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At least 397 records · Page 22Linked to original sources

PubMed2003

Mpi recombinase globally modulates the surface architecture of a human commensal bacterium.

The mammalian gut represents a complex and diverse ecosystem, consisting of unique interactions between the host and microbial residents. Bacterial surfaces serve as an interface that promotes and responds to this dynamic exchange, a process essential to the biology of both symbionts. The human intestinal microorganism, Bacteroides fragilis, is able to extensively modulate its surface. Analysis of the B. fragilis genomic sequence, together with genetic conservation analyses, cross-species cloning experiments, and mutational studies, revealed that this organism utilizes an endogenous DNA inversion factor to globally modulate the expression of its surface structures. This DNA invertase is necessary for the inversion of at least 13 regions located throughout the genome, including the promoter regions for seven of the capsular polysaccharide biosynthesis loci, an accessory polysaccharide biosynthesis locus, and five other regions containing consensus promoter sequences. Bacterial DNA invertases of the serine site-specific recombinase family are typically encoded by imported elements such as phage and plasmids, and act locally on a single region of the imported element. In contrast, the conservation and unique global regulatory nature of the process in B. fragilis suggest an evolutionarily ancient mechanism for surface adaptation to the changing intestinal milieu during commensalism.

Bacterial Capsules↗

PubMed1992

Shape distributions of protein topography.

A method is presented for measuring protein surface shape. It is an improvement of an earlier method that intersects a sphere with the solvent-excluded volume of a protein molecule. The new method, called a shape distribution, produces a more sophisticated description of the region of the sphere inside the protein than is provided by simply measuring the region's area or solid angle. This method is applied to the prediction of molecular complexes in three systems: the hemoglobin nonallosteric interface, trypsin and trypsin inhibitor, and heme and apomyoglobin. It does not uniquely predict the correct structure, even though the individual structures are taken from the experimentally determined complex structure. However, it does provide a list of several hundred predicted complexes, one of which is correct, and from which the correct complex might be extracted by a subsequent chemical filter.

Algorithms↗

PubMed2007

Comprehensive analysis of proteins of pH fractionated samples using monolithic LC/MS/MS, intact MW measurement and MALDI-QIT-TOF MS.

A comprehensive platform that integrates information from the protein and peptide levels by combining various MS techniques has been employed for the analysis of proteins in fully malignant human breast cancer cells. The cell lysates were subjected to chromatofocusing fractionation, followed by tryptic digestion of pH fractions for on-line monolithic RP-HPLC interfaced with linear ion trap MS analysis for rapid protein identification. This unique approach of direct analysis of pH fractions resulted in the identification of large numbers of proteins from several selected pH fractions, in which approximately 1.5 microg of each of the pH fraction digests was consumed for an analysis time of ca 50 min. In order to combine valuable information retained at the protein level with the protein identifications obtained from the peptide level information, the same pH fraction was analyzed using nonporous (NPS)-RP-HPLC/ESI-TOF MS to obtain intact protein MW measurements. In order to further validate the protein identification procedures from the fraction digest analysis, NPS-RP-HPLC separation was performed for off-line protein collection to closely examine each protein using MALDI-TOF MS and MALDI-quadrupole ion trap (QIT)-TOF MS, and excellent agreement of protein identifications was consistently observed. It was also observed that the comparison to intact MW and other MS information was particularly useful for analyzing proteins whose identifications were suggested by one sequenced peptide from fraction digest analysis.

Amino Acid Sequence↗

PubMed2005

Profiling fatty acids in vegetable oils by reactive pyrolysis-gas chromatography with dimethyl carbonate and titanium silicate.

