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PubMed1999

Dissecting functions of the retinoblastoma tumor suppressor and the related pocket proteins by integrating genetic, cell biology, and electrophoretic techniques.

The members of the 'pocket protein' family, comprising the retinoblastoma tumor suppressor (pRB) and its relatives, p107 and p130, negatively regulate cell proliferation and modulate fundamental biological processes including embryonic development, differentiation, homeostatic tissue renewal, and defense against cancer. The large, multidomain pocket proteins act by binding a plethora of cell fate-determining and growth-stimulatory proteins, the most prominent of which are the E2F/DP transcription factors. These protein-protein interactions are in turn regulated by carefully orchestrated phosphorylation events on multiple serine and threonine residues of pRB, p107, and p130, events which are carried out, at least in part, by the cyclin-dependent kinases that form the key elements of the cell cycle machinery. Here we discuss the recently obtained new insights into the diverse functions of the pRB family, and show examples of how integration of genetic, cell biology, and a range of electrophoretic approaches help to advance our understanding of the biological roles played by the pocket proteins in both normal and cancer cells.

Amino Acid Sequence↗

PubMed1999

The microbial proteome database--an automated laboratory catalogue for monitoring protein expression in bacteria.

Laboratories devoted to high-throughput characterisation of purified proteins arrayed via two-dimensional (2-D) gel electrophoresis face an arduous task in maintaining a centralised and constantly evolving record of information relating to the characterisation of proteins and their responses following biological challenges. The Microbial Proteome Database (MPD) has been conceived as an in-house resource for complementing the plethora of genomic databases available for such organisms. The database utilises commercially available software to provide an electronic 'lab book' of information obtained daily from 2-D electrophoresis gels, image analysis packages, protein characterisation methodologies, and biological experimentation. The MPD begins from a single 2-D gel image (a 2-D 'reference map') with clickable spots that link to a 'protein catalogue' (ProtCat) with spot information including protein identity, changes in expression determined under experimental conditions, cellular location, mass, and pI. The entry for each protein then contains further links to gel images corresponding to the presence of the particular protein within different subproteomes (as defined by the pH of narrow- and wide-range immobilised pH gradients or from differential extraction methods used to determine the location of the protein within a functional cell). The database currently contains information from strains of three microbial species (Escherichia coil, Pseudomonas aeruginosa and Staphylococcus aureus) and 32 master gel images. The rapid accessibility of information obtained from microbial proteomes is an essential step towards the integrated analysis of these organisms at the gene, transcript, protein and functional levels and will aid in reducing turnaround times between sample preparation and the discovery of molecules of biological significance.

Automation↗

PubMed2000

Neuroprotective effects of phenolic A ring oestrogens.

We have formulated the 'phenolic A ring hypothesis' for the neuroprotective effects of oestrogens based upon several observations: (i) structure-activity relationships show that a phenolic A ring and at least two additional rings are required for neuroprotection while oestrogenicity requirements are more stringent; (ii) neuroprotection with phenolic A ring compounds occurs in cells that lack oestrogen receptors and are not antagonized by anti-oestrogens; (iii) phenolic A ring compounds rapidly activate a variety of signal transduction pathways that are known to be involved in cell homeostasis; and (iv) in vivo, treatment with oestrogens results in a neuronal type-independent neuronal protection from ischaemic insult. Potential mechanisms of actions that may be involved in the neuroprotective effects of phenolic A ring compounds are: (i) oestrogen redox cycling that potently inhibits oxidative stress; (ii) interactions with signal transduction pathways including the transcription factor cAMP response element binding protein; and (iii) induction of anti-apoptotic proteins. These signalling pathways may individually or collectively contribute to the plethora of neuronal cell types that are protected from a variety of insults by oestrogen-like compounds.

Animals↗

PubMed1991

Psychosocial adjustment in women with breast cancer.

