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At least 343 records · Page 19Linked to original sources
PubMed1997

Biological variability in the structures of diphosphoinositol polyphosphates in Dictyostelium discoideum and mammalian cells.

Previous structural analyses of diphosphoinositol polyphosphates in biological systems have relied largely on NMR analysis. For example, in Dictyostelium discoideum, diphosphoinositol pentakisphosphate was determined by NMR to be 4- and/or 6-PPInsP5, and the bisdiphosphoinositol tetrakisphosphate was found to be 4, 5-bisPPInsP4 and/or 5,6-bisPPInsP4 [Laussmann, Eujen, Weisshuhn, Thiel and Vogel (1996) Biochem. J. 315, 715-720]. We now describe three recent technical developments to aid the analysis of these compounds, not just in Dictyostelium, but also in a wider range of biological systems: (i) improved resolution and sensitivity of detection of PPInsP5 isomers by microbore metal-dye-detection HPLC; (ii) the use of the enantiomerically specific properties of a rat hepatic diphosphatase; (iii) chemical synthesis of enantiomerically pure reference standards of all six possible PPInsP5 isomers. Thus we now demonstrate that the major PPInsP5 isomer in Dictyostelium is 6-PPInsP5. Similar findings obtained using the same synthetic standards have been published [Laussmann, Reddy, Reddy, Falck and Vogel (1997) Biochem. J. 322, 31-33]. In addition, we show that 10-25% of the Dictyostelium PPInsP5 pool is comprised of 5-PPInsP5. The biological significance of this new observation was reinforced by our demonstration that 5-PPInsP5 is the predominant PPInsP5 isomer in four different mammalian cell lines (FTC human thyroid cancer cells, Swiss 3T3 fibroblasts, Jurkat T-cells and Chinese hamster ovary cells). The fact that the cellular spectrum of diphosphoinositol polyphosphates varies across phylogenetic boundaries underscores the value of our technological developments for future determinations of the structures of this class of compounds in other systems.

3T3 Cells↗
PubMed2006

A geographic information systems-based, weights-of-evidence approach for diagnosing aquatic ecosystem impairment.

A Geographic Information Systems-based, watershed-level assessment using Bayesian weights of evidence (WOE) and weighted logistic regression (WLR) provides a method to determine and compare potential environmental stressors in lotic ecosystems and to create predictive models of general or species-specific biological impairment across numerous spatial scales based on limited existing sample data. The WOE/WLR technique used in the present study is a data-driven, probabilistic approach conceptualized in epidemiological research and both developed for and currently used in minerals exploration. Extrapolation of this methodology to a case-study watershed assessment of the Great and Little Miami watersheds (OH, USA) using archival data yielded baseline results consistent with previous assessments. The method additionally produced a quantitative determination of physical and chemical watershed stressor associations with biological impairment and a predicted comparative probability (i.e., favorability) of biological impairment at a spatial resolution of 0.5 km2 over the watershed study region. Habitat stressors showed the greatest spatial association with biological impairment in low-order streams (on average, 56% of total spatial association), whereas water chemistry, particularly that of wastewater effluent, was associated most strongly with biological impairment in high-order reaches (on average, 79% of total spatial association, 28% of which was attributed to effluent). Significant potential stressors varied by land-use and stream order as well as by species. This WOE/WLR method provides a highly useful "tier 1" watershed risk assessment product through the integration of various existing data sources, and it produces a clear visual communication of areas favorable for biological impairment and a quantitative ranking of candidate stressors and associated uncertainty.

Bayes Theorem↗
PubMed2002

Characterization of the performance of a 200-kV field emission gun for cryo-electron microscopy of biological molecules.

The value of an electron microscope equipped with a field emission gun (FEG) was first revealed in materials science applications. More recently, the FEG has played a crucial role in breaking the 10A barrier in single-particle reconstructions of frozen hydrated biological molecules. The standard high-resolution performance tests for electron microscopes are made close to focus, at several hundreds of A underfocus at a magnification of 500,000x or more. While this is appropriate for materials science specimens, it is not suitable for observing frozen hydrated biological specimens with which the optimum underfocus is of the order of 1 micron or so and the magnification is limited by radiation damage to roughly 30,000 to 60,000x. Thus, in order to access the performance of a cryo-electron microscope for high-resolution 3D electron microscopy of biological molecules, additional tests are necessary. We present here resolution tests of a 200-kV FEG using frozen hydrated virus suspensions. The extent and amplitude of the contrast transfer function are used as a test of the performance. We propose that small spherical viruses close to 300A in diameter, such as the picornaviruses or phages, make good specimens for testing the performance of an electron microscope in cryo-mode.

