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At least 757 records · Page 42Linked to original sources
PubMed2004

Divergence of the mRNA targets for the Ssb proteins of bacteriophages T4 and RB69.

The single-strand binding (Ssb) protein of phage T4 (T4 gp32, product of gene 32) is a mRNA-specific autogenous translational repressor, in addition to being a sequence-independent ssDNA-binding protein that participates in phage DNA replication, repair and recombination. It is not clear how this physiologically essential protein distinguishes between specific RNA and nonspecific nucleic acid targets. Here, we present phylogenetic evidence suggesting that ssDNA and specific RNA bind the same gp32 domain and that plasticity of this domain underlies its ability to configure certain RNA structures for specific binding. We have cloned and characterized gene 32 of phage RB69, a relative of T4 We observed that RB69 gp32 and T4 gp32 have nearly identical ssDNA binding domains, but diverge in their C-terminal domains. In T4 gp32, it is known that the C-terminal domain interacts with the ssDNA-binding domain and with other phage-induced proteins. In translation assays, we show that RB69 gp32 is, like T4 gp32, an autogenous translational repressor. We also show that the natural mRNA targets (translational operators) for the 2 proteins are diverged in sequence from each other and yet can be repressed by either gp32. Results of chemical and RNase sensitivity assays indicate that the gp32 mRNA targets from the 2 related phages have similar structures, but differ in their patterns of contact with the 2 repressors. These and other observations suggest that a range of gp32-RNA binding specificities may evolve in nature due to plasticity of the protein-nucleic acid interaction and its response to modulation by the C-terminal domain of this translational repressor.

Amino Acid Sequence↗
PubMed2000

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors.

Kinins are important mediators in cardiovascular homeostasis, inflammation, and nociception. Two kinin receptors have been described, B1 and B2. The B2 receptor is constitutively expressed, and its targeted disruption leads to salt-sensitive hypertension and altered nociception. The B1 receptor is a heptahelical receptor distinct from the B2 receptor in that it is highly inducible by inflammatory mediators such as bacterial lipopolysaccharide and interleukins. To clarify its physiological function, we have generated mice with a targeted deletion of the gene for the B1 receptor. B1 receptor-deficient animals are healthy, fertile, and normotensive. In these mice, bacterial lipopolysaccharide-induced hypotension is blunted, and there is a reduced accumulation of polymorphonuclear leukocytes in inflamed tissue. Moreover, under normal noninflamed conditions, they are analgesic in behavioral tests of chemical and thermal nociception. Using whole-cell patch-clamp recordings, we show that the B1 receptor was not necessary for regulating the noxious heat sensitivity of isolated nociceptors. However, by using an in vitro preparation, we could show that functional B1 receptors are present in the spinal cord, and their activation can facilitate a nociceptive reflex. Furthermore, in B1 receptor-deficient mice, we observed a reduction in the activity-dependent facilitation (wind-up) of a nociceptive spinal reflex. Thus, the kinin B1 receptor plays an essential physiological role in the initiation of inflammatory responses and the modulation of spinal cord plasticity that underlies the central component of pain. The B1 receptor therefore represents a useful pharmacological target especially for the treatment of inflammatory disorders and pain.

Animals↗
PubMed2005

Calcium-permeable acid-sensing ion channel is a molecular target of the neurotoxic metal ion lead.

Acid-sensing ion channels (ASICs) are emerging as fundamental players in the regulation of neural plasticity and in pathological conditions. Here we showed that lead (Pb2+), a well known neurotoxic metal ion, reversibly and concentration-dependently inhibited ASIC currents in the acutely dissociated spinal dorsal horn and hippocampal CA1 neurons of rats. In vitro expression of ASIC subunits in combination demonstrated that both ASIC1 and -3 subunits were sensitive to Pb2+. Mechanistically, Pb2+ reduced the pH sensitivity of ASICs independent of membrane voltage change. Moreover, Pb2+ inhibited the ASIC-mediated membrane depolarization and the elevation of intracellular Ca2+ concentration. In addition, we compared the effect of Pb2+ with that of Ca2+ or amiloride to explore the possible interactions of Pb2+ and Ca2+ in regulating ASICs, and we found that Pb2+ inhibited ASIC currents independent of the amiloride/Ca2+ blockade. Because ASIC1b and -3 subunits are mainly expressed in peripheral neurons, our data identified ASIC1a-containing Ca2+-permeable ASIC as a novel central target of Pb2+ action, which may contribute to Pb2+ neurotoxicity.

