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PubMedDate not supplied

Architecture of native human alpha 2-macroglobulin studied by cryoelectron microscopy and three-dimensional reconstruction.

The architecture of the native human alpha 2-macroglobulin was studied by cryoelectron microscopy and image processing techniques. The lip, padlock, doughnut, and four-petaled flower views of this homotetrameric proteinase inhibitor were observed in the frozen-hydrated specimen, and a new view, termed eye view, was also characterized. The present three-dimensional reconstruction demonstrates that all these electron microscope views derive from a single three-dimensional structure. The molecule is composed of two horizontal bodies and of two oblique arches, which border a large central cavity. The polymorphism and the flexibility of the native alpha 2-macroglobulin are discussed.

Freezing↗
PubMedDate not supplied

Presentation of the SIGMA software: Software of Imagery and Graphics for Molecular Architecture.

Sigma (Software of Imagery and Graphics for Molecular Architecture) is a software package designed for visualization and exploration of three-dimensional (3D) molecular electron microscopy data. It comprises a text and two graphic modes. In the text mode, a language allows the writing of scripts for repetitive tasks. The two graphic modes are based on the multiwindow environment with a mouse as pointer. The first graphic mode is dedicated to vectorial objects and the second to pixel/voxel objects. The data imported by SIGMA have various origins such as 3D reconstruction volumes, Protein Data Bank data, or geometrical objects like spheres, cubes, or cylinders. These 3D objects are interactively rotated, translated, and rendered with SIGMA. This software, written in C language, runs on Silicon Graphics workstations using the X-Window plus Motif environment. The specific 3D routines are based on the Silicon Graphics GL library.

Animals↗
PubMedDate not supplied

Lumbricus terrestris hemoglobin--the architecture of linker chains and structural variation of the central toroid.

The extracellular giant hemoglobin from the earthworm Lumbricus terrestris was reconstructed at 14.9-A resolution from cryo-electron microscope images, using a new procedure for estimating parameters of the contrast transfer (CTF) function. In this approach, two important CTF parameters, defocus and amplitude contrast ratio, can be refined iteratively within the framework of 3D projection alignment procedure, using minimization of sign disagreement between theoretical CTF and cross-resolution curves. The 3D cryo-EM map is in overall good agreement with the recent X-ray crystallography map of Royer et al. (2000, Proc. Natl. Acad. Sci. USA 97, 7107-7111), and it reveals the local threefold arrangement of the three linker chains present within each 1/12 of the complex. The 144 globin chains and 36 linker chains within the complex are clearly visible, and the interdigitation of the 12 coiled-coil helical spokes forming the central toroidal piece is confirmed. Based on these findings, two mechanisms of the dodecameric unit assembly are proposed and termed "zigzag" and "pairwise" polymerizations. However, the detection by cryo-EM of 12 additional rod-like bodies within the toroid raises the possibility that the architecture of the toroid is more complex than previously thought or that yet unknown ligands or allosteric effectors for this oxygen carrier are present.

Animals↗
PubMed1999

The role of prestress and architecture of the cytoskeleton and deformability of cytoskeletal filaments in mechanics of adherent cells: a quantitative analysis.

Mechanical properties of adherent cells were investigated using methods of engineering mechanics. The cytoskeleton (CSK) was modeled as a filamentous network and key mechanisms and corresponding molecular structures which determine cell elastic behavior were identified. Three models of the CSK were considered: open-cell foam networks, prestressed cable nets, and a tensegrity model as a special case of the latter. For each model, the modulus of elasticity (i.e. an index of resistance to small deformation) was given as a function of mechanical and geometrical properties of CSK filaments whose values were determined from the data in the literature. Quantitative predictions for the elastic modulus were compared with data obtained previously from mechanical tests on adherent cells. The open-cell foam model yielded the elastic modulus (10(3)-10(4)Pa) which was consistent with measurements which apply a large compressive stress to the cell. This suggests that bending of CSK filaments is the key mechanism for resisting large compression. The prestressed cable net and tensegrity model yielded much lower elastic moduli (10(1)-10(2)Pa) which were consistent with values determined from equilibrium measurements at low applied stress. This suggests that CSK prestress and architecture are the primary determinants of the cell elastic response. The tensegrity model revealed the possibility that buckling of microtubules of the CSK also contributed to cell elasticity.

Cell Adhesion↗
PubMed2000

Modeling the evolution of genetic architecture: A continuum of alleles model with pairwise AxA epistasis.

