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PubMed2006

Energy balance alters dunning R3327-H prostate tumor architecture, androgen receptor expression, and nuclear morphometry in rats.

BACKGROUND: We hypothesize that diet or energy restriction may alter prostate tumor architecture and nuclear morphometry in a manner predictive of indolent biology. METHODS: Adult male rats bearing the Dunning R3327-H tumor were provided free-access to the AIN76 diet or 30% diet/energy restriction for 16 weeks. Tumor tissue was harvested and stained for biomarker evaluation by quantitative digital image analysis. RESULTS: Compared to controls, tumors from restricted rats showed a contracted stromal compartment with an increased epithelial/glandular area, and a greater number of smaller and more homogeneous glands. In parallel, the nuclei in tumors harvested from diet-restricted rats were smaller in size, showed a lower proportion with androgen receptor (AR) staining, and reduced intensity of AR staining. CONCLUSIONS: Our observations support the hypothesis that diet/energy restriction alters prostate tumor architecture, AR expression, and nuclear morphology consistent with a more differentiated and less aggressive phenotype.

Animals↗
PubMed2003

A novel approach to the recognition of protein architecture from sequence using Fourier analysis and neural networks.

A novel method is presented for the prediction of protein architecture from sequence using neural networks. The method involves the preprocessing of protein sequence data by numerically encoding it and then applying a Fourier transform. The encoded and transformed data are then used to train a neural network to recognize a number of different protein architectures. The method proved significantly better than comparable alternative strategies such as percentage dipeptide frequency, but is still limited by the size of the data set and the input demands of a neural network. Its main potential is as a complement to existing fold recognition techniques, with its ability to identify global symmetries within protein structures its greatest strength.

Algorithms↗
PubMed2004

Three acidic residues are at the active site of a beta-propeller architecture in glycoside hydrolase families 32, 43, 62, and 68.

Multiple-sequence alignment of glycoside hydrolase (GH) families 32, 43, 62, and 68 revealed three conserved blocks, each containing an acidic residue at an equivalent position in all the enzymes. A detailed analysis of the site-directed mutations so far performed on invertases (GH32), arabinanases (GH43), and bacterial fructosyltransferases (GH68) indicated a direct implication of the conserved residues Asp/Glu (block I), Asp (block II), and Glu (block III) in substrate binding and hydrolysis. These residues are close in space in the 5-bladed beta-propeller fold determined for Cellvibrio japonicus alpha-L-arabinanase Arb43A [Nurizzo et al., Nat Struct Biol 2002;9:665-668] and Bacillus subtilis endo-1,5-alpha-L-arabinanase. A sequence-structure compatibility search using 3D-PSSM, mGenTHREADER, INBGU, and SAM-T02 programs predicted indistinctly the 5-bladed beta-propeller fold of Arb43A and the 6-bladed beta-propeller fold of sialidase/neuraminidase (GH33, GH34, and GH83) as the most reliable topologies for GH families 32, 62, and 68. We conclude that the identified acidic residues are located at the active site of a beta-propeller architecture in GH32, GH43, GH62, and GH68, operating with a canonical reaction mechanism of either inversion (GH43 and likely GH62) or retention (GH32 and GH68) of the anomeric configuration. Also, we propose that the beta-propeller architecture accommodates distinct binding sites for the acceptor saccharide in glycosyl transfer reaction.

Amino Acid Sequence↗
PubMed1992

Architectural features of pre-mRNA introns in the fission yeast Schizosaccharomyces pombe.

The architectural features of 73 introns found in 36 genes of the fission yeast Schizosaccharomyces pombe have been compiled and tabulated. The introns from S. pombe can be grouped into two size classes. Intron features are discussed in comparison to intron features of Saccharomyces cerevisiae and other eukaryotes. The results indicate that S. pombe displays quite different architectural features than the budding yeast S. cerevisiae. However, particularly in the 3' region, S. pombe introns also appear to differ from mammalian introns.