Cryoelectron Microscopy↗
PubMed2005

Molecular MR imaging in oncology.

The implementation and integration of systems biology approaches with the emerging nanosciences and microchip technology will revolutionize profoundly molecular imaging and fuel the drive toward a more predictive and individualized health care. In combination with informatics platforms, key gene and protein targets will be identified, and serve as more effective targets for diagnostic and therapeutic interventions. Drug development also will be expedited by the judicious selection of more appropriate molecular biomarkers that will serve as objective end points of treatment efficacy, in addition to facilitating the development of new target-specific therapeutics. Finally, with the more widespread proliferation of high-field magnets and advancements in imaging hardware; acquisition methods; and novel,"smart" MR agents, the ability to achieve higher resolution analyses of tumor biology, cell track-ing, and gene expression will be realized more fully. Although radiologists will continue to serve as diagnostic consultants and assist in management decisions, the contributions from new developments in the biologic and molecular sciences will significantly alter the scope of our profession. Radiologists will be required to participate more actively in the individualized care of the patient and cultivate a deeper understanding of the underlying molecular basis of disease and molecular pharmacology for facilitating selection of the most appropriate combination of imaging studies that address biologically relevant questions. These radical changes in our profession will necessitate the re-education and emergence of a small cadre of professionals that is educated broadly in multiple scientific disciplines, and demonstrate expertise in clinical care and the basic sciences. The optimistic view is that this already is happening.

Biomarkers↗
PubMedDate not supplied

Comparative evaluation of endodontic management of teeth with unformed apices with mineral trioxide aggregate and calcium hydroxide.

PURPOSE: The purpose of this study was to compare mineral trioxide aggregate (MTA) and calcium hydroxide (Ca(OH)2) for their efficacies and time taken for formation of apical biological calcific barriers and resolution of periapical radiolucencies, if present at baseline, in teeth with unformed apices. METHODS: Twenty nonvital permanent maxillary incisors with unformed apices, stratified according to the size of periapical radiolucencies and stage of root development, were equally allocated to MTA and Ca(OH)2 groups. In group 1 (MTA group), after 7 days of disinfection with Ca(OH)2, MTA was packed into the apical one third of the root canals and obturation with gutta percha (GP) was performed in 90% (9/10) of cases within 15 to 30 days. In group 2 (Ca(OH)2 group), obturation was performed following clinical and radiographic depiction of the apical stop. RESULTS: The mean time taken for apical biological barrier formation was 3 +/- 2.9 months for group 1 and 7 +/- 2.5 months for group 2 (P=.008). The periapical radiolucencies were resolved in 4.6 +/- 1.5 months for group 1 and 4.4 +/- 1.3 months for group 2 (P=.83). The total treatment was completed in 0.75 +/- 0.4859 months and 7 +/- 2.5 months for groups 1 and 2, respectively. CONCLUSION: The 2 materials were found to be equally efficacious in the management of nonvital teeth with unformed apices. Time taken to complete the treatment and the biological barrier formation in group 1 was significantly less than that for group 2. The healing time for periapical radiolucencies was almost identical.

Adolescent↗
PubMed1998

The second decade--into the third millenium.

NMR spectroscopy is one of the principal experimental techniques of structural biology, with abilities to determine atomic resolution structures as well as investigate dynamics and intermolecular interactions of biological macromolecules. There is plenty of room for continued progress of this young branch of science, based on further technical advances as well as innovative funding strategies and project organization.

Animals↗
PubMed1999

B-DNA at atomic resolution reveals extended hydration patterns.

Despite the importance of hydration around DNA in the understanding of its conformation and interactions with other molecules in many biological processes, only limited atomic resolution information is available. Crystal-engineering techniques, which were originally developed to mimic DNA base triplets in a crystal lattice, also eliminate the rotational disorder of oligonucleotides around their helical axis and thereby enhance the resolution of the structure analysis. We have determined the low-temperature crystal structure of the synthetic DNA decamer d(GGCCAATTGG) at atomic resolution (1. 15 A) using 17700 reflections and have characterized the highly organized hydration patterns in both grooves. The narrow d(AATT) minor groove is occupied by an 'extended hydration spine' alternately bridging base pairs and phosphate O1P atoms of opposite strands, while a distinctive pattern of parallel water ribbons is observed in the major groove. This analysis provides structural insight into the correlation found between narrow minor-groove width and occurrence of the B(I) conformation and can be used to design new minor-groove binders. By their location between adjacent helices, two fully hydrated magnesium ions further stabilize the crystal packing. The structure also provides details of the hydration and conformation of G.GC triple helices.