Acid Sensing Ion Channels↗
PubMed2003

Activation of erbB-1 signaling in tanycytes of the median eminence stimulates transforming growth factor beta1 release via prostaglandin E2 production and induces cell plasticity.

The activation of transforming growth factor alpha (TGFalpha)-erbB-1 and neuregulin-erbB-4 signaling pathways in hypothalamic astrocytes has been shown to play a key role in the process by which the neuroendocrine brain controls luteinizing hormone-releasing hormone (LHRH) secretion. Earlier studies suggested that tanycytes, an ependymoglial cell type of the median eminence, regulate LHRH release during the estrous cycle by undergoing plastic changes that alternatively allow or prevent direct access of the LHRH nerve terminals to the portal vasculature. Neither the molecules responsible for these plastic changes nor the underlying controlling mechanisms have been identified. Here we show that cultured tanycytes express erbB-1 and erbB-2, two of the four members of the erbB receptor family, and respond to TGFalpha with receptor phosphorylation, release of prostaglandin E2 (PGE2), and a PGE2-dependent increase in the release of TGFbeta1, a growth factor previously implicated in the glial control of LHRH secretion. Blockade of either erbB-1 receptor signal transduction or prostaglandin synthesis prevented the stimulatory effect of TGFalpha on both PGE2 and TGFbeta1 release. Time-lapse studies revealed that TGFalpha and TGFbeta1 have dramatically opposite effects on tanycyte plasticity. Whereas TGFalpha promotes tanycytic outgrowth, TGFbeta1 elicits retraction of tanycytic processes. Blockade of metalloproteinase activity abolished the effect of TGFbeta1, suggesting that TGFbeta1 induces tanycytic retraction by facilitating dissolution of the extracellular matrix. Prolonged (>12 hr) exposure of tanycytes to TGFalpha resulted in focal tanycytic retraction, an effect that was abolished by immunoneutralization of TGFbeta1 action, indicating that the retraction was attributable to TGFalpha-induced TGFbeta1 formation. These in vitro results identify tanycytes as targets of TGFalpha action and demonstrate that activation of erbB-1-mediated signaling in these cells results in plastic changes that, involving PGE2 and TGFbeta1 as downstream effectors, mimic the morphological plasticity displayed by tanycytes during the hours encompassing the preovulatory surge of LHRH.

Animals↗
PubMed2007

Conditional mouse models to study developmental and pathophysiological gene function in muscle.

This chapter will review conditional mouse model systems that have been developed to study gene function in skeletal, cardiac, and vascular smooth muscle cells in vivo with an emphasis on the utility of these models for investigating developmental and pathophysiological gene function in muscle. In general, these systems have utilized muscle-specific/selective promoter-enhancers in conjunction with site-specific DNA recombinases, e.g., Cre-loxP, and fusion proteins with these recombinases that confer temporal control, such as tamoxifen-inducible CreER systems. A major focus of this chapter will be to discuss unique challenges of studying Cre-mediated mutagenesis/gene targeting in these muscle types during development and in the adult animal, some of which are inherent of the muscle cell type being studied. For example, unlike cardiac and skeletal muscle cells, the vascular SMC is extremely plastic and able to undergo rapid phenotypic modulation to various environmental cues in vivo. Thus, employing SMC marker gene promoter enhancers for conditional gene targeting in SMCs must take into account the possibility and/or certainty that the particular SMC promoter enhancers used may or may not be transcriptionally active in SMCs of a vessel wall under normal and some pathophysiological conditions. Moreover, individual floxed loci within the same muscle cell type and tissue have different degrees of sensitivity to Cre, most likely dependent on the chromatin state of that particular gene, i.e., closed/condensed state or open/active state. Thus, Cre recombination may be ineffective for specific floxed gene DNA. Lastly, rigorous efforts must be made to confirm the degree of recombination in a tissue, taking into full account the multicellularity of the tissue, to understand the extent of the physiological effect in that organ.