There is a plethora of studies investigating psychosocial adjustment in women with breast cancer, its correlates, clinical course, and prognosis. These studies have been conducted with varying degrees of methodologic rigor. An assessment has been made of the quality of this existing evidence to identify from the best evidence the factors which predict the adjustment status of women with breast cancer. Studies have been reviewed, using methodologic standards for the critical appraisal of studies on prognosis, developed by Sackett and colleagues in the Department of Clinical Epidemiology and Biostatistics at McMaster University (Hamilton, Ontario, Canada). Few of the studies investigating psychosocial adjustment of women with breast cancer meet all of the criteria for reviewing studies of clinical course and prognosis. This review focuses the direction and methodologic rigor required in future investigations. In particular, studies are needed that employ prospective designs and that deliberately measure or control for the extraneous prognostic variables that may affect adjustment. Future investigations need to incorporate adequate precision in measurement so that measures of the psychosocial variables are objective, reliable, and valid.

Adaptation, Psychological↗

PubMed2000

Multiparameter analysis of progeny of individual cells by laser scanning cytometry.

BACKGROUND: Effectiveness of antitumor drugs to suppress unrestricted proliferation of cancer cells is commonly measured by cell clonogenicity assays. Assays of clonogenicity are also used in studies of stem/progenitor cells and in analysis of carcinogenic transformation. The conventional assays are limited to providing information about frequency of colonies (cloning efficiency) and do not reveal the qualitative (phenotype) attributes of individual colonies that may yield clues on mechanisms by which cell proliferation was affected by the studied agent. METHODS: Laser scanning cytometry (LSC) was adapted to identify and characterize size and phenotype of colonies of MCF-7 cells growing in microscope slide chambers, untreated and treated with the cytotoxic ribonuclease, onconase (Onc). Individual colonies were located and data representing each colony were segmented based on >650-nm fluorescence excited by a He-Ne laser of the cells whose protein was stained with BODIPY 630/650-X. The DNA of the cells was stained with propidium iodide (red fluorescence) whereas specific proteins (estrogen receptor [ER] or tumor suppressor p53) were detected immunocytochemically (green fluorescence), each excited by an Ar ion laser. RESULTS: A plethora of attributes of individual colonies were measured, such as (a) morphometric features (area, circumference, area/circumference ratio, DNA or protein content per area ratio), (b) number of cells (nuclei), (c) DNA content, (d) protein content and protein/DNA ratio, and (e) expression of ER or p53 per colony, per total protein, per nucleus or per DNA, within a colony. Also cell cycle distribution within individual colonies and heterogeneity of colonies with respect to all the measured features could be assessed. The colonies growing in the presence of Onc had many of the above attributes different than the colonies from the untreated cultures. CONCLUSIONS: Analysis of the features of cell colonies by LSC provides a wealth of information about the progeny of individual cells. Changes in colony size and phenotype, reflecting altered cell shape, cell size, colony protein/DNA ratio, and expression of individual proteins, may reveal mechanisms by which drugs suppress the proliferative capacity of the cells. This may include inducing growth imbalance and differentiation and modulating expression of the genes that may be associated with cell cycle, apoptosis, or differentiation in a progeny of individual cells. Extensions of LSC may make it applicable for automatic analysis of cloning efficiency and multiparameter analysis of cell colonies in soft agar. Such analyses may be useful in studies of the mechanisms and effectiveness of antitumor drugs, in the field of carcinogenesis, and for analyzing primary cultures and assessing tumor prognosis and drug sensitivity. The assay can also be adapted to analysis of microbial colonies.

Boron Compounds↗

PubMed2000

Toward standardization of methods of determination of fracture properties of acrylic bone cement and statistical analysis of test results.