Base Sequence↗
PubMed1997

Active site architecture of polymorphic forms of human glutathione S-transferase P1-1 accounts for their enantioselectivity and disparate activity in the glutathione conjugation of 7beta,8alpha-dihydroxy-9alpha,10alpha-ox y-7,8,9,10-tetrahydrobenzo(a)pyrene.

In this study, we demonstrate that the active site architecture of the human glutathione (GSH) S-transferase Pi (GSTP1-1) accounts for its enantioselectivity in the GSH conjugation of 7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9, 10-tetrahydrobenzo(a) pyrene (anti-BPDE), the ultimate carcinogen of benzo(a)pyrene. Furthermore, we report that the two polymorphic forms of human GSTP1-1, differing in their primary structure by a single amino acid in position 104, have disparate activity toward (+)-anti-BPDE, which can also be rationalized in terms of their active site structures. When concentration of (+)-anti-BPDE, which among four BPDE isomers is the most potent carcinogen, was varied and GSH concentration was kept constant at 2 mM (saturating concentration), both forms of hGSTP1-1 [hGSTP1-1(V104) and hGSTP1-1(I104)] obeyed Michaelis-Menten kinetics. The V(max) of GSH conjugation of (+)-anti-BPDE was approximately 3.4-fold higher for hGSTP1-1(V104) than for hGSTP1-1(I104). Adherence to Michaelis-Menten kinetics was also observed for both isoforms when (-)-anti-BPDE, which is a weak carcinogen, was used as the variable substrate. However, (-)-anti-BPDE was a relatively poor substrate for both isoforms as compared with (+)-anti-BPDE. Moreover, there were no significant differences between hGSTP1-1(V104) and hGSTP1-1(I104) in either V(max) or K(m) for (-)-anti-BPDE. The mechanism of differences in kinetic properties and enantioselectivity of hGSTP1-1 variants toward anti-BPDE was investigated by modeling of the two proteins with conjugation product molecules in their active sites. Molecular modeling studies revealed that the differences in catalytic properties of hGSTP1-1 variants as well as the enantioselectivity of hGSTP1-1 in the GSH conjugation of anti-BPDE can be rationalized in terms of the architecture of their active sites. Our results suggest that the population polymorphism of hGSTP1-1 variants with disparate enzyme activities may, at least in part, account for the differential susceptibility of individuals to carcinogens such as anti-BPDE and possibly other similar carcinogens.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1999

Communicative competence and the architecture of the mind/brain.

Cognitive pragmatics is concerned with the mental processes involved in intentional communication. I discuss a few issues that may help clarify the relationship between this area and the broader cognitive science and the contribution that they give, or might give, to each other. Rather than dwelling on the many technicalities of the various theories of communication that have been advanced, I focus on the different conceptions of the nature and the architecture of the mind/brain that underlie them. My aims are, first, to introduce and defend mentalist views of communication in general; second, to defend one such view, namely that communication is a cognitive competence, that is, a faculty, and the underlying idea that the architecture of the mind/brain is domain-specific; and, third, to review the (scarce) neuropsychological evidence that bears on these issues.

Brain↗
PubMed1998

Ionic control of chromosome architecture in living and permeabilized cells.

Studies with isolated chromatin show that higher order chromosome architecture can be regulated by ionic conditions; however, the physiological relevance of these findings remains unknown. In the present study, chromosome architecture was analyzed in situ in living and detergent-extracted cells exposed to different ionic conditions. In intact mitotic endothelial cells, chromosomes instantly unfolded as detected by phase contrast microscopy when the salt concentration in the culture medium was increased from 110 to 410 mM NaCl or from 0 to 65 mM MgCl2. When the ions were removed and the preexisting culture conditions were restored, chromosomes refolded into their original shapes and subsequently underwent mitotic division. Similar reversible effects were observed on nucleolar structure in living interphase cells as well as on mitotic chromosomes exposed to high salt after cell membranes were removed by treatment with Triton X-100. This permeabilized mitotic cell model was then used to identify proteins that remained tightly associated with chromatin during the ion-driven chromosome unfolding-refolding cycle and which therefore could be important for maintenance of chromosome structure. Under these conditions in which disassembled chromosomes retained their ability to fully recondense, more than 95% of Topoisomerase I was extracted whereas approximately 25% of Topoisomerase IIalpha and 50% of Histone H1 remained tightly associated with chromatin. These data demonstrate the sensitivity of chromosome structure to variations in ionic concentration in situ and suggest that there are at least two distinct pools of Histone H1 and Topoisomerase IIalpha associated with chromatin during mitosis, one of which may be required for chromosome compaction.