Animals↗
PubMed1995

Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice.

Regulation of neurite outgrowth and structural plasticity may involve the expression of intrinsic determinants controlling growth competence. We have tested this concept by targeting constitutive expression of the growth-associated protein GAP-43 to the neurons of adult transgenic mice. Such mice showed striking spontaneous nerve sprouting at the neuromuscular junction and in the terminal field of hippocampal mossy fibers. In control mice, these nerve fibers did not express GAP-43, and did not sprout spontaneously. Lesion-induced nerve sprouting and terminal arborization during reinnervation were greatly potentiated in GAP-43-overexpressing mice. A mutant GAP-43 that cannot be phosphorylated by PKC had reduced sprout-promoting activity. The results establish GAP-43 as an intrinsic presynaptic determinant for neurite outgrowth and plasticity.

Animals↗
PubMed2001

Devising an integrated methodology for analyzing energy use and CO2 emissions from Taiwan's petrochemical industries.

Input-output modeling and multiplier analysis are used to assess Taiwan's five petrochemical industries, based upon their economic contribution and potential impacts on energy consumption and CO2 emission. In addition, a consolidated index system was developed for evaluating energy and economic efficiencies as well as targets for CO2 reduction. Results indicate that petrochemical materials (PM) make a major contribution to economic development, with lesser contributions from plastic materials (PL) and artificial fibres (AF). PM has the highest energy multiplier while PL has the largest induced potential for energy consumption. Plastic and rubber products (PP, RP) are relatively insignificant energy consumers. AF has the highest CO2 multiplier, and its induced potential for CO2 emission is the most significant. The consolidated index shows that the upstream petrochemical industries perform rather poorly in an integrated view of economic, energy, and CO2 emission, and should be seen as the primary targets for CO2 reduction. Investment of the petrochemical industries in Taiwan should be adjusted to improve energy efficiency, economic bases, and lower CO2 emissions.

Carbon Dioxide↗
PubMed2002

CFTR gene transfer to lung epithelium--on the trail of a target cell.

Cystic fibrosis (CF) is a lethal inherited disease that afflicts up to 1 in 2,500 people in the western world. Since 1989, when mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene were identified as responsible for the disease, intense effort has been applied to the development of replacement gene therapy strategies to cure CF. Problems with basic gene delivery techniques along with limited knowledge of the pathogenesis of CF have hindered progress so far. However, recent insights into the expression patterns and functions of CFTR in developing and adult lungs are now advancing our understanding of this disease. It is becoming apparent that progress in gene delivery to cure CF may be best served by identification of a target cell(s) around which gene transfer strategies can be specifically tailored to most closely reproduce the effects of normal CFTR expression. In fact, accurate restoration of endogenous expression patterns may be crucial, not only for disease reversal, but also to avoid potentially deleterious effects of inappropriate expression. This approach is in turn confounded however, by ill-defined stem and progenitor cell pathways within the lung epithelium. Nonetheless, studies to date suggest that these pathways are relatively plastic and may respond differently during homeostasis compared with repair following injury. It may therefore be feasible to target the lung epithelium in a non-cell specific manner and allow endogenous differentiation pathways to subsequently establish correct CFTR distribution patterns. In this review, emerging information on CFTR expression and function in developing and adult lungs is discussed in the context of putative stem cell populations and their potential for current gene delivery approaches.

Animals↗
PubMed2001

Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders.

