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At least 1,243 records · Page 69Linked to original sources
PubMed2002

New space warping method for the simulation of large-scale macromolecular conformational changes.

A space warping method, facilitating the modeling of large-scale conformational changes in mesoscopic systems, is presented. The method uses a set of "global (or collective) coordinates" that capture overall behavior, in conjunction with the set of atomic coordinates. Application of the space warping method to energy minimization is discussed. Several simulations where the method is used to determine the energy minimizing structures of simple central force systems are analyzed. Comparing the results and behavior of the space warping method to simulations involving atomic coordinates only, it is found that the space warping method scales better with system size and also finds lower minima when the potential energy surface has multiple minima. It is shown that the transformation of [Ala16]+ in vacuo from linear to globular is captured efficiently using the space warping method.

Biopolymers↗
PubMed1991

Transforming growth factor-beta 1 stimulates synthesis of proteoglycan aggregates in calf articular cartilage organ cultures.

Previous work showed that transforming growth factor-beta 1 (TGF-beta 1), added alone to bovine cartilage organ cultures, stimulated [35S]sulfate incorporation into macromolecular material but did not investigate the fidelity of the stimulated system to maintain synthesis of cartilage-type proteoglycans. This paper provides evidence that chondrocytes synthesize the appropriate proteoglycan matrix under TGF-beta 1 stimulation: (i) there is a coordinated increase in hyaluronic acid and proteoglycan monomer synthesis, (ii) link-stable proteoglycan aggregates are assembled, (ii) the hybrid chondroitin sulfate/keratan sulfate monomeric species is synthesized, and (iv) there is an increase in protein core synthesis. Some variation in glycosylation patterns was observed when proteoglycans synthesized under TGF-beta 1 stimulation were compared to those synthesized under basal conditions. Thus comparing TGF-beta 1 to basal samples respectively, the monomers were larger (Kav on Sepharose CL-2B = 0.29 vs 0.41), the chondroitin sulfate chains were longer by approximately 3.5 kDa, the percentage of total glycosaminoglycan in keratan sulfate increased slightly from approximately 4% (basal) to approximately 6%, and the unsulfated disaccharide decreased from 28% (basal) to 12%. All of these variations are in the direction of a more anionic proteoglycan. Since the ability of proteoglycans to confer resiliency to the cartilage matrix is directly related to their anionic nature, these changes would presumably have a beneficial effect on tissue function.

Animals↗
PubMed1993

Inhibition of the active lymph pump in rat mesenteric lymphatics by hydrogen peroxide.

The lymphatic system plays an important role in the regulation of fluid and macromolecular exchange. It is a key "safety factor" against the formation of gross edema. Spontaneous contractions in collecting lymphatics of the rat intestine are necessary for the normal transportation of lymph. Hydrogen peroxide is one of the compounds released in inflammation. Therefore, the effects of H2O2 on the pumping activity of spontaneously contracting lymphatics were evaluated in the anesthetized rat (n = 16). Diameter oscillations of the mesenteric collecting lymphatics were monitored before and after the application of H2O2 (4 and 37 microM). The activity of the lymph pump was evaluated using: contraction frequency (F), stroke volume (SV), ejection fraction (EF), and lymph pump flow (LPF). These parameters were determined from the lymphatic diameter tracings. The following changes in lymphatic activity were seen after a 20 minute exposure to 37 microM H2O2: 1) F declined 85%, from 11.6 +/- 1.5 to 1.9 +/- 1.9 cpm. 2) SV fell over 93%. 3) EF decreased 93%, from 0.57 +/- .07 to 0.05 +/- .04. 4) LPF fell dramatically (> 95%) from 41.5 +/- 10.5 to 2.6 +/- 2.5 nl/min. In conclusion, H2O2 produced an intense inhibition of the active lymph pump and it is possible that the inhibition of the active pump contributes to the edema which occurs during inflammation.

Animals↗
PubMed2005

Linking experimental results, biological networks and sequence analysis methods using Ontologies and Generalised Data Structures.