Animals↗
PubMed2000

Role of Surface Molecular Architecture and Energetics of Hydrogen Bonding Sites in Adsorption of Polymers and Surfactants.

Hydrogen bonding is generally thought to be an ubiquitous adsorption mechanism, which often foils selective adsorption schemes. Through investigation of hydrogen bonding energy and its dependence on surface molecular architecture, it may be possible to develop new methodologies to control the adsorption of surfactants and polymeric flocculants, depressants, and dispersants used in particulate processing industries. A model system using Stöber silica spheres and polyethylene oxide, a polymer known for its ability to form hydrogen bonds, was examined. The effect of two different surface treatments of the silica particles, calcination and rehydroxylation, upon the adsorption of two polymer molecular weights was studied. The adsorption behavior was then linked to the respective surface structures via characterization of the surfaces using FTIR, NMR, and Raman techniques. In this paper role of hydrogen bonding sites and surface architecture on adsorption is discussed. Copyright 2000 Academic Press.

Journal Article↗
PubMed1996

The architecture of the heat-inducible Drosophila hsp27 promoter in nuclei.

Transcriptional activation of the Drosophila hsp27 gene in response to heat shock critically relies on binding sites for heat shock factor (HSF) about 300 bp upstream of the transcription start site. In contrast to the well-characterised heat-inducible hsp70 and hsp26 promoters, no other transcription factor binding sites have been identified closer to the TATA box. In order to understand the structural requirements for activation from a distance we studied the protein-DNA interactions at the hsp27 promoter in Drosophila embryos and tissue culture cells before and after heat induction. Genomic footprinting with nucleases and a chemical probe, the 1,10-phenanthroline cuprous complex (OP-Cu), suggests that the DNA between the TATA box and the heat shock elements (HSEs) is constitutively organised by a positioned nucleosome, effectively shortening the distance between the distal HSEs and the TATA box. Protection of the TATA element from nuclease attack and the OP-Cu reactivity pattern around the start site of transcription is consistent with the constitutive presence of TFIID and the "poised polymerase", a transcription machinery blocked in an early phase of elongation. The general transcription factors at the TATA box and the positioned nucleosome are separated by a stable structure, presumably a protein bound to a palindromic sequence. These constitutive features define the "preset" architecture of the promoter within which the induced binding of HSF in vivo is observed. Our study highlights the importance of positioned nucleosomes as architectural elements within promoters and identifies a new regulatory sequence that may function either to direct a nucleosome boundary or to mediate signals of distant activator proteins.

Animals↗
PubMed1999

Molecular architecture of the rod domain of the Dictyostelium gelation factor (ABP120).

The Dictyostelium discoideum gelation factor is a two-chain actin-cross-linking protein that, in addition to an N-terminal actin-binding domain, has a rod domain constructed from six tandem repeats of a 100-residue motif that has an immunoglobulin fold. To define the architecture of the rod domain of gelation factor, we have expressed in E. coli a series of constructs corresponding to different numbers of gelation factor rod repeats and have characterised them by chemical crosslinking, ultracentrifugation, column chromatography, matrix-assisted laser desorption ionisation (MALDI) mass spectrometry and NMR spectroscopy. Fragments corresponding to repeats 1-6 and 5-6 dimerise, whereas repeats 1-5 and single repeats 3 and 4 are monomeric. Repeat 6 interacts weakly and was present as monomer and dimer when analysed by analytical ultracentrifugation. Proteolytic digestion of rod5-6 resulted in the generation of two polypeptides that roughly corresponded to rod5 and part of rod6. None of these polypeptides formed dimers after chemical crosslinking. Stable dimerisation therefore appears to require repeats 5 and 6. Based on these data a model of gelation factor architecture is presented. We suggest an arrangement of the chains where only the carboxy-terminal repeats interact as was observed for filamin/ABP280, the mammalian homologue of gelation factor.