It is currently a widely accepted opinion that adaptive, plastic changes in the molecular and cellular components of neuronal signaling systems correlate with the effects on mood and cognition observed after long-term treatment with antidepressant drugs. Protein phosphorylation represents a key step for most signaling systems, and it is involved in the regulation of virtually all cellular functions. Two serine/threonine kinases, Ca2+ /calmodulin-dependent protein kinase II and cyclic AMP-dependent protein kinase, have been shown to be activated in the brain following antidepressant treatment. The changes in kinase activity are mirrored by changes in the phosphorylation of selected protein substrates in subcellular compartments (presynaptic terminals and microtubules), which, in turn, may contribute to the modulation of synaptic transmission observed with antidepressants. The molecular consequences of protein kinase activation may account for some of the alterations in neural function induced by antidepressants, and may suggest novel possible strategies of pharmacological intervention.

Animals↗
PubMed1996

The regulated secretion and vectorial targeting of neurotrophins in neuroendocrine and epithelial cells.

The varied roles that neurotrophins play in the development and activity-dependent plasticity of the nervous system presumably require that the sites and quantity of neurotrophin release be precisely regulated. As a step toward understanding how different neurotrophins are sorted and secreted by neurons, we expressed nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 in cell lines used as models for neuronal protein sorting. All three neurotrophins were secreted by a regulated pathway in transfected AtT-20 and PC12 neuroendocrine cells, with a 3-6-fold increase in neurotrophin release in response to 8-bromo-cAMP or depolarization, respectively. To determine if the propeptide directs the intracellular sorting of mature NGF, we examined mutants in which regions spanning the propeptide were deleted. These mutants underwent regulated release in every case in which expression could be detected. Similarly, NGF sorting was not significantly altered by mutations which specifically abolished N-glycosylation or proteolytic processing sites within the NGF precursor. Finally, we found that all three neurotrophins were secreted 65-75% basolaterally by polarized Madin-Darby canine kidney epithelial cells. These findings suggest that the determinants of regulated neurotrophin secretion lie within the mature neurotrophin moiety and that NGF, brain-derived neurotrophic factor, and neurotrophin-3 are likely to be sorted similarly and released in a regulated manner by neurons.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Modern synthetic methods for fluorine-substituted target molecules.

Fluorine has come to be recognized as a key element in materials science: in heat-transfer agents, liquid crystals, dyes, surfactants, plastics, elastomers, membranes, and other materials. Furthermore, many fluorine-containing biologically active agents are finding applications as pharmaceuticals and agrochemicals. Progress in synthetic fluorine chemistry has been critical to the development of these fields and has led to the invention of many novel fluorinated molecules as future drugs and materials. As a result of the electronic effects of fluorine substituents, fluorinated substrates and reagents often exhibit unusual and unique chemical properties, which often make them incompatible with established synthetic methods. Thus, the problem of how to control the unusual properties of compounds with fluorine substituents deserves much attention, so as to promote the design of facile, efficient, and environmentally benign methods for the synthesis of valuable organofluorine targets.

Chemistry, Agricultural↗
PubMed1995

The alpha-Ca2+/calmodulin kinase II: a bidirectional modulator of presynaptic plasticity.

The alpha-Ca2+/calmodulin kinase II (alpha CaMKII) is required for long-term potentiation in the CA1 region of the hippocampus. Here, we report that this kinase also has a crucial role in presynaptic plasticity. Paired-pulse facilitation is blunted in the CA1 region of mice heterozygous for a targeted mutation of alpha CaMKII, confirming that this kinase can promote neurotransmitter release. Unexpectedly, field and whole-cell recordings of posttetanic potentiation show that the synaptic responses of mutants are larger than those of controls, indicating that alpha CaMKII can also inhibit transmitter release immediately after tetanic stimulation. Thus, alpha CaMKII has the capacity either to potentiate or to depress excitatory synaptic transmission depending on the pattern of presynaptic activation.

Animals↗
PubMed2005

Task-switching with antisaccades versus no-go trials: a comparison of inter-trial effects.