A succinct critical review of the literature on the fatigue, fatigue crack propagation, and fracture toughness (herein collectively termed "fracture properties") of acrylic bone cement is presented, whereby it is pointed out that a plethora of test conditions have been used. This situation precludes meaningful interstudy comparisons and mitigates against a definitive delineation of the effect of a named variable on a specified fracture property. A case for standardization of test conditions is thus made, culminating in the presentation of a recommended set of such conditions. In addition, it is shown that many literature parametric studies employed inappropriate statistical methods for performing pairwise comparisons, and all these studies have not addressed the issue of possible interactions between the parameters being investigated. A methodology for addressing these deficiencies is presented in the present report, and its use is illustrated with a set of notional fatigue test results.

Acrylates↗

PubMed2000

The effect of 50 Hz magnetic field on GCSmRNA expression in lymphoma B cell by mRNA differential display.

Magnetic fields (MFs) of various characteristics can lead to plethora effects in biological system. From a molecular point of view, we hypothesized that there must be a fundamental difference in gene expression between the MF exposed and the unexposed cell. To identify the classes of genes that are regulated, 0.8 mT 50 Hz MF-induced changes in gene expression were examined in a Daudi cell culture using differential display and reverse transcriptase-polymerase chain reaction. A candidate cDNA (signatured as MF-CB) that was observed in the sham-exposed but not in MF-exposed cultures was recovered and reamplified. After verification by Northern blot, the cDNA was cloned and sequenced. It was found that 254-base pair of 5'-end MF-CB cDNA clone was identical to gcs in open reading frame (ORF) range. Based on the preliminarily sequence, the prolonged length of 5'-end MF-CB cDNA was obtained by PCR amplification and its sequence analysis showed the same results as its original fragment. In order to further determine whether MF-CB cDNA is from gcs, two Northern blots were probed with gcs and MF-CB cDNA, respectively, and the data revealed signals of the same size and expression pattern on the two probe filters, which demonstrated that MF-CB is an EST (expression sequence tag) of gcs. gcs is a gene, identified recently (GenBank accession number D89866), encoding ceramide glucosyltransferase (GCS), which has been implicated as a causal element in human cell growth and differentiation. In an additional experiment, time-dependent changes in the transcription of gcs induced by 0.8 mT MF were observed by Northern blot with a sharp and reproducible inhibition effect after 20 min exposure and a reduction after 20-24 h exposure. The study demonstrates for the first time that 50 Hz MF can lead to changes in gcs transcription, which provides a new clue to elucidate the mechanism by which MF influence cell growth and differentiation.

Amino Acid Sequence↗

PubMed2001

An arrow for wingless to take-off.

The Wnt family of secreted glycoproteins is involved in the regulation of diverse developmental processes. The classical Wnt/beta-catenin pathway has been thoroughly investigated resulting in the identification of a plethora of components involved in the activation of beta-catenin target genes. Moreover, two additional Wnt-triggered pathways have been identified. These various signalling cascades require at least one component that confers signalling specificity. This function is fulfilled at least in part by the Wnt receptor Frizzled. The recent identification of a potential Frizzled co-receptor, an LDL-receptor-related-protein (LRP), sheds more light on Wnt-signal transduction specificity and promises more exciting revelations.

Animals↗

PubMed2001

DNA analysis on electrophoretic microchips: effect of operational variables.

Applicability of modern microfabrication technology to electrophoresis microchips initiated a rapidly moving interdisciplinary field in analytical chemistry. Electric field mediated separations in microfabricated devices (electrophoresis microchips) are significantly faster than conventional gel electrophoresis, usually completed in seconds to minutes. Electrophoretic separation of DNA molecules on microfabricated devices proved to have the potential to improve the throughput of analysis by orders of magnitude. The flexibility of electrophoresis microchips allows the use of a plethora of separation matrices and conditions. In this paper, we report on electric field mediated separation of fluorescent intercalator-labeled dsDNA fragments in polyvinylpyrrolidone matrix-filled microchannel structures. The separations were detected in real time by a confocal, single-point laser-induced fluorescence/photomultiplier setup. Effects of the sieving matrix concentration (Ferguson plot), migration characteristics (reptation plot), separation temperature (Arrhenius plot), as well as applied electric field strength and intercalator concentration on the separation of DNA fragments are thoroughly discussed.