Animals↗
PubMed2000

Liquid crystalline ordering of procollagen as a determinant of three-dimensional extracellular matrix architecture.

The precise molecular mechanisms that determine the three-dimensional architectures of tissues remain largely unknown. Within tissues rich in extracellular matrix, collagen fibrils are frequently arranged in a tissue-specific manner, as in certain liquid crystals. For example, the continuous twist between fibrils in compact bone osteons resembles a cholesteric mesophase, while in tendon, the regular, planar undulation, or "crimp", is akin to a precholesteric mesophase. Such analogies suggest that liquid crystalline organisation plays a role in the determination of tissue form, but it is hard to see how insoluble fibrils could spontaneously and specifically rearrange in this way. Collagen molecules, in dilute acid solution, are known to form nematic, precholesteric and cholesteric phases, but the relevance to physiological assembly mechanisms is unclear. In vivo, fibrillar collagens are synthesised in soluble precursor form, procollagens, with terminal propeptide extensions. Here, we show, by polarized light microscopy of highly concentrated (5-30 mg/ml) viscous drops, that procollagen molecules in physiological buffer conditions can also develop long-range nematic and precholesteric liquid crystalline ordering extending over 100 microm(2) domains, while remaining in true solution. These observations suggest the novel concept that supra-fibrillar tissue architecture is determined by the ability of soluble precursor molecules to form liquid crystalline arrays, prior to fibril assembly.

Animals↗
PubMed2000

Electron microscopy and subunit-subunit interaction studies reveal a first architecture of COP9 signalosome.

The COP9 signalosome is involved in signal transduction, whereas the 26 S proteasome lid is a regulatory subcomplex of the 26 S proteasome responsible for degradation of ubiquitinated proteins. COP9 signalosome and lid possess significant sequence homologies among their eight core subunits and are likely derived from a common ancestor. Surprisingly, from our two-dimensional electron microscopy data, a common architectural plan for the two complexes could not be deduced. None-the-less, the two particles have structural features in common. Both COP9 signalosome and lid lack any symmetry in subunit arrangement and exhibit a central groove, possibly qualified for scaffolding functions.Filter-binding assays with recombinant COP9 signalosome components revealed a multitude of subunit-subunit interactions, supporting the asymmetrical appearance of the complex in electron microscopy. On the basis of two-dimensional images and subunit interaction studies, a first architectural model of COP9 signalosome was created. The fact that four distinct classes of particle views were identified and that only 50 % of the selected particles could be classified indicates a high degree of heterogeneity in electron microscopic images. Different orientations with respect to the viewing axis and conformational variety, presumably due to different grades of phosphorylation, are possible reasons for the heterogeneous appearance of the complex. Our biochemical data show that recombinant COP9 signalosome subunits 2 and 7 are phosphorylated by the associated kinase activity. The modification of COP9 signalosome subunit 2 might be essential for c-Jun phosphorylation. Dephosphorylation does not inactivate the associated kinase activity. Although substrate phosphorylation by COP9 signalosome is significantly decreased by lambda protein phosphatase treatment, "autophosphorylation" is increased.

COP9 Signalosome Complex↗
PubMed2001

A double chain reversal loop and two diagonal loops define the architecture of a unimolecular DNA quadruplex containing a pair of stacked G(syn)-G(syn)-G(anti)-G(anti) tetrads flanked by a G-(T-T) Triad and a T-T-T triple.