Antisaccades involve the suppression of a pre-potent prosaccade and a vector inversion to generate the novel ocular motor response of looking away from the target. Antisaccades have also been found to prolong the latencies of saccades in upcoming trials, an effect that we attribute to a form of immediate plasticity in the ocular motor system. Our goal was to determine whether the inter-trial effects of antisaccades were similar to that of no-go trials, where subjects must suppress making a saccade when the target appears without substituting a novel ocular motor response. We tested 12 subjects with two different blocks of saccadic trials. In one, prosaccades randomly alternated with antisaccades. In the other, prosaccades alternated with no-go trials. We analyzed the error rates and latencies of prosaccades that followed antisaccades versus no-go trials, compared to repeated prosaccades, to determine if inter-trial effects were present for both types of responses that required prosaccade suppression. No-go responses increased the error rates of prosaccades in the following trial less than antisaccades did. However, no-go trials had the same effect on the latencies of upcoming prosaccades as antisaccades. The inhibitory effect that prolongs the latencies of prosaccades after antisaccades likely stems from the need to inhibit a prosaccade, a function that is also required in no-go trials. The greater impairment of prosaccade accuracy after an antisaccade may reflect either additional control mechanisms involved in vector inversion or a different form of inhibitory control that operates during antisaccades and not during no-go responses.

Adult↗
PubMed1993

Rapid plastic response following early retinal lesions in rats.

Following an early retinal lesion, aberrant uncrossed projections from the opposite, undamaged, retina form in the target visual nuclei. The present study has examined the development of such aberrant projections by making retinal lesions in newborn rat pups, and then examining the nature of the uncrossed retinocollicular projection at different ages following the lesion. Intravitreal injections of horseradish peroxidase were made into the intact eye, and the uncrossed projection was subsequently revealed histochemically. A mature aberrant projection forms as early as postnatal day 9. On postnatal days 5 and 2, aberrant projections are discernable amongst the exuberant uncrossed terminals of normal developing rats, although the former have not matured to form the dense terminal fields characteristic of older projections. Aberrant projections were also detectable as early as 12 h following the lesion, revealed as a relative increase in the density of uncrossed label. These results indicate that lesion-induced plastic responses by intact retinal arbors are initiated shortly after the insult, and they caution the use of retinal lesions in studies of normal retinotopic connectivity during development.

Animals↗
PubMed2000

Online head motion tracking applied to the patient registration problem.

Image-guided systems for surgical procedures in the region of the head require a method to correlate the diagnostic image data with the corresponding site of pathology in the patient. Considering that patient movement can occur, detection and correction of such movement errors during the acquisition of images is a basic prerequisite for accurate treatment. For this reason, we developed a new registration method based upon on-line tracking of the patient's head to solve the problem of registration in the presence of head motion. The method provides non-invasive active patient registration for correction of movements during imaging and continuous update of the patient's head position during surgery. The patient motion correction applies the rigid body model to register the images using feature correspondence. The new registration method is described, and results of experiments that were performed to evaluate its accuracy and reliability in a plastic skull model and in patients are presented. The error analysis resulted in a final target registration error of 0.90 mm +/- 0.16 mm using experimental model data and 1.58 mm +/- 0.26 mm using clinical patient data. In addition, the residual registration error is modeled as a function of the measured and predicted head motion in order to determine the error that is introduced by motion tracking during image data acquisition. Furthermore, the clinical application of the method is demonstrated for oto-, rhino-, and neurosurgical procedures in the region of the head.

Algorithms↗
PubMed1999

Chemicals from biotechnology: molecular plant genetics will challenge the chemical and the fermentation industry.

Industrial biotechnology has evolved as a significant manufacturing tool for products like fuel-grade ethanol, organic acids and bulk amino acids, but most items are still speciality products for food and pharmaceutical applications. Current development projects within the chemical industry, including lactic acid and 1,3-propanediol based polymers and plastics, indicate that new biotechnological processes and products may soon approach the market place, clearly targeted at the leading petrochemical bulk outlets. This is flanked by a strategic shift by the major chemical companies in to "life sciences"-pharmaceuticals, agrochemicals and the seed business as well as biotech fine chemicals. The recent tremendous achievements in molecular plant genetics and transgenic crop breeding will boost agrobiotechnology, agriculture and renewable raw materials as compelling projects for chemistry and biotechnology. New plant-based production routes may challenge established chemical and biochemical domains, but at the same time open new horizons to valuable feedstocks, intermediates and end-products.