A novel methodology in on-line pyrolysis-gas chromatography (Py-GC) for the fast analysis of fatty acids in vegetable oils with minimal sample treatment and the use of non-toxic reagents is described. Pyrolysis at 500 degrees C for 10 s of sub-microgram quantity of vegetable oil dissolved in dimethyl carbonate (DMC) and in the presence of nanopowder titanium silicon oxide resulted in the production of fatty acid methyl esters (FAMEs) as unique products. Pyrolysis performed by means of a resistively heated filament pyrolyser interfaced to a GC-MS apparatus enabled the direct analysis of evolved FAMEs. The DMC/Py-GC-MS analysis was tested on soybean, coconut, linseed, walnut and olive oil and the results compared to the classical BF(3)-methanol as reference methodology. The DMC method exhibited a lower precision and was biased towards lower levels of polyunsaturated fatty acids (PUFA) in comparison to the BF(3)-methanol method, but was more advantageous in terms of reduced sample treatment, waste generation and risk factors of employed chemicals.

Fatty Acids↗

PubMed2004

Clinical experience with an implantable, intracardiac, continuous flow circulatory support device: physiologic implications and their relationship to patient selection.

BACKGROUND: We have been investigating continuous-flow circulatory support devices for 20 years. Unlike pulsatile assist devices, continuous-flow pumps have a simplified pumping mechanism and they do not require compliance chambers or valves. In the 1980s, clinical experience with the Hemopump proved a high-speed, intravascular, continuous-flow pump could safely augment the circulation. Subsequently, a decade of animal experiments with a larger, longer-term continuous-flow pump (the Jarvik 2000) confirmed the safety and efficacy of intraventricular placement, leading to its clinical application. METHODS: We analyzed the physiologic and anatomic effect of using the Jarvik 2000 pump for cardiac support in 23 patients in whom the device was applied as a bridge to transplant under the protocol approved by the Food and Drug Administration Investigational Device Exemption. The device was used as a bridge to transplantation in 20 patients and as destination therapy in 3 patients. RESULTS: In the bridge-to-transplant group, 14 patients underwent transplantation, 5 died during the circulatory support period and 1 is in an ongoing study. The support period lasted an average of 90 days. For the survivors, the follow-up period has averaged 16 months. Within the first 48 postoperative hours, the average cardiac index increased by 65% (from 1.77 +/- 0.24 to 2.92 +/- 0.60 L. min(-1). m(-2), p = 0.00000002), the systemic vascular resistance decreased by 42% (from 1604 +/- 427 to 930 +/- 330 dynes/sec per cm(2), p = 0.00001), and the pulmonary capillary wedge pressure (PCWP) decreased by 41.8% (from 23 +/- 5.1 to 13.4 +/- 6.6 mm Hg, p = 0.00009). Similar results were seen for the patients undergoing destination therapy. Cardiac index increased 89.5% (from 1.9 +/- 0.1 to 3.6 +/- 0.6, p = 0.046) and PCWP decreased by 52.2% (from 23 +/- 10 to 11 +/- 2, p = 0.22). In that group, 1 patient died unexpectedly from an accident 382 days after device implantation. The 2 survivors remain in New York Heart Association (NYHA) functional class I at 700 to 952 days after implantation. CONCLUSIONS: The Jarvik 2000 can offer effective long-term support for patients with chronic heart failure and NYHA class IV status. However, the new physiology produced by continuous offloading of the heart throughout the cardiac cycle has introduced unique clinical problems. The understanding of the problems generated by this biotechnological interface is essential for obtaining optimal clinical outcomes.

Adult↗

PubMed2003

Predicted protein-protein interaction sites from local sequence information.

Protein-protein interactions are facilitated by a myriad of residue-residue contacts on the interacting proteins. Identifying the site of interaction in the protein is a key for deciphering its functional mechanisms, and is crucial for drug development. Many studies indicate that the compositions of contacting residues are unique. Here, we describe a neural network that identifies protein-protein interfaces from sequence. For the most strongly predicted sites (in 34 of 333 proteins), 94% of the predictions were confirmed experimentally. When 70% of our predictions were right, we correctly predicted at least one interaction site in 20% of the complexes (66/333). These results indicate that the prediction of some interaction sites from sequence alone is possible. Incorporating evolutionary and predicted structural information may improve our method. However, even at this early stage, our tool might already assist wet-lab biology.