DNA↗

PubMed1995

Cytochrome c oxidase: chemistry of a molecular machine.

The plethora of proposed chemical models attempting to explain the proton pumping reactions catalyzed by the CcO complex, especially the number of recent models, makes it clear that the problem is far from solved. Although we have not discussed all of the models proposed to date, we have described some of the more detailed models in order to illustrate the theoretical concepts introduced at the beginning of this section on proton pumping as well as to illustrate the rich possibilities available for effecting proton pumping. It is clear that proton pumping is effected by conformational changes induced by oxidation/reduction of the various redox centers in the CcO complex. It is for this reason that the CcO complex is called a redox-linked proton pump. The conformational changes of the proton pump cycle are usually envisioned to be some sort of ligand-exchange reaction arising from unstable geometries upon oxidation/reduction of the various redox centers. However, simple geometrical rearrangements, as in the Babcock and Mitchell models are also possible. In any model, however, hydrogen bonds must be broken and reformed due to conformational changes that result from oxidation/reduction of the linkage site during enzyme turnover. Perhaps the most important point emphasized in this discussion, however, is the fact that proton pumping is a directed process and it is electron and proton gating mechanisms that drive the proton pump cycle in the forward direction. Since many of the models discussed above lack effective electron and/or proton gating, it is clear that the major difficulty in developing a viable chemical model is not formulating a cyclic set of protein conformational changes effecting proton pumping (redox linkage) but rather constructing the model with a set of physical constraints so that the proposed cycle proceeds efficiently as postulated. In our discussion of these models, we have not been too concerned about which electron of the catalytic cycle was entering the site of linkage, but merely whether an ET to the binuclear center played a role. However, redox linkage only occurs if ET to the activated binuclear center is coupled to the proton pump. Since all of the models of proton pumping presented here, with the exception of the Rousseau expanded model and the Wikström model, have a maximum stoichiometry of 1 H+/e-, they inadequately explain the 2 H+/e- ratio for the third and fourth electrons of the dioxygen reduction cycle (see Section V.B). One way of interpreting this shortfall of protons is that the remaining protons are pumped by an as yet undefined indirectly coupled mechanism. In this scenario, the site of linkage could be coupled to the pumping of one proton in a direct fashion and one proton in an indirect fashion for a given electron. For a long time, it was assumed that at least some elements of such an indirect mechanism reside in subunit III. While recent evidence argues against the involvement of subunit III in the proton pump, subunit III may still participate in a regulatory and/or structural capacity (Section II.E). Attention has now focused on subunits I and II in the search for residues intimately involved in the proton pump mechanism and/or as part of a proton channel. In particular, the role of some of the highly conserved residues of helix VIII of subunit I are currently being studied by site directed mutagenesis. In our opinion, any model that invokes heme alpha 3 or CuB as the site of linkage must propose a very effective means by which the presumedly fast uncoupling ET to the dioxygen intermediates is prevented. It is difficult to imagine that ET over the short distance from heme alpha 3 or CuB to the dioxygen intermediate requires more than 1 ns. In addition, we expect the conformational changes of the proton pump to require much more than 1 ns (see Section V.B).

Amino Acid Sequence↗

PubMed1993

Olfactory receptors: transduction, diversity, human psychophysics and genome analysis.