Biotechnology↗
PubMed1992

Afferent-boundary interactions in the developing neostriatal mosaic.

The caudate-putamen (neostriatum) of the mammalian basal ganglia is composed of two neurochemically distinct compartments termed patch (island, striosome) and matrix that overall contribute to a mosaic organization. In the present study, the distribution of the developmentally regulated extracellular matrix molecule tenascin, as well as several other neural cell adhesion molecules, was examined in the neostriatal mosaic of the early postnatal mouse and compared with tyrosine hydroxylase distribution following partial destruction of the dopaminergic nigrostriatal projection. During normal neostriatal development, tenascin is most dense within the matrix compartment and highly concentrated in boundaries around patches. This pattern is apparent on embryonic day 18, and for the most part disappears by postnatal day 12. Tenascin immunoreactivity is altered in the neostriatum following lesions of the nigrostriatal pathway in the first postnatal week revealed by an overall reduced expression of this molecule and a marked reduction in tenascin staining of boundaries at the interface of tyrosine hydroxylase-rich patch and tyrosine hydroxylase-poor matrix compartments. When compared to tyrosine hydroxylase immunoreactivity, other cell adhesion molecules tested failed to show altered intensities and patterns of immunoreactivity within the neostriatum after similar lesions. Reduced levels of tenascin in the lesioned neostriatum, in register with altered levels of tyrosine hydroxylase immunostaining of dopaminergic inputs, suggests that axons may affect the expression of particular recognition molecules in their target structures. The fact that boundaries are malleable can be related to afferent-induced plastic events in the differentiation of cellular elements in the developing nigrostriatal system.

Animals↗
PubMed1995

Co-existence of NADPH-diaphorase, fibroblast growth factor-2 and fibroblast growth factor receptor in spinal autonomic system suggests target-specific actions.

In the rat spinal cord, we found substantial co-existence of fibroblast growth factor-2, fibroblast growth factor receptor (type-1 or flg) immunoreactivity and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase activity (a histochemical marker for neuronal nitric oxide synthase) in preganglionic autonomic cell groups of intermediate layers VI, VII and X. Anti-fibroblast growth factor-2 and anti-nitric oxide synthase binding sites were confined to the cytoplasm of reactive neurons as judged by immunogold electron microscopy. Within the major autonomic nucleus, i.e. intermediolateral column, three different populations were identified: (i) fibroblast growth factor and fibroblast growth factor receptor, (ii) fibroblast growth factor/NADPH-diaphorase and (iii) NADPH-diaphorase-only stained cell groups. Sympathoadrenal neurons were prelabelled with fluorescent tracer Fast Blue and co-stained for fibroblast growth factor-like protein and NADPH-diaphorase, suggesting heterologous diversification of neuronal phenotypes and functional organization in the spinal autonomic system. Our findings suggest intriguing roles for nitric oxide and fibroblast growth factor-2 cytokine in the preganglionic sympathetic spinal cord system: The "short-term" diffusible messenger nitric oxide may act as "tonic" and/or "phasic" signal within rostrocaudally oriented function-specific preganglionic units necessary for integrated target control. The "long-term" messenger fibroblast growth factor-2 may be involved in, for example, cytokine-dependent regulation of neuronal NADPH-diaphorase/nitric oxide synthase. Furthermore, co-existence of NADPH-diaphorase, fibroblast growth factor-2 and receptor in sympathoadrenal neurons suggest mutual target-specific regulatory functions, e.g. hormone release and blood perfusion or maintenance of phenotype and plasticity responsiveness of adrenal medullary tissue.

Animals↗