Crystallization↗
PubMed2026

Mobile elements in pituitary neuroendocrine tumors: integrative evidence and future directions.

Mobile genetic elements (MGEs), including LINE-1 retrotransposons, Alu and SVA elements, and human endogenous retroviruses (HERVs), constitute nearly half of the human genome and are increasingly understood to influence multiple dimensions of cancer evolution. Yet, pituitary neuroendocrine tumors (PitNETs) remain almost absent from mobilome research, despite exhibiting genomic and epigenetic contexts permissive to retroelement activation. In this review, we synthesize current evidence linking MGEs to PitNET biology and delineate unresolved but testable mechanisms. Structural genomic studies demonstrate that Alu-mediated non-allelic homologous recombination contributes to germline mutagenesis in MEN1 and AIP, reinforcing the notion that repetitive DNA architecture shapes PitNET predisposition. Transcriptomic analyses reveal global derepression of transposable elements and LINE-1 hypomethylation in subsets of tumors, while mechanistic connections to chromatin instability emerge from recurrent ATRX/DAXX deficiency and TP53 inactivation, both established repressors of retroelements. Furthermore, the retrocopy-derived long non-coding RNA RPSAP52 exemplifies how mobilome-origin transcripts can be co-opted as oncogenic regulators in PitNETs, acting through HMGA2-dependent proliferative networks. Preliminary data also suggest endogenous retroviral activation, with consistent upregulation of HERV envelope genes across distinct tumor subtypes. Nevertheless, no study has yet systematically mapped somatic mobile-element insertions (MEIs), quantified LINE-1 protein activity, or profiled HERV expression at locus resolution in PitNETs. Mobilome biology represents a tractable and conceptually rich frontier with diagnostic, prognostic, and therapeutic potential in pituitary tumorigenesis.

Humans↗
PubMed2002

Three-dimensional high-resolution second-harmonic generation imaging of endogenous structural proteins in biological tissues.

We find that several key endogenous protein structures give rise to intense second-harmonic generation (SHG)-nonabsorptive frequency doubling of an excitation laser line. Second-harmonic imaging microscopy (SHIM) on a laser-scanning system proves, therefore, to be a powerful and unique tool for high-resolution, high-contrast, three-dimensional studies of live cell and tissue architecture. Unlike fluorescence, SHG suffers no inherent photobleaching or toxicity and does not require exogenous labels. Unlike polarization microscopy, SHIM provides intrinsic confocality and deep sectioning in complex tissues. In this study, we demonstrate the clarity of SHIM optical sectioning within unfixed, unstained thick specimens. SHIM and two-photon excited fluorescence (TPEF) were combined in a dual-mode nonlinear microscopy to elucidate the molecular sources of SHG in live cells and tissues. SHG arose not only from coiled-coil complexes within connective tissues and muscle thick filaments, but also from microtubule arrays within interphase and mitotic cells. Both polarization dependence and a local symmetry cancellation effect of SHG allowed the signal from species generating the second harmonic to be decoded, by ratiometric correlation with TPEF, to yield information on local structure below optical resolution. The physical origin of SHG within these tissues is addressed and is attributed to the laser interaction with dipolar protein structures that is enhanced by the intrinsic chirality of the protein helices.

Animals↗
PubMed2002

Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays.

Small molecules that alter protein function provide a means to modulate biological networks with temporal resolution. Here we demonstrate a potentially general and scalable method of identifying such molecules by application to a particular protein, Ure2p, which represses the transcription factors Gln3p and Nil1p. By probing a high-density microarray of small molecules generated by diversity-oriented synthesis with fluorescently labelled Ure2p, we performed 3,780 protein-binding assays in parallel and identified several compounds that bind Ure2p. One compound, which we call uretupamine, specifically activates a glucose-sensitive transcriptional pathway downstream of Ure2p. Whole-genome transcription profiling and chemical epistasis demonstrate the remarkable Ure2p specificity of uretupamine and its ability to modulate the glucose-sensitive subset of genes downstream of Ure2p. These results demonstrate that diversity-oriented synthesis and small-molecule microarrays can be used to identify small molecules that bind to a protein of interest, and that these small molecules can regulate specific functions of the protein.

Dioxanes↗
PubMed2004

Quantifying labial blood flow using optical Doppler tomography.