A continuum of alleles model with pair-wise AxA epistasis is proposed and its transmission genetic, and variational properties are analysed. The basic idea is that genes control the values of underlying variables, which affect the genotypic value of phenotypic characters proportional to a "scaling factor". Epistasis is the influence of one gene on the average effect of another gene. In this model, epistasis is introduced as a mutational effect of one gene on the scaling factors of another gene. In accordance with empirical results, the model assumes that the average direct effect of mutations is zero, as is the average epistatic effect. The model predicts that, on average, a mutation at one locus increases the expected mutational variance of mutations at another interacting locus. The increase in mutational variance is predicted to be equal to the variance of the pair-wise epistatic effects. This result is consistent with the observation that mutant phenotypes tend to be more variable than the wildtype phenotype. Another generic result of this model is that the frequency of canalizing mutations can at most be equal to the frequency of de-canalizing mutations. Furthermore, it is predicted that the mutational variance of a character increases at least linearly with the size of the character; hence this model is scale variant. In the case of two characters it is shown that the dimensionality of the locus-specific mutational effect distribution is invariant, i.e. the rank of the mutational covariance matrix M is invariant. While in additive models the mutational covariance matrix is always and entirely invariant, the invariance in the case of epistatic models is unexpected. Epistatic interactions can change the magnitude of the mutational (co)variances at a locus and can thus influence the structure of the mutational covariance matrix. However, in the present model the dimensionality of the mutational effect distribution remains the same. A consequence of this result is that, in this model, the genetic architecture of a set of characters is always evolvable i.e. no hard constraints can evolve.

Alleles↗
PubMed2001

Gel-based fluorescence resonance energy transfer (gelFRET) analysis of nucleoprotein complex architecture.

A gel-based fluorescence resonance energy transfer (gelFRET) assay was developed for analysis of the architecture of nucleoprotein complexes. gelFRET is based on fluorescence analysis of nucleoprotein complexes separated by polyacrylamide gel electrophoresis. These complexes are separated from free components and nonspecific complexes, enabling fluorescence analysis of complexes containing all components in stoichiometric proportions. gelFRET can be used to investigate the structural organization of nucleoprotein complexes through comparison of the relative efficiencies of energy transfer from donor fluorophores linked to different positions on DNA to an acceptor fluorophore linked to a unique position on the binding protein. We have applied gelFRET to analysis of the orientation of binding by heterodimeric transcription factors. By using Fos-Jun heterodimers as a model system we have identified the structural determinants that control the orientation of heterodimer binding. gelFRET can be applied to studies of a variety of biological processes that influence the proximity of two sites within a complex, such as the assembly of transcription regulatory complexes.

Deoxyribonucleoproteins↗
PubMed2000

Quantitative assessment of angiogenesis and tumor vessel architecture by computer-assisted digital image analysis: effects of VEGF-toxin conjugate on tumor microvessel density.

Tumor growth is angiogenesis dependent. As a consequence, strategies aimed at disrupting this mechanism are heavily investigated. Several angiogenesis assays are used to directly compare the efficacy of anti-angiogenic compounds. However, objective assessment of new vascular growth has been difficult to achieve. The aim of this study was to test and develop a computer-assisted image analysis method that would give an unbiased quantification of the microvessel density. Human tumors were grown in athymic mice and tumor biopsies were taken after a weeklong treatment with VEGF-toxin conjugate. Frozen tumor sections were prepared and stained with PE-conjugated anti-CD-31 antibodies and vessels were imaged with a fluorescence microscope. Vessel density was analyzed by quantifying PE-positive pixels per recorded field. In addition, images were further processed to investigate morphological differences by an automated binarization and skeletonization protocol. This procedure allowed the computer-assisted estimation of important angiogenic parameters such as total vessel number, length, and branch points. Based on these indices, differences in the angiogenic response between control tumors and those treated with VEGF-toxin conjugate were readily detected (P < 0.007 for all parameters). More importantly, computer-generated measurements correlated well with manual microvessel counts and showed significantly less variation. Our results suggest that computer-assisted image analysis represents a rapid, objective, and alternative method for the quantitative assessment of tumor angiogenesis and vessel architecture.

Adenocarcinoma↗
PubMed2001

Water diffusion changes in Wallerian degeneration and their dependence on white matter architecture.