Binding Sites↗

PubMed2003

On-line coupled liquid chromatography-gas chromatography.

On-line coupled liquid chromatography-gas chromatography (LC-GC) is a powerful technique that combines the best features of LC and GC and is ideal for the analysis of complex samples. This review describes the unique features of on-line coupled LC-GC. The different interfaces and evaporation techniques are presented, along with their advantages and disadvantages. Guidelines are given for selecting a suitable LC-GC technique and representative applications are noted.

Chromatography, Gas↗

PubMed2000

Structure of basic phospholipase A2 from Agkistrodon halys Pallas: implications for its association, hemolytic and anticoagulant activities.

The basic phospholipase A2 (PLA2) from the venom of Agkistrodon halys Pallas is a potent hemolytic toxin and anticoagulant. Crystal structure of the enzyme complexed with detergent n-octyl beta-D-glucopyranoside (beta-OG) in monoclinic crystal form has been determined to 2.6 A resolution. Beta-OG molecules were found in the hydrophobic channels of the enzyme. SDS-PAGE and dynamic light scattering measurements showed that the enzyme had a strong tendency to dimerise in aqueous solution. In the crystal structure the enzyme molecules associate into a tetramer with pseudo 222 symmetry, and the interfacial recognition site linked dimers constituting the tetramer have intensive interface interactions, and may be stable in solution. The structure reveals a unique positively charged face at the C-terminal region and a characteristic non-cationic 'anticoagulant' region (53-77). The face is supposed to be the hemolytic site, and based on sequence and structure comparison residues Trp70 and Glu53 instead of the basic residues in 'anticoagulant' region might play an important role in the anticoagulant activity.

Agkistrodon↗

PubMed2003

Embryogenesis and gene targeting of coagulation factors in mice.

Genetic or acquired thrombophilia of the pregnant mother has been associated with the occurrence of gestational vascular disease and recurrent fetal loss and may contribute to the aetiology of pre-eclampsia. This chapter reviews insights into this link between thrombophilia and pregnancy complications that were gained from the study of genetically altered mice. These studies strongly support the notion of a cause-effect relationship between altered function of the thrombomodulin-protein C pathway and adverse pregnancy outcome. Analysis of the mouse models highlights unique aspects of vascular structure and function at the feto-maternal interface, and exposes new biological functions of natural anticoagulant pathways in pregnancy. These roles are unrelated to the maintenance of vascular patency and may be mediated through specific signalling pathways activated by coagulation factors. Abnormal signalling by placental trophoblasts at the feto-maternal interface is suggested as a hitherto unrecognized mechanism that may underlie adverse pregnancy outcome associated with haemostatic disorders.

Animals↗

PubMed2001

Structural features of the Abeta amyloid fibril elucidated by limited proteolysis.

Although the gross morphology of amyloid fibrils is fairly well understood, very little is known about how the constituent polypeptides fold within the amyloid folding motif. In the experiments reported here, we used trypsin and chymotrypsin to conduct limited proteolysis studies on synthetic amyloid fibrils composed of the Alzheimer's disease peptide Abeta(1-40). In both reactions, the extreme N-terminal proteolytic fragment is released from fibrils as rapidly as it is from the Abeta monomer, while other proteolytic fragments are generated much more slowly. Furthermore, aggregated material isolated by centrifugation of intermediate digestion time points from both proteases contains, in addition to full-length material, peptides that possess mature C-termini but truncated N-termini. These data strongly suggest that the N-terminal region of Abeta is not involved in the beta-sheet network of the amyloid fibril, while the C-terminus is essentially completely engaged in protective-presumably beta-sheet-structure. In both digests, release of the extreme N-terminal fragments of Abeta(1-40) reaches plateau values corresponding to about 80% of the total available Abeta. This suggests that there are two classes of peptides in the fibril: while the majority of Abeta molecules have an exposed N-terminus, about 20% of the peptides have an N-terminus that is protected from proteolysis within the fibril structure. The most likely cause of this heterogeneity is the lateral association of protofilaments into the fibril structure, which would be expected to generate a unique environment for those Abeta N-termini located at protofilament packing interfaces and/or in the interior core region between the packed protofilaments. This suggests that the N-terminal region of Abeta, while not directly involved in the beta-sheet network of the fibril, may contribute to fibril stability by participating in protofilament packing.