The emerging understanding of the molecular basis of olfactory mechanisms allows one to answer some long-standing questions regarding the complex recognition machinery involved. The ability of the olfactory system to detect chemicals at sub-nanomolar concentrations is explained by a plethora of amplification devices, including the coupling of receptors to second messenger generation through GTP-binding proteins. Specificity and selectivity may be understood in terms of a diverse repertoire of olfactory receptors of the seven-transmembrane-domain receptor superfamily, which are probably disposed on olfactory sensory neurons according to a clonal exclusion rule. Signal termination may be related to sets of biotransformation enzymes that process odorant molecules, as well as to receptor desensitization. Many of the underlying molecular components show specific expression in olfactory epithelium, with a well-orchestrated developmental sequence of emergence, possibly related to sensory neuronal function and connectivity requirements. A general model for molecular recognition in biological receptor repertoires allows a prediction of the number of olfactory receptors necessary to achieve efficient detection and sheds light on the analogy between the immune and olfactory systems. The molecular cloning and mapping of a human genomic olfactory receptor cluster on chromosome 17 provides insight into olfactory receptor diversity, polymorphism and evolution. Combined with future genotype-phenotype correlation, with particular reference to specific anosmia, as well as with computer-based molecular modelling, these studies may provide insight into the odorant specificity of olfactory receptors.

GTP-Binding Proteins↗

PubMed1988

Bone cell biology: the regulation of development, structure, and function in the skeleton.

Bone cells compose a population of cells of heterogeneous origin but restricted function with respect to matrix formation, mineralization, and resorption. The local, mesenchymal origin of the cells which form the skeleton contrasts with their extraskeletal, hemopoietic relatives under which bone resorption takes place. However, the functions of these two diverse populations are remarkably related and interdependent. Bone cell regulation, presently in its infancy, is a complicated cascade involving a plethora of local and systemic factors, including some components of the skeletal matrices and other organ systems. Thus, any understanding of bone cell regulation is a key ingredient in understanding not only the development, maintenance, and repair of the skeleton but also the prevention and treatment of skeletal disorders.

Animals↗

PubMed2006

Genetics of Parkinson's disease and parkinsonism.

Until 10 years ago, conventional wisdom held that Parkinson's disease was not a genetic disorder. Since that time, there have been a plethora of genetic findings, culminating in the cloning of several genes that derive from the loci given the nomenclature PARK1-PARK12 (OMIM 168600). Recently, these research findings have begun to impact clinical practice, and this impact is likely to increase. The primary purpose of this article is to outline these genetic advances, discuss their importance for current practice in clinical and related settings, and outline briefly how they are influencing research into the causes of and possible future treatments for this prevalent disorder.

Aged↗

PubMed1992

New magnetic resonance techniques for evaluating cerebrovascular disease.

Magnetic resonance (MR) imaging of acute stroke has made important contributions to diagnosis. Several novel MR technologies, now in preclinical and clinical development, will contribute to stroke diagnosis and perhaps help to guide therapy. MR angiography is the most clinically advanced new MR technology and offers the clinician a method to image noninvasively the extra- and intracranial vasculature. Diffusion-weighted MR imaging can demonstrate ischemic lesions quantitatively within minutes of onset in experimental stroke models, and human application is proceeding. Perfusion MR studies can reveal the presence or absence of cerebral perfusion in specific arterial territories. MR spectroscopy can assess tissue metabolites in vivo and reveal changes in these metabolites associated with ischemic injury. The combination of these new MR techniques should provide a plethora of information about the extent of ischemic lesions, associated vascular and perfusion deficits, and metabolic consequences. This information will afford the clinician the opportunity to assess and subtype ischemic stroke patients more rapidly and could be used to monitor therapeutic responses.

Animals↗

PubMed2007

Polishing a diamond in the rough: "Cu--H" catalysis with silanes.

The value of a novel chemical transformation is often underappreciated at the time of its discovery. The reasons are doubtlessly manifold, but the "chemical zeitgeist" subtly determines how the new reaction will be received by the chemical community. The enantioselective reduction of carbonyls by copper-catalyzed hydrosilylation was certainly outshone by other asymmetric hydrogenation techniques. A seminal report at an early stage indicated the considerable potential of this catalytic process, yet it was disregarded for more than a decade. A refined mechanistic picture in connection with a plethora of new chiral ligands then led to copper-catalyzed 1,2- as well as 1,4-reductions of carbonyl compounds with excellent levels of enantioselection at high substrate-to-catalyst ratios and even more remarkable substrate-to-ligand ratios. The tide is turning for inexpensive copper catalysts in asymmetric hydride transfer reactions!