This study investigates water diffusion changes in Wallerian degeneration. We measured indices derived from the diffusion tensor (DT) and T2-weighted signal intensities in the descending motor pathways of patients with small chronic lacunar infarcts of the posterior limb of the internal capsule on one side. We compared these measurements in the healthy and lesioned sides at different levels in the brainstem caudal to the primary lesion. We found that secondary white matter degeneration is revealed by a large reduction in diffusion anisotropy only in regions where fibers are arranged in isolated bundles of parallel fibers, such as in the cerebral peduncle. In regions where the degenerated pathway crosses other tracts, such as in the rostral pons, paradoxically there is almost no change in diffusion anisotropy, but a significant change in the measured orientation of fibers. The trace of the diffusion tensor is moderately increased in all affected regions. This allows one to differentiate secondary and primary fiber loss where the increase in trace is considerably higher. We show that DT-MRI is more sensitive than T2-weighted MRI in detecting Wallerian degeneration. Significant diffusion abnormalities are observed over the entire trajectory of the affected pathway in each patient. This finding suggests that mapping degenerated pathways noninvasively with DT-MRI is feasible. However, the interpretation of water diffusion data is complex and requires a priori information about anatomy and architecture of the pathway under investigation. In particular, our study shows that in regions where fibers cross, existing DT-MRI-based fiber tractography algorithms may lead to erroneous conclusion about brain connectivity.

Aged↗
PubMed1995

The HMG-14/-17 chromosomal protein family: architectural elements that enhance transcription from chromatin templates.

Chromosomal proteins HMG-14 and HMG-17 enhance the transcriptional potential of chromatin when incorporated into nucleosomes during, but not after, chromatin assembly on replicating DNA. Two molecules of either HMG-14 or HMG-17 can bind to nucleosome cores, independently of the underlying DNA sequence, in a cooperative fashion to limit nucleosome mobility and stabilize the structure of the nucleosome core without stabilizing the higher order chromatin structure. By modifying the structure of nucleosomes, the proteins affect the local structure of the chromatin fiber leading to an increase in the rate of transcriptional elongation but not initiation. We suggest that HMG-14/-17 are architectural elements which assist in the assembly of an unfolded chromatin fiber thereby decreasing the repressive activity of histones and facilitating transcriptional processes.

Animals↗
PubMed1999

The host-cell architectural protein HMG I(Y) modulates binding of herpes simplex virus type 1 ICP4 to its cognate promoter.

The productive infection cycle of herpes simplex virus is controlled in part by the action of ICP4, an immediate-early gene product that acts as both an activator and repressor of transcription. ICP4 is autoregulatory, and IE-3, the gene that encodes it, contains a high-affinity binding site for the protein at its cap site. Previously, we had demonstrated that this site could be occupied by proteins found in nuclear extracts from uninfected cells. A HeLa cell cDNA expression library was screened with a DNA probe containing the IE-3 gene cap site, and clones expressing the architectural chromatin proteins HMG I and HMG Y were identified by this technique. HMG I is shown to augment binding of ICP4 to its cognate site in in vitro assays and to enhance the activity of this protein in short-term transient expression assays.

Animals↗
PubMed2000

Different architectures in the assembly of infectious bursal disease virus capsid proteins expressed in insect cells.

Infectious bursal disease virus (IBDV) capsid is formed by the processing of a large polyprotein and subsequent assembly of VPX/VP2 and VP3. To learn more about the processing of the polyprotein and factors affecting the correct assembly of the viral capsid in vitro, different constructs were made using two baculovirus transfer vectors, pFastBac and pAcYM1. Surprisingly, the expression of the capsid proteins gave rise to different types of particles in each system, as observed by electron microscopy and immunofluorescence. FastBac expression led to the production of only rigid tubular structures, similar to those described as type I in viral infection. Western blot analysis revealed that these rigid tubules are formed exclusively by VPX. These tubules revealed a hexagonal arrangement of units that are trimer clustered, similar to those observed in IBDV virions. In contrast, pAcYM1 expression led to the assembly of virus-like particles (VLPs), flexible tubules, and intermediate assembly products formed by icosahedral caps elongated in tubes, suggesting an aberrant morphogenesis. Processing of VPX to VP2 seems to be a crucial requirement for the proper morphogenesis and assembly of IBDV particles. After immunoelectron microscopy, VPX/VP2 was detected on the surface of tubules and VLPs. We also demonstrated that VP3 is found only on the inner surfaces of VLPs and caps of the tubular structures. In summary, assembly of VLPs requires the internal scaffolding of VP3, which seems to induce the closing of the tubular architecture into VLPs and, thereafter, the subsequent processing of VPX to VP2.

