of the mutant structure deviates from that of the native structure by as much as 1.7 A, while the structure of each domain barely changes. The mutant enzyme has a more closed conformation compared with the wild-type enzyme as a result of the replacement of Ala with Leu at residue 172. These structural variations were found independent of the crystal packing, because the structure of wild type was the same in crystals obtained in different precipitants. The hinge regions for the movement of domains are located around the active cleft of the enzyme, an observation that implies that the mobility of domains around the hinge is indispensable for the activity of the enzyme. The larger side chain at the mutated site contributed to the thermostability of the mutant protein by enhancing the local packing of side chains, and also by shifting the backbone of the opposing domain.

3-Isopropylmalate Dehydrogenase↗
PubMed1995

Molecular dynamics simulation of fungal cellulose-binding domains: differences in molecular rigidity but a preserved cellulose binding surface.

A total of 23 fungal cellulose-binding domain (CBD) sequences were aligned. Structural models of the cellulose-binding domain of an exoglucanase (CBHII) and of three endoglucanases (EGI, EGII and EGV) from Trichoderma reesei cellulases were homology modelled based on the NMR structure of the fungal cellobiohydrolase CBHI, from the same organism. The completed models and the known structure of the CBHI cellulose-binding domain were refined by molecular dynamics simulations in water. All four models were found to be very similar to the structure of the CBHI cellulose-binding domain and sequence comparison indicated that in general the three-dimensional structures of fungal cellulose-binding domains are very similar. In all the CBDs studied, two disulphide bridges apparently stabilize the polypeptide fold. From the models, and additional disulphide bridge was predicted in EGI and CBHII, and in eight further CBDs from other organisms. Three highly conserved aromatic residues on the hydrophilic side of the wedge make this surface flat. This surface is expected to make contact with the substrate. Three invariant amino acids, Gln7, Asn29 and Gln34, on this flat face are in suitable positions for hydrogen bonding with the cellulose surface. Analysis of the differences in the protein surface properties indicated that the endoglucanases tend to be more hydrophilic than the exoglucanases. The largest structural variation was found around positions 12-16. The fungal CBD sequences are discussed in relation to variations in function and pH dependence. Comparison of the modelled structures with experimental binding data for the CBHI and EGI allowed the formulation of a qualitative relationship to cellulose affinity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1986

Cardiovascular characteristics of the young with borderline hypertension.

Borderline hypertension generally describes blood pressure levels at the margins of an established disease state. Prior to adulthood, this definition becomes less clear. Juveniles with blood pressure levels at the extremes of the normal distribution may be borderline hypertensive, hypertensive, or normal. Aberrant mechanisms that progress to essential hypertension have their onset in the young. Evidence is emerging that demonstrates variation in neurogenic function in young people. Other functional and structural variations have also been described prior to adulthood. These observations are beginning to characterize young people having borderline hypertension and also those with a greater risk for progressing to essential hypertension.

Adolescent↗
PubMed1994

Isolation of Insertion Sequence ISRLdTAL1145-1 from a Rhizobium sp. (Leucaena diversifolia) and Distribution of Homologous Sequences Identifying Cross-Inoculation Group Relationships.

Insertion sequence (IS) element ISRLdTAL1145-1 from Rhizobium sp. (Leucaena diversifolia) strain TAL 1145 was entrapped in the sacB gene of the positive selection vector pUCD800 by insertional inactivation. A hybridization probe prepared from the whole 2.5-kb element was used to determine the distribution of homologous sequences in a diverse collection of 135 Rhizobium and Bradyrhizobium strains. The IS probe hybridized strongly to Southern blots of genomic DNAs from 10 rhizobial strains that nodulate both Phaseolus vulgaris (beans) and Leucaena leucocephala (leguminous trees), 1 Rhizobium sp. that nodulates Leucaena spp., 9 R. meliloti (alfalfa) strains, 4 Rhizobium spp. that nodulate Sophora chrysophylla (leguminous trees), and 1 nonnodulating bacterium associated with the nodules of Pithecellobium dulce from the Leucaena cross-inoculation group, producing distinguishing IS patterns for each strain. Hybridization analysis revealed that ISRLdTAL1145-1 was strongly homologous with and closely related to a previously isolated element, ISRm USDA1024-1 from R. meliloti, while restriction enzyme analysis found structural similarities and differences between the two IS homologs. Two internal segments of these IS elements were used to construct hybridization probes of 1.2 kb and 380 bp that delineate a structural similarity and a difference, respectively, of the two IS homologs. The internal segment probes were used to analyze the structures of homologous IS elements in other strains. Five types of structural variation in homolog IS elements were found. The predominate IS structural type naturally occurring in a strain can reasonably identify the strain's cross-inoculation group relationships. Three IS structural types were found in Rhizobium species that nodulate beans and Leucaena species, one of which included the designated type IIB strain of R. tropici (CIAT 899). Weak homology to the whole IS probe, but not with the internal segments, was found with two Bradyrhizobium japonicum strains. The taxonomic and ecological implications of the distribution of ISRLdTAL1145-1 are discussed.