The structure of a closely integrated data warehouse is described that is designed to link different types and varying numbers of biological networks, sequence analysis methods and experimental results such as those coming from microarrays. The data schema is inspired by a combination of graph based methods and generalised data structures and makes use of ontologies and meta-data. The core idea is to consider and store biological networks as graphs, and to use generalised data structures (GDS) for the storage of further relevant information. This is possible because many biological networks can be stored as graphs: protein interactions, signal transduction networks, metabolic pathways, gene regulatory networks etc. Nodes in biological graphs represent entities such as promoters, proteins, genes and transcripts whereas the edges of such graphs specify how the nodes are related. The semantics of the nodes and edges are defined using ontologies of node and relation types. Besides generic attributes that most biological entities possess (name, attribute description), further information is stored using generalised data structures. By directly linking to underlying sequences (exons, introns, promoters, amino acid sequences) in a systematic way, close interoperability to sequence analysis methods can be achieved. This approach allows us to store, query and update a wide variety of biological information in a way that is semantically compact without requiring changes at the database schema level when new kinds of biological information is added. We describe how this datawarehouse is being implemented by extending the text-mining framework ONDEX to link, support and complement different bioinformatics applications and research activities such as microarray analysis, sequence analysis and modelling/simulation of biological systems. The system is developed under the GPL license and can be downloaded from http://sourceforge.net/projects/ondex/

Algorithms↗
PubMed2002

Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel.

Sympathetic nervous system (SNS) regulation of cardiac action potential duration (APD) is mediated by beta adrenergic receptor (betaAR) activation, which increases the slow outward potassium ion current (IKS). Mutations in two human I(KS) channel subunits, hKCNQ1 and hKCNE1, prolong APD and cause inherited cardiac arrhythmias known as LQTS (long QT syndrome). We show that betaAR modulation of I(KS) requires targeting of adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) and protein phosphatase 1 (PP1) to hKCNQ1 through the targeting protein yotiao. Yotiao binds to hKCNQ1 by a leucine zipper motif, which is disrupted by an LQTS mutation (hKCNQ1-G589D). Identification of the hKCNQ1 macromolecular complex provides a mechanism for SNS modulation of cardiac APD through IKS.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

New trends in macromolecular X-ray crystallography.

Advances in experimental and computational techniques have reaffirmed the role of protein X-ray crystallography as one of the primary providers of structural information both to enhance our fundamental understanding of biological systems and also to assist the design and optimization of important therapeutics. Today, the most important challenge facing macromolecular X-ray crystallography is the need to grow suitable crystals of a given protein. Once this has been accomplished, most often the question is not whether the structure will be solved but rather how fast this will be done. A dramatic example of this is the crystal structure of cytochrome c oxidase. The search for crystallization conditions took about 15 years and then the structure was solved in about one year.

Crystallography, X-Ray↗
PubMed2005

Essential properties of drug-targeting delivery systems.

How, if at all, can drug delivery help to create ideal drugs? After four decades of trying, an effective site-specific drug-delivery system has not yet been developed. This review draws attention to the pharmacokinetic conditions that must be met to achieve a successful performance by site-selective drug-carrier delivery systems. In a drug-carrier approach, a drug is attached to a macromolecular carrier via a chemically labile linker. The carrier transports the drug to its site of action and releases it at the target site. For this simple approach to work, several fundamental conditions (nonspecific interactions, target site access, drug release and drug suitability) must be satisfied. The importance of these essential requirements, not always recognized in the development of drug-delivery systems, is discussed and illustrated by recent examples selected from the literature.

Animals↗
PubMed1993

Gut macromolecular permeability in pancreatitis correlates with severity of disease in rats.

BACKGROUND: Increased intestinal macromolecular permeability could allow absorption of substances from the bowel into the systemic circulation and contribute to multiple organ system failure. METHODS: Mild, intermediate, and severe grades of pancreatitis were induced in rats using intravenous caerulein and intraductal glycodeoxycholic acid. [14C]polyethylene glycol (molecular weight, 3350 daltons; 1.1 microCi/142 mg) was instilled into the distal duodenum. At 24 hours, the animals were killed, ascitic fluid was collected for trypsinogen activation peptide measurement, and pancreatic specimens were collected and scored for based on the degree of necrosis, inflammation, and hemorrhage. RESULTS: Gut permeability to polyethylene glycol 3350 (PEG 3350) was increased in animals with early experimental pancreatitis (5.4% +/- 1.2%, n = 20) when compared with control animals (1.8% +/- 0.2%; n = 6) (P = 0.0005). Furthermore, intestinal macromolecular permeability to PEG 3350 correlated with severity of disease as predicted by the method of induction of pancreatitis (P = 0.0003), the histological findings (P = 0.0002), and total ascitic trypsinogen activation peptides content (P = 0.029). CONCLUSIONS: Increased gut permeability in experimental pancreatitis can be correlated with pancreatitis severity.

Animals↗
PubMed2004

The split-ubiquitin membrane-based yeast two-hybrid system.