Animals↗
PubMed2005

ADHD: strategies to unravel its genetic architecture.

Attention deficit/hyperactivity disorder (ADHD) is a common and impairing neuropsychiatric disorder with onset at preschool age and strong persistence over time. Its validity as a psychiatric disorder has been established according to Robins and Guze criteria. Genetic factors predominate in the etiology of ADHD. This paper summarizes the current status of genetic research into ADHD, and describes eight factors that complicate research into genetically complex disorders as ADHD. These factors are that multiple genes of small main effects are involved rather than main genes, the relevant phenotype is unknown, presence of clinical heterogeneity, presence of genetic heterogeneity, gene-environment correlation, gene-environment interaction, importance of endophenotypes, and importance of developmental factors. The further unraveling of the genetic architecture of ADHD will depend to a large extent on how well these complicating factors are handled or even used.

Attention Deficit Disorder with Hyperactivity↗
PubMed1997

3D architecture of myocardial microcirculation in intact rat heart: a study with micro-CT.

The branching geometry of the coronary arterial tree may play a significant role in the observed spatial heterogeneity in myocardial perfusion. To provide more insight into this possibility we used a micro-CT scanner to image the intact rat heart and its opacified coronary arterial tree, for quantitative analysis of the coronary arterial architecture. Results show a consistent pattern of branching throughout the heart wall.

Animals↗
PubMed1990

A theoretical model of endochondral ossification and bone architectural construction in long bone ontogeny.

The role of mechanical stresses in the formation of endochondral ossification patterns and the construction of basic bone architecture in human long bones is investigated using a three-dimensional generalized model of long bone development. The distribution of mechanical stress which is created in developing bones as a result of intermittent mechanical loading is calculated using a computer model that mathematically represents the bone's geometry, material properties and loading conditions. The process of endochondral ossification is simulated by iteratively converting cartilaginous regions of the computer model to bone, based on the calculated intermittent hydrostatic and shear stress distributions. Once local regions of mineralized bone have formed, these regions are remodeled according to an algorithm which relates bone density to a mechanical stress stimulus. The results simulated the correct sequence of the appearance of morphological structures which are common to long bones in the human appendicular skeleton. These developmental structures include the site of the first endochondral bone and the secondary ossification center and the tubular nature of long bones. Our results suggest that mechanical loading histories may influence bone morphogenesis beginning from the early stages of endochondral ossification and continuing throughout life. The stress-based algorithms may be part of the 'rules of construction' or 'developmental constraints' which guide limb ontogeny.

Algorithms↗
PubMed1992

Stereo architecture of the connective tissue cores of the lingual papillae in the treeshrew (Tupaia glis).

The stereo architecture of the lingual connective tissue cores (CTC) in the treeshrew (Tupaia glis) (which has the primitive characteristics of primates) was observed by scanning electron microscopy, and compared to that of other animal orders. The tongue of the treeshrew has three vallate papillae which are situated in the posterior part of the tongue, while some macaques have several vallate papillae. Among numerous filiform papillae, fungiform papillae are sporadically distributed. A filiform papilla consists of a bundle of several slender spine-like processes arranged in a circle at the basal margin. After removal of the epithelium, the CTC of the filiform papilla looks like a human hand raised with the palm facing towards the tongue tip. The fungiform CTC in the threeshrew is columnar in shape (rather similar to that of Insectivora and Rodentia) and at the top there are several round depressions for taste buds. In the treeshrew several large rod-shaped processes are derived from the postero-lateral margin of the tongue, as in Carnivora (dogs and cats), where foliate papillae are located in many other animal species. The treeshrew has numerous characteristics similar to those of the crab-eating macaque (Primates), but at the same time it has some characteristics similar to those of Insectivora, Rodentia, Carnivora and Artiodactyla.

Animals↗
PubMed1990

Nuclear architecture of human pachytene spermatocytes: quantitative analysis of associations between nucleolar and XY bivalents.