The architecture of G-G-G-G tetrad-aligned DNA quadruplexes in monovalent cation solution is dependent on the directionality of the four strands, which in turn are defined by loop connectivities and the guanine syn/anti distribution along individual strands and within individual G-G-G-G tetrads. The smallest unimolecular G-quadruplex belongs to the d(G2NnG2NnG2NnG2) family, which has the potential to form two stacked G-tetrads linked by Nn loop connectivities. Previous studies have focused on the thrombin-binding DNA aptamer d(G2T2G2TGTG2T2G2), where Nn was T2 for the first and third connecting loops and TGT for the middle connecting loop. This DNA aptamer in K(+) cation solution forms a unimolecular G-quadruplex stabilized by two stacked G(syn)-G(anti)-G(syn)-G(anti) tetrads, adjacent strands which are antiparallel to each other and edge-wise connecting T2, TGT and T2 loops. We now report on the NMR-based solution structure of the d(G2T4G2CAG2GT4G2T) sequence, which differs from the thrombin-binding DNA aptamer sequence in having longer first (T4) and third (GT4) loops and a shorter (CA) middle loop. This d(G2T4G2CAG2GT4G2T) sequence in Na(+) cation solution forms a unimolecular G-quadruplex stabilized by two stacked G(syn)-G(syn)-G(anti)-G(anti) tetrads, adjacent strands which have one parallel and one antiparallel neighbors and distinct non-edge-wise loop connectivities. Specifically, the longer first (T4) and third (GT4) loops are of the diagonal type while the shorter middle loop is of the double chain reversal type. In addition, the pair of stacked G-G-G-G tetrads are flanked on one side by a G-(T-T) triad and on the other side by a T-T-T triple. The distinct differences in strand directionalities, loop connectivities and syn/anti distribution within G-G-G-G tetrads between the thrombin-binding DNA aptamer d(G2T2G2TGTG2T2G2) quadruplex reported previously, and the d(G2T4G2CAG2GT4G2T) quadruplex reported here, reinforces the polymorphic nature of higher-order DNA architectures. Further, these two small unimolecular G-quadruplexes, which are distinct from each other and from parallel-stranded G-quadruplexes, provide novel targets for ligand recognition. Our results demonstrate that the double chain reversal loop connectivity identified previously by our laboratory within the Tetrahymena telomere d(T2G4)4 quadruplex, is a robust folding topology, since it has now also been observed within the d(G2T4G2CAG2GT4G2T) quadruplex. The identification of a G-(T-T) triad and a T-T-T triple, expands on the available recognition alignments for base triads and triples.

Aptamers, Nucleotide↗
PubMedDate not supplied

Cytoskeleton architecture of C6 rat glioma cell subclones differing in intermediate filament protein expression.

Whole-mount electron microscopy was used in conjunction with immunogold labeling to characterize the cytoskeleton architecture of C6 rat glioma cell subclones. These subclones differ in intermediate filament (IF) protein composition and either contain vimentin (subclone C6D8) or do not express any of the known cytoplasmic IF proteins (subclone C6D10) (Röser et al., 1991). In C6D8 cells short thin (3 nm) connecting filaments frequently linked vimentin to actin filaments and, in addition, connected vimentin filaments to each other. Occasionally, direct contacts were noticed between actin and vimentin filaments. Thin connecting filaments were present at a significantly higher number in IF-deficient C6D10 cells, forming a dense cytoplasmic network in conjunction with actin filament bundles as the dominating structure. The data indicate that thin connecting filaments are present in C6 cells independent of the expression of cytoplasmic IF proteins. They suggest that structural linkages between vimentin and actin filaments mediated by thin connecting filaments could play a major role in determining the cytoskeleton architecture of these cells.