Amino Acid Sequence↗

PubMed2003

A pH-dependent aquomet-to-hemichrome transition in crystalline horse methemoglobin.

In 1947, Perutz and co-workers reported that crystalline horse methemoglobin undergoes a large lattice transition as the pH is decreased from 7.1 to 5.4. We have determined the pH 7.1 and 5.4 crystal structures of horse methemoglobin at 1.6 and 2.1 A resolution, respectively, and find that this lattice transition involves a 23 A translation of adjacent hemoglobin tetramers as well as changes in alpha heme ligation and the tertiary structure of the alpha subunits. Specifically, when the pH is lowered from 7.1 to 5.4, the Fe(3+) alpha heme groups (but not the beta heme groups) are converted from the aquomet form, in which the proximal histidine [His87(F8)alpha] and a water molecule are the axial heme ligands, to the hemichrome (bishistidine) form, in which the proximal histidine and the distal histidine [His58(E7)alpha] are the axial heme ligands. Hemichrome formation is coupled to a large tertiary structure transition in the eight-residue segment Pro44(CD2)alpha-Gly51(D7)alpha that converts from an extended loop structure at pH 7.1 to a pi-like helix at pH 5.4. The formation of the pi helix forces Phe46(CD4)alpha out of the alpha heme pocket and into the interface between adjacent hemoglobin tetramers where it participates in crystal lattice contacts unique to the pH 5.4 structure. In addition, the transition from aquomet alpha subunits to bishistidine alpha subunits is accompanied by an approximately 1.2 A movement of the alpha heme groups to a more solvent-exposed position as well as the creation of a solvent channel from the interior of the alpha heme pocket to the outside of the tetramer. These changes and the extensive rearrangement of the crystal lattice structure allow the alpha heme group of one tetramer to make direct contact with an alpha heme group on an adjacent tetramer. These results suggest possible functional roles for hemichrome formation in vivo.

Animals↗

PubMed2006

Thermodynamic and dynamic characteristics of hydroxypropylmethylcellulose adsorbed films at the air-water interface.

Surface pressure isotherms and structural and surface dilatational properties of three hydroxypropylmethycelluloses (HPMCs, called E4M, E50LV, and F4M) adsorbed films at the air-water interface were determined. In this work we present evidence that HPMC molecules are able to diffuse and saturate the air-water interface at very low concentrations in the bulk phase. As bulk concentration increased, structural changes at a molecular level occurred at the interface. These changes corresponded to transition from an expanded structure (structure I) to a condensed one (structure II). When the surface concentration of HPMC was high enough, the collapse of the monolayer was observed. The three HPMCs formed very elastic films at the air-water interface, even at low surface pressures. E4M showed features that make it unique. For instance it showed the highest surface activity, mainly at low bulk concentrations (<10(-4) wt %). The differences observed in surface activity may be attributed to differences in the hydroxypropyl molar substitution and molecular weight of HPMC. All three HPMCs formed films of similar viscoelasticity and elastic dilatational modulus, which can be accounted for by their similar degree of methyl substitution.

Air↗

PubMed2006

Immunological synapse arrays: patterned protein surfaces that modulate immunological synapse structure formation in T cells.