Journal Article↗

PubMed1991

Muscle spindle ultrastructure revealed by conventional and high-resolution scanning electron microscopy.

Muscle spindles in the tenuissimus muscle of mature golden Syrian hamsters were examined by conventional and high-resolution scanning electron microscopy (HRSEM). For conventional SEM, entire muscles were first fixed in 2.5% buffered glutaraldehyde. Spindles were then isolated with a dissecting microscope under darkfield illumination and postfixed in 1.0% OsO4. Some spindles were treated with 8 N HCl at 60 degrees C to clearly expose intrafusal fiber surfaces once the outer capsular sheath was mechanically disrupted. Preparation for HRSEM included aldehyde/osmium fixation and freeze-cleavage in liquid N2. The cytosol and certain cellular elements were also selectively extracted by immersion in 0.1% OsO4 for varying time intervals. In these preparations, the capsular sleeve showed a multilayered pattern of vesicle-laden cells with variant surface topography in different regions, including filopodia and small bristle-like surface-projections. An interlacing three-dimensional network of collagen fibrils intervened between the capsular lamellae. Within the spindles, sensory and fusimotor nerve endings closely adhered to the outer surfaces of intrafusal fibers. Sensory nerve terminals were enveloped by a prominent external lamina, and those that were cleaved open contained a plethora of elongated mitochondria that ran parallel with the longitudinal axis, along with vesicles, axoplasmic filaments, and lysosomes. Multiple adhesion sites between the sensory nerve membrane and the underlying sarcolemma of the intrafusal fiber were also observed in select regions. Fusimotor nerve endings were covered externally by processes of Schwann cells and their axoplasm was filled with a multitude of cellular organelles and synaptic vesicles.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Anatomy of the bilioduodenal junction of the opossum.

Prevention of reflux is a major function of the terminal biliary duct system at its junction with the duodenum. We examined this area via scanning electron microscopy and light microscopy to explore anatomic features that might play such a role in the Virginia opossum, a species with a highly developed sphincter of Oddi (SO). The terminal apparatus, most of which consists of a dilated extramural ampulla, has a lumen with abundant folds. Mucus is produced by the lining epithelium and by a plethora of glands. Three muscle layers constitute the SO: an inner longitudinal, an outer circular, and a less consistent outermost longitudinal. The terminal apparatus forms an acute angle and narrows as it enters the duodenum; at this point, the SO becomes continuous with the muscularis externa of the intestine. Four anatomical features with potential antireflux properties may be identified: mucus production, luminal folds, and the narrow opening and oblique course of the intramural duct.

Animals↗

PubMed2003

Tyramine and octopamine: antagonistic modulators of behavior and metabolism.

The phenolamines tyramine and octopamine are decarboxylation products of the amino acid tyrosine. Although tyramine is the biological precursor of octopamine, both compounds are independent neurotransmitters, acting through various G-protein coupled receptors. Especially, octopamine modulates a plethora of behaviors, peripheral and sense organs. Both compounds are believed to be homologues of their vertebrate counterparts adrenaline and noradrenaline. They modulate behaviors and organs in a coordinated way, which allows the insects to respond to external stimuli with a fine tuned adequate response. As these two phenolamines are the only biogenic amines whose physiological significance is restricted to invertebrates, the attention of pharmacologists was focused on the corresponding receptors, which are still believed to represent promising targets for new insecticides. Recent progress made on all levels of octopamine/tyramine research enabled us to better understand the molecular events underlying the control of complex behaviors.

Animals↗