Actins↗
PubMed1996

Molecular and Supramolecular Architecture of the Salmo gairdneri Proteinaceous Eggshell during Development

A detailed developmental study of eggshell architecture of the fish Salmo gairdneri (rainbow trout) was performed using transmission and scanning electron microscopy. Thioglycollic acid treatment and freeze-fracturing reveal that fibrils ca. 5-10 nm in diameter constitute each lamella of the helicoidal eggshell. Freeze-fracturing also permits a direct visualization of the helicoidal architecture. Laser-Raman studies of the eggshell indicate abundant antiparallel beta-pleated-sheet conformation in the eggshell proteins of S. gairdneri during all developmental stages. Apparently, this conformation dictates formation of the helicoidal structure. Disulfide bonds, together with isopeptide bonds, cross-link S. gairdneri eggshell proteins throughout development.

Journal Article↗
PubMed1997

Automated electron microscope tomography of frozen-hydrated chromatin: the irregular three-dimensional zigzag architecture persists in compact, isolated fibers.

The potential of electron microscope tomography as a tool for obtaining three-dimensional (3D) information about large macromolecular assemblies is greatly extended by automation of data collection. With the implementation of automated control of tilting, focusing, and digital image recording described here, tilt series of frozen-hydrated specimens can be collected with the requisite low dose. Long chromatin fibers were prepared in 90 mM monovalent ions to maintain a fully compact conformation, and after vitrification were completely contained within the ice layer. Tilt series of this material were recorded at 5 degrees tilt increments between +60 degrees and -60 degrees, with a cumulative dose of approximately 35 e-/A2 for the series. This extremely low dose data was successfully aligned, then reconstructed by weighted backprojection. The underlying architecture of the fibers is an irregular 3D zigzag of interconnected nucleosomes, with the linker DNA between successive nucleosomes in a largely extended conformation. The visualization of this structural motif within long, frozen-hydrated chromatin fibers at relatively high salt extends our previous studies on small fragments at low ionic strength and is in agreement with the observation of this architecture in chromatin fibers in situ in sectioned nuclei.

Animals↗
PubMed2002

Changes in the microvascular architecture of colorectal liver metastases following the administration of SMANCS/lipiodol.

BACKGROUND: Liver metastases are the major cause of death for patients with colorectal cancer. Surgical resection is at present the only curative option. Styrene maleic acid neocarzinostatin [SMANCS/Lipiodol (S/L)] targets the unique vascular architecture of tumor blood vessels, which are hyperpermeable and lack a well-developed lymphatic system. Here we report changes in the microvascular architecture of liver metastases by scanning electron microscopy (SEM) following the administration of S/L. MATERIALS AND METHODS: Liver metastases were induced by the intrasplenic injection of dimethylhydrazine induced colon cancer cells in mice. In this model tumor angiogenesis occurs at day 10, while exponential tumor growth occurs at day 16. Changes in the tumor microvasculature were observed at 3 weeks following treatment with S/L at these time points by SEM of corrosion casts. RESULTS: Tumors treated with S/L at day 10 appear similar to day 10 controls. Tumor vessels, 50 +/- 18 microm in diameter, are easily identified from hepatic vessels. Within the hepatic sinusoids are avascular spaces, 144 +/- 60 microm in diameter, which correspond to tumor cell aggregates at the initial stages of growth. Similarly, day 16 treated tumors appear comparable to day 16 controls. These vessels are narrower (84 +/- 32 microm vs. 150 +/- 70 microm) than their control counterparts. This is in contrast to vessels (216 +/- 36 microm in diameter) of a complex nature at 3 weeks. CONCLUSIONS: S/L exerts a marked and immediate effect on the tumor microvessels at both the angiogenic and the exponential phases of tumor growth. This agent is effective at the microvascular level during inhibition of metastatic growth.

Animals↗
PubMed2003

Self-organized criticality and emergent oscillations in models of termite architecture with crowding.

The termite architecture model of O'Toole et'al. (1999) is extended to incorporate arbitrary halting time-scales. It is shown that this also means that the assumption of synchronous building must be relaxed. Numerical simulations show that ordered nest architecture emerges under a wide range of time-scales but also that there is an optimal region of halting times. This optimal region is explained by the emergence of synchronized periods of termite activity. The correlation length of the building distribution is shown to diverge providing strong evidence that the model is self-organized critical.

Animals↗