Nucleolar association and heterochromatin coalescence have both been invoked as mechanisms involved in the origin of chromosomal associations between nucleolar bivalents themselves, as well as between these bivalents and the XY pair, during meiotic prophase in human spermatocytes. However, these mechanisms do not satisfactorily explain how associating bivalents meet each other within the nuclear space. To elucidate this problem, we have characterized different types of nucleolar-nucleolar and nucleolar-XY bivalent associations, and their frequencies, in light and electron microscope serial sections of spermatocyte nuclei. In the pachytene nucleus, nucleolar bivalent associations were found to involve only one nucleolar sphere of RNP granules connected through a fibrillar center to a chromatin mass composed of two, or more, nucleolar-bivalent short arms. Structural relationships between these elements were examined using 3D computer models of various nucleolar associations. XY and nucleolar bivalents were usually located towards the nuclear periphery associated with the inner face of the nuclear envelope. Some nucleolar bivalents, whether single or associated appeared beside or over XY chromatin. When nucleolar-bivalent short arms (BK) were found over nucleolar or over XY chromatin, their telomeres were unattached to the nuclear envelope and the corresponding synaptonemal complexes were not observed. Ninety nucleoli were found in sixty pachytene nuclei. Thirty six percent of these nucleoli were bound to associated BKs and the remaining 64% to single BKs. Over 40% of individual spermatocytes showed at least one cluster of associated BKs and about 20% presented single or multiple BKs associated with the XY pair. The frequencies of random BK associations, over the total or restricted areas of the nuclear envelope, were calculated according to a probabilistic nuclear model. A correspondence was found in comparing the observed frequencies of associated BKs with those calculated on the basis of bouquet formation. Such an analysis strongly suggests that the occurrence of associations between nucleolar bivalents may arise at random within the bouquet. Thus, the architecture of the meiocyte nucleus, particularly the organization of the bouquet, may be the primary mechanism by which nucleolar bivalents meet each other and, consequently, become associated either through common nucleolus formation or by heterochromatin coalescence.

Cell Nucleolus↗
PubMedDate not supplied

Arteriohepatic dysplasia (Alagille's syndrome): unusual hepatic architecture and function.

BACKGROUND: Alagille's syndrome, also called arteriohepatic dysplasia, is a congenital anomaly consisting of hepatic, ocular, skeletal, and cardiac anomalies. The abdominal imaging findings were reviewed in eight patients with biopsy-proven Alagille's syndrome. One patient also had coexistent hepatocellular carcinoma. METHODS: Seven right upper quadrant sonograms, six hepatic CT studies, five hepatobiliary imaging studies, two hepatic MRI examinations, and two sulphur colloid liver spleen radionuclide studies were reviewed. RESULTS: The most striking abnormality was gross distortion of hepatic architecture. Five patients (63%) had marked external hepatic contour abnormalities, usually with either the entire liver or lobe having a predominately spherical shape. The portal vein was displaced by the spherical parenchymal component in four cases. Three other patients demonstrated marked hepatomegaly with no external contour abnormality. Hepatobiliary imaging studies demonstrated markedly prolonged excretion of the radiopharmaceutical in three of four patients examined. CONCLUSIONS: A diagnosis of Alagile's syndrome is suggested when a large, deformed and somewhat spherical liver is encountered, especially when hepatobiliary imaging studies demonstrate delayed excretion of radiopharmaceutical.

Adolescent↗
PubMed1983

Architecture of the basal region of the subcommissural organ in the brush-tailed possum (Trichosurus vulpecula).

The architecture of the basal region of the subcommissural organ (SCO) and the subjacent neuropil was studied in the brush-tailed possum, Trichosurus vulpecula (Marsupialia). Several structural features suggest that the basal mode of SCO-secretion may be as prominent as the well-established apical secretion. Some of the features that speak in favour of basal secretion are: (1) the existence of deep processes of secretion-laden SCO cells which reach and surround the capillaries in the hypendyma and the subjacent neuropil; (2) the presence of perivascular spaces, some of which may contain a material that resembles the secretory product of the SCO; (3) positive staining by means of paraldehyde-fuchsin of secretory material in the pericapillary zone of vessels in the hypendyma and its corresponding neuropil; (4) presence of labyrinths of the basal lamina of capillaries and associated nerves. The presence of nerve and other cell processes adjacent to the perivascular space, labyrinths and capillary wall suggests discharge into the capillaries of material such as the basal secretory product of the SCO. However, the absence of fenestrae in capillary endothelium in the context of the foregoing observations is enigmatic and speaks against the possibility of a conventional release of secretion. Nevertheless, it is possible that a secretory product containing particles of low molecular weight combined with some specific features of the local capillary endothelium, which facilitate transport, may be critical factors making possible transfer of such product(s) from the SCO to the capillaries.

Animals↗