T cells are activated by recognition of foreign peptides displayed on the surface of antigen presenting cells (APCs), an event that triggers assembly of a complex microscale structure at the T cell-APC interface known as the immunological synapse (IS). It remains unresolved whether the unique physical structure of the synapse itself impacts the functional response of T cells, independent of the quantity and quality of ligands encountered by the T cell. As a first step toward addressing this question, we created multicomponent protein surfaces presenting lithographically defined patterns of tethered T cell receptor (TCR) ligands (anti-CD3 "activation sites") surrounded by a field of tethered intercellular adhesion molecule-1 (ICAM-1), as a model substrate on which T cells could be seeded to mimic T cell-APC interactions. CD4(+) T cells seeded on these surfaces polarized and migrated; on contact with activation sites, T cells assembled an IS with a structure modulated by the physical pattern of ligand encountered. On surfaces patterned with focal spots of TCR ligand, T cells stably interacted with activation sites, proliferated, and secreted cytokines. In contrast, T cells interacting with activation sites patterned to preclude centralized clustering of TCR ligand failed to form stable contacts with activation sites, exhibited aberrant PKC- clustering in a fraction of cells, and had significantly reduced production of IFN-gamma. These results suggest that focal clustering of TCR ligand characteristic of the "mature" IS may be required under some conditions for full T cell activation.

Animals↗

PubMed2000

Dynamic criteria for melting in two dimensions

The two-dimensional (2D) melting transition is analyzed on the basis of the long-time behavior of a modified Lindemann parameter in 2D gamma(L)(t) and the bond-angular correlation function g(6)(t). Using video microscopy complete positional data are obtained over five decades in time for an ensemble of superparamagnetic colloidal particles confined to an air-water interface. We find that each of the three phases (solid/hexatic/isotropic liquid) is uniquely characterized by the long-time behavior of gamma(L)(t), g(6)(t), and the non-Gaussian parameter of the relative neighbor-neighbor displacement.

Journal Article↗

PubMed2004

The Retinome - defining a reference transcriptome of the adult mammalian retina/retinal pigment epithelium.

BACKGROUND: The mammalian retina is a valuable model system to study neuronal biology in health and disease. To obtain insight into intrinsic processes of the retina, great efforts are directed towards the identification and characterization of transcripts with functional relevance to this tissue. RESULTS: With the goal to assemble a first genome-wide reference transcriptome of the adult mammalian retina, referred to as the retinome, we have extracted 13,037 non-redundant annotated genes from nearly 500,000 published datasets on redundant retina/retinal pigment epithelium (RPE) transcripts. The data were generated from 27 independent studies employing a wide range of molecular and biocomputational approaches. Comparison to known retina-/RPE-specific pathways and established retinal gene networks suggest that the reference retinome may represent up to 90% of the retinal transcripts. We show that the distribution of retinal genes along the chromosomes is not random but exhibits a higher order organization closely following the previously observed clustering of genes with increased expression. CONCLUSION: The genome wide retinome map offers a rational basis for selecting suggestive candidate genes for hereditary as well as complex retinal diseases facilitating elaborate studies into normal and pathological pathways. To make this unique resource freely available we have built a database providing a query interface to the reference retinome 1.

Adult↗

PubMed1998

Basics of flow cytometry.