OBJECTIVES: Changes in the oral microvasculature occur in a variety of diseases. Optical Doppler tomography (ODT) combines laser Doppler flowmetry with optical coherence tomography (OCT) to produce high-resolution tomographic images of biological tissues that also detect the velocity and direction of blood flow. The objective of this study was to determine the feasibility of ODT to image labial blood flow. A prototype ODT imaging system was constructed that characterized and measured labial blood flow in healthy subjects. MATERIALS AND METHODS: A prototype ODT instrument was constructed using a diode light source with a central wavelength of 1300 nanometers, a 40-nanometer spectral width and 2.4 microwatts output power. To verify the accuracy of the system, the flow rates of a phantom material (Intralipid) pumped through a capillary tube at various speeds was measured. To evaluate the clinical feasibility of the ODT prototye, the mucosal aspect of the upper and lower lips at the midline was imaged in 9 healthy volunteers. The sample arm of the instrument consisted of a fiberoptic probe with a 2-mm in diameter polished glass lens attached to the end. The probe was placed approximately 3 mm from the mucosal surface of the lip and oriented perpendicular to the surface. A motorized translation stage moved the fiber in a superior to inferior direction while the subject's head was stabilized by placing the chin into a chin rest. Imaging time for a 12-mm x 2.5-mm scan was approximately 64 seconds. RESULTS: The phantom experiments revealed that accuracy of this novel ODT prototype to measure flow was within 5%. In vivo labial blood flow velocity ranged from 11.8 to 43.1 mm/second in the upper lip and 8.2 to 53.2 mm/second in the lower lip. There were no statistically significant differences between flow rates in the upper and lower lips. OCT images and Doppler velocity signals were successfully integrated producing in vivo images of labial blood in all of the subjects (15 images). The resulting cross-sectional images revealed microscopic details of labial structures and, to the best of our knowledge, are the first ODT images of the labial microvasculature. CONCLUSIONS: The results of this in vivo study prove the feasibility of ODT to quantify labial blood flow and produce high spatial resolution images specifically localizing vessels anatomically. ODT provides both flow speed and flow direction information. ODT is noninvasive and offers the advantages of high volumetric flow sensitivity.

Anatomy, Cross-Sectional↗
PubMed2006

Studying cellular architecture in three dimensions with improved resolution: Ta replicas revisited.

Metal replicas have been used for surface analysis of biological structures with a variety of spatial resolutions. Platinum (Pt) has been the metal of choice because it provides very stable replicas and images of high contrast. Some other metals, such as tantalum (Ta) have been reported to provide better resolution on isolated macromolecular complexes and cellular structures. Our goal is to study the gain in detail with Ta and to evaluate if it provides enough detail and resolution to assist in the study of complex volumes of intact cellular structures obtained by methods that reach molecular resolution. To this purpose Pt and Ta replicas of cellular structures and viruses have been studied by transmission electron microscopy (TEM). Replicas of Ta show new details on the surface of two types of isolated viral particles such as 100 nm bunyaviruses and large, > 300 nm, vaccinia virus (VV). Inside cells, the structural pieces that build VV immature particles are visualized only in Ta replicas. Looking for smaller intracellular complexes, new details are also seen in nuclear pores from Ta replicas. Additional masses, most likely representing the cargo during transport, are distinguished in some of the pores. Visualization of proteins in plasma membranes strongly suggests that detail and resolution of Ta replicas are similar to those estimated for 3D maps currently obtained by electron tomography of viruses and cells.

Animals↗
PubMed2000

Three-dimensional spectral precision distance microscopy of chromatin nanostructures after triple-colour DNA labelling: a study of the BCR region on chromosome 22 and the Philadelphia chromosome.