Protein-protein interactions are essential in almost all biological processes, extending from the formation of cellular macromolecular structures and enzymatic complexes to the regulation of signal transduction pathways. It is assumed that approximately one-third of all proteins in eukaryotic cells are membrane associated. Because of their hydrophobic nature, the analysis of membrane-protein interactions is difficult to be studied in a conventional two-hybrid assay. We described here a new genetic method for in vivo detection of membrane-protein interactions in the budding yeast Saccharomyces cerevisiae. The system uses the split-ubiquitin approach based on the detection of the in vivo processing of a reconstituted split ubiquitin. On interaction of X and Y proteins, ubiquitin reconstitution occurs and leads to the proteolytic cleavage and subsequent release of a transcription factor that triggers the activation of a reporter system enabling easy detection. In this manner, and in contrast to the conventional yeast-two hybrid system in which interactions occur in the nucleus, the membrane-based yeast two-hybrid system represents an in vivo system that detects interactions between membrane proteins in their natural environment.

Amino Acid Sequence↗
PubMed1998

Macromolecular cytosolic delivery: cell membranes as the primary obstacle.

The "evolution" of a thing, a custom, an organ is thus by no means its progressus toward a goal, even less a logical progressus by the shortest route and with the least expenditure of force, but a succession of more or less profound, mutually independent processes of subduing, plus the resistances they encounter, the attempts at transformation for the purpose of defense and reaction, and the results of successful counteractions. The form is fluid, but the "meaning" is even more so.

Bacteria↗
PubMed2006

Multi-resolution anchor-point registration of biomolecular assemblies and their components.

An atomic scale interpretation facilitates the assignment of functional properties to 3D reconstructions of macromolecular assemblies in electron microscopy (EM). Such a high-resolution interpretation is typically achieved by docking the known atomic structures of components into the volumetric EM maps. Docking locations are often determined by maximizing the cross-correlation coefficient of the two objects in a slow, exhaustive search. If time is of essence, such as in related visualization and image processing fields, the matching of data is accelerated by incorporating feature points that form a compact description of 3D objects. The complexity reduction afforded by the feature point representation enables a near-instantaneous matching. We show that such reduced matching can also deliver robust and accurate results in the presence of noise or artifacts. We therefore propose a novel multi-resolution registration technique employing feature-based shape descriptions of the volumetric and structural data. The pattern-matching algorithm carries out a hierarchical alignment of the point sets generated by vector quantization. The search-space complexity is reduced by an integrated tree-pruning technique, which permits the detection of subunits in large macromolecular assemblies in real-time. The efficiency and accuracy of the novel algorithm are validated on a standard test system of homo-oligomeric assemblies.

Algorithms↗
PubMed1984

A study of an infected bone tissue (osteomyelitis) by small-angle X-ray scattering.

The small-angle X-ray scattering method has been applied to evaluate various macromolecular parameters such as the specific inner surface, the transversal lengths, the length of crystallinity, the range of amorphous zone and the percentage of porosity in pure human bone and osteomyelitis, an infection of bone tissue. The hydroxyapatite crystals of bone being uniformly dispersed throughout the hydrated collagenous matrix creating a large mineral matrix interface, we found the bone samples to behave as a densely packed two phase system. The theories of Kratky and Porod have been utilized to evaluate the macromolecular parameters. These findings may shed light on tertiary structural deformation of human bone when it is infected.

Bone and Bones↗
PubMed2001

Inulin as a carrier for contrast agents in magnetic resonance imaging.

Magnetic resonance angiography (MRA) has put forth an impetus for the development of macromolecular GdIII complexes that have a prolonged lifetime in the vascular system. Herein, we report the synthesis and GdIII complexation of a new sugar conjugate based on inulin and the DO3A ligand (DO3A = 1,4,7,10-tetraazacyclododecan-1,4,7-triacetic acid). Two API-DO3ASQ conjugates (API = O-(aminopropyl)inulin, SQ = squaric acid = 3,4-dihydroxy-3-cyclobutene-1,2-dione) with different degrees of substitution (ds = 0.7 and ds = 1.5) were prepared from API by using the diethyl ester of squaric acid as a linking agent for the DO3A chelate. The efficacies of the resulting GdIII compounds were evaluated by investigation of their water 1H longitudinal-relaxation-rate enhancements at variable field (NMRD). A dramatic increase in relaxivity was observed in the more highly substituted conjugate (ds = 1.5); this prompted us to do a variable-temperature (17)O study in order to further characterize the relaxation parameters involved in this system. [Gd(API-DO3ASQ)] shows promising properties for application as a contrast agent for MRI.

Chelating Agents↗