In summary, a beginner requires fundamental knowledge about flow cytometric instrumentation in order to effectively use this technology. It is important to remember that flow cytometers are very complex instruments that are composed of four closely related systems. The fluidic system transports particles from a suspension through the cytometer for interrogation by an illumination system. The resulting light scattering and fluorescence is collected, filtered, and converted into electrical signals by the optical and electronics system. The data storage and computer control system saves acquired data and is also the user interface for controlling most instrument functions. These four systems provide a very unique and powerful analytical tool for researchers and clinicians. This is because they analyze the properties of individual particles, and thousands of particles can be analyzed in a matter of seconds. Thus, data for a flow cytometric sample are a collection of many measurements instead of a single bulk measurement. Basic knowledge of instrumentation is a tremendous aid to designing experiments that can be successfully analyzed using flow cytometry. For example, it is important to know the emission wavelength of the laser in the instrument that will be used for analysis. This wavelength is critical knowledge for selecting probes. It is also important to understand that a different range of wavelengths is detected for each fluorescent channel. This will aid selection of probes that are compatible with the flow cytometer. Understanding the complication that emission spectra overlap contributes to detection can be used to guide fluorochrome selections for multicolor analysis. All of these experiment design considerations that rely on knowledge of how flow cytometers work are a very practical and effective means of avoiding wasted time, energy, and costly reagents. Data analysis is a paramount issue in flow cytometry. Analysis includes interpreting as well as presenting data that has been stored in list-mode files. Data analysis is very graphically oriented. There are a number of types of graphic representation that are available to visually aid data analysis. Two standard types of displays are used. These data plots are one-parameter histograms and bivariate plots. A user must be familiar with these two fundamental types of display in order to effectively analyze data. Histograms are the most simple modes of data representation. Histograms allow visualization of a single acquired parameter. Mean fluorescence and distributional statistics can be obtained based on markers that the user can graphically set on the plot. Percentages of positively expressing particles relative to a control sample can also obtained in a similar manner. In addition, multiple histograms can be overlayed on one another to depict qualitative and quantitative differences in two or more samples. Two-parameter data plots are somewhat more complicated than histograms; however, they can yield more information. Two-parameter dot plots of FSC vs SSC allow visualization of both light-scattering parameters that are important for identifying populations of interest. Bivariate fluorescent plots allow discrimination of dual-labeled populations that might remain hidden if histograms were used to display fluorescent data. Two-parameter plots that combine one light-scattering parameter and a fluorescent parameter are useful for analyzing control samples to elucidate the origin of nonspecific binding. Data analysis is very graphically oriented. Experience and pattern recognition become important when using two-parameter data plots for qualitative as well as quantitative analysis. The technique of gating or drawing regions on dual parameter light-scatter plots allows one to exclude information and examine the population of interest by disallowing particles that might confound or interfere with analysis. This is one of the fundamental uses for gating. (ABSTRACT TRUNCATED)

Animals↗

PubMed2003

CTLA-4. FasL induces alloantigen-specific hyporesponsiveness.

The APC:T cell interface can be effectively targeted with immunotherapeutic proteins. We previously described a unique trans signal converter protein, CTLA-4. Fas ligand (FasL), that has the inherent capacities to tether the T cell inhibitor FasL (CD95 ligand) to the surfaces of B7 (CD80 and CD86)-positive APC (via CTLA-4:B7 interaction), and in so doing, to simultaneously interfere with B7-to-CD28 T cell activation signals. Given the continuing need for agents capable of inducing allograft tolerance without generalized immunosuppression, we have explored in depth the functional activity of CTLA-4. FasL in human allogeneic MLR. CTLA-4. FasL inhibits 1 degrees MLR and induces specific hyporesponsiveness in 2 degrees MLR, with both effects only partially reversible with exogenous IL-2. Moreover, the presence of exogenous IL-2 during the 1 degrees MLR does not affect the induction of hyporesponsiveness upon restimulation. Furthermore, CTLA-4. FasL enables partial activation of allostimulated T cells, reduces the fraction of actively dividing cells, and increases the percentage of dead cells among dividing T cells. Taken together, these findings suggest that CTLA-4. FasL-mediated inhibition of secondary alloantigenic responses involves both anergy induction and clonal deletion. Thus, CTLA-4. FasL, a paradigmatic trans signal converter protein, manifests unique functional properties and emerges as a potentially useful immunotherapeutic for modulating alloresponsiveness.

Antibodies, Blocking↗

PubMed1985

Professional women: are distress and disease inevitable?

The unique sources of stress for professional women are discrimination, stereotyping, the marriage/work interface, and social isolation. The behavioral, physiological, and psychological consequences of mismanaged stress are examined and four preventive stress management moderators specifically for professional women suggested. These moderators that influence the stress-strain relationships are a mentor, locus of control, self-confidence, and self-awareness. Finally, a three-point research agenda is outlined for extending understanding of stress among professional women.

Adult↗