Topological analysis of the three-dimensional (3D) chromatin nanostructure and its function in intact cell nuclei implies the use of high resolution far field light microscopy, e.g. confocal laser scanning microscopy (CLSM). However, experimental evidence indicates that, in practice, under biologically relevant conditions, the spatial resolution of CLSM is limited to about 300 nm in the lateral direction and about 700 nm in the axial direction. To overcome this shortcoming, the use of a recently developed light microscopical approach, spectral precision distance microscopy (SPDM) is established. This approach is based on the precise localization of small labelling sites of a given target in spectrally differential images. By means of quantitative image analysis, the bary centres (intensity weighted centroid analogous to the centre of mass) of these independently registered labelling sites can be used as point markers for distance and angle measurements after appropriate calibration of optical aberrations (here, polychromatic shifts). In combination with specific labelling of very small chromatin target sites with dyes of different spectral signatures by fluorescence in situ hybridization (FISH), SPDM presently allows us to analyse the nuclear topology in three-dimensionally conserved nuclei with a 'resolution equivalent', many times smaller than the conventional optical resolution. Chronic myelogeneous leukaemia (CML) is genetically characterized by the fusion of parts of the BCR and ABL genes on chromosomes 22 and 9, respectively. In most cases, the fusion leads to a translocation t(9; 22) producing the Philadelphia chromosome. SPDM was applied to analyse the 3D chromatin structure of the BCR region on the intact chromosome 22 and the BCR-ABL fusion gene on the Philadelphia chromosome (Ph) by using a new triple-colour FISH protocol: two different DNA probes were used to detect the BCR region and the third DNA probe was used to identify the location of the ABL gene. Consistent 3D distance measurements down to values considerably smaller than 100 nm were performed. The angle distributions between the three labelled sites on the Philadelphia chromosome territory were compared to two state-of-the-art computer models of nuclear chromatin structure. Significant differences between measured and simulated angle distributions were obtained, indicating a complex and non-random angle distribution.

Bone Marrow Cells↗
PubMed2006

Two-photon excitation fluorescence microscopy with a high depth of field using an axicon.

In conventional two-photon excitation fluorescence microscopy, the numerical aperture of the objective determines the lateral resolution and the depth of field. In some situations, as with functional imaging of dynamic events distributed in live biological tissue, an improved temporal resolution is needed; as a consequence, it is imperative to use optics with a high depth of field to simultaneously image objects at different axial positions. With a conventional microscope objective, increasing the depth of field is achieved at the expense of lateral resolution. To overcome this limitation, we have incorporated an axicon in a two-photon excitation fluorescence microscopy system; measurements have shown that an axicon provides a depth of field in excess of a millimeter, while the lateral resolution is maintained at the micrometer scale. Thus axicon-based two-photon microscopy has been shown to yield a high-resolution projection image of a sample with a single 2D scan of the laser beam while maintaining the improved tissue penetration typical of two-photon microscopy.

Equipment Design↗
PubMedDate not supplied

Diffracted-light contrast enhancement: a re-examination of oblique illumination.

A re-examination and modification of the very old oblique illumination technique has resulted in a method for contrast enhancement in microscopes, diffracted-light contrast (DLC), which provides high-contrast, high-resolution images of unstained biological material. The technique, which utilizes the diffracted light from the edge of a small, opaque plate, provides shadowcast images similar to those obtained by Nomarski DIC, anaxial illumination, modulation contrast, or single-sideband microscopy; however, it requires only a single additional component, which can be added to any bright field microscope. The contrast and three-dimensionality of the final image can be controlled by inserting differently shaped edges. Any bright field condenser will work with the technique and, consequently, it is a technique that may be especially useful with relatively basic, inexpensive laboratory and teaching microscopes although the image produced on a research grade microscope is of very high quality, comparable to that obtained with DIC.

Microscopy↗
PubMed1997

Critical review of recent developments in fluorescence detection for capillary electrophoresis.

Recent developments in capillary electrophoresis with fluorescence detection are reviewed. Instrumental advances have led to increased sensitivity and, therefore, a growing number of applications. Capillary electrophoresis has been coupled with various techniques to achieve multi-dimensional separations. Other advances have focused on temporal resolution when sampling from biological environments, increased sample throughput especially for DNA analysis, and fast separation times. New technologies including chip and channel electrophoretic separations with fluorescence detection are also discussed.

DNA↗
PubMed2005

Comparative study between the polysaccharide-based chiralcel OJ and chiralcel OD CSPSs in chromatographic enantioseparation of imidazole analogues of fluoxetine and miconazole.

The enantiomeric separation of a series of imidazole analogues of Fluoxetine and Miconazole endowed with potent antifungal activity was performed using cellulose tris(4-methylbenzoate) (Chiralcel OJ) and cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD) as chiral stationary phases. Binary mixtures of n-hexane and alcohol as well as pure alcohols (ethanol or 2-propanol) were used as eluents. The enantiomer elution order was monitored by chiroptical detectors based on on-line optical rotation and circular dichroism measurements. For some of the compounds studied very high enantioseparation factor values (alpha > 7) on Chiralcel OJ CSP were observed. In order to study the chiroptical characteristics of the two most biologically active compounds, chromatographic resolutions were carried out on a semipreparative scale. Assignment of the absolute configuration was empirically established by comparing the CD spectra of the separated enantiomers with those obtained from the enantiomers of Miconazole.

Antidepressive Agents, Second-Generation↗