Journal Article↗
PubMed1999

New methods for the characterisation of biopharmaceuticals: conjugate vaccines against Haemophilus influenzae type b.

Modern physicochemical methods allow biological pharmaceuticals, particularly those arising from recombinant DNA technology, to be characterised with a degree of precision not previously possible. These techniques, which tell us what a material is (rather than what it does) provide an approach complementary to traditional bioassays for the control of biological pharmaceuticals. As we come to understand the mechanisms by which structural variation modulates the various biological activities of a product, structure-based assays will be able to replace biological identity and potency assays, although replacement of safety tests to find trace impurities (such as endotoxin) may be more difficult.

Animal Testing Alternatives↗
PubMed2007

Syntheses, structures, spectroscopy, and chromotropism of new complexes arising from the reaction of nickel(II) nitrate with diphenyl(dipyrazolyl)methane.

The complexes [(dpdpm)Ni(2-NO3)2] (1), [(dpdpm)Ni(2-NO3)(1-NO3)(CH3CN)] (2), [(dpdpm)2Ni(1-NO3)(H2O)]NO3 (3), and [(dpdpm)2Ni(H2O)2][NO3]2 (4) (dpdpm = diphenyl(dipyrazolyl)methane, Ph2C(C3N2H3)2), have been prepared and characterized by IR and UV-vis-NIR spectroscopy and X-ray diffraction studies. X-ray studies have confirmed that complexes 1-4 all adopt variously distorted octahedral structures in the solid state, the largest distortions arising from the small bite-angle of the bidentate nitrate ligand in 1 and 2. Magnetic moment measurements indicate that these solids are paramagnetic with two unpaired electrons. The solution 1H NMR data show that the paramagnetism is maintained in solution. Absorption spectra of 1-4 show three main bands in the region of 350-1000 nm representing spin allowed (d-d) transitions from the ground state 3A2g to the excited states 3T2g, 3T1g(3F), and 3T1g(3P). A weak shoulder was also detected at about 700-800 nm in most spectra, representing spin-forbidden transitions 3A2g 1Eg. A comparison of the crystal field parameters 10Dq and B for 1-4 to the corresponding values for related complexes indicated that these parameters are fairly insensitive to structural variations within this family of complexes. The 10Dq/B ratios show greater variations, but no clear correlations are apparent between 10Dq/B and such structural features as the nature of ligator atoms (N:O ratio), the bonding mode of the nitrate ligand, or the overall charge. Complexes 1 (green) and 2 (blue) interconvert as a function of temperature (solutions and solid samples), concentration of CH3CN (solutions), or CH3CN vapor pressure (solid samples).

Acetonitriles↗
PubMed1998

Antineoplastic agents. 386. Isolation of sesterstatins 1-3 from the marine sponge Hyrtios erecta.

The Republic of Maldives' black marine sponge Hyrtios erecta has been found to contain three cancer cell-line inhibitory pentacyclic sesterterpenes designated sesterstatins 1-3 (2-4). One of the sesterterpenes, sesterstatin 2, specifically inhibited the Gram-positive opportunist Staphylococcus aureus. All three of the P-388 lymphocytic-leukemia-active (ED50 0.46 to 4.3 micrograms/mL) sesterstatins were obtained in trace quantities (3.0 x 10-7 to 5.4 x 10-7% yields) and represent structural variations on the more usual scalarin-type porifera sesterterpenes. The structures were elucidated by highfield (500 MHz) 2D NMR techniques augmented by HRMS results.

Animals↗