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At least 397 records · Page 22Linked to original sources
PubMed2006

A complete mutational fitness map of the hepatitis C virus nonstructural 3 protease: relation to recognition by cytotoxic T lymphocytes.

The hepatitis C virus nonstructural (NS) 3/4A protease sequence is highly conserved for reasons not fully understood. We determined the protease activity in 181 NS3/4A gene products in which each protease residue was replaced by alanine or glycine. Unexpectedly, most (87%) protease residues could be replaced and protease activity would be retained. Using these data, we were able to identify a human leukocyte antigen A2-restricted epitope in which substitutions at 5 of 9 residues destroyed the protease. The NS3 protease shows an unexpectedly high plasticity, and it is therefore important to identify target sequences in which the appearance of mutations is restricted by viral fitness.

3C Viral Proteases↗
PubMed2005

Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes.

The macrophage lineage displays extreme functional and phenotypic heterogeneity, which appears to be because, in large part, of the ability of macrophages to functionally adapt to changes in their tissue microenvironment. This functional plasticity of macrophages plays a critical role in their ability to respond to tissue damage and/or infection and to contribute to clearance of damaged tissue and invading microorganisms, to recruitment of the adaptive immune system, and to resolution of the wound and of the immune response. Evidence has accumulated that environmental influences, such as stromal function and imbalances in hormones and cytokines, contribute significantly to the dysfunction of the adaptive immune system. The innate immune system also appears to be dysfunctional in aged animals and humans. In this review, the hypothesis is presented and discussed that the observed age-associated 'dysfunction' of macrophages is the result of their functional adaptation to the age-associated changes in tissue environments. The resultant loss of orchestration of the manifold functional capabilities of macrophages would undermine the efficacy of both the innate and adaptive immune systems. The macrophages appear to maintain functional plasticity during this dysregulation, making them a prime target of cytokine therapy that could enhance both innate and adaptive immune systems.

Aging↗
PubMed2005

Deafferentation and neurotrophin-mediated intraspinal sprouting: a central role for the p75 neurotrophin receptor.

Axonal plasticity in the adult spinal cord is governed by intrinsic neuronal growth potential and by extracellular cues. The p75 receptor (p75(NTR)) binds growth-promoting neurotrophins (NTs) as well as the common receptor for growth-inhibiting myelin-derived proteins (the Nogo receptor) and so is well situated to gauge the balance of positive and negative influences on axonal plasticity. Using transgenic mice lacking the extracellular NT-binding domain of p75(NTR) (p75-/- mice), we have examined the influence of p75(NTR) on changes in the density of primary afferent (calcitonin gene-related peptide-expressing) and descending monoaminergic (serotonin- and tyrosine hydroxylase-expressing) projections to the dorsal horn after dorsal rhizotomy, with and without concomitant application of exogenous nerve growth factor and NT-3. We found that, in intact p75-/- mice, the axon density of all populations was equal to or less than that in wild-type mice but that rhizotomy-induced intraspinal sprouting was significantly augmented. Monoaminergic axon sprouting was enhanced in both nerve growth factor- and NT-3-treated p75-/- mice compared with similarly treated wild-type mice. Primary afferent sprouting was particularly robust in NT-3-treated p75-/- mice. These in vivo results illustrate the interactions of p75(NTR) with NTs, with their respective tropomyosin-related kinase receptors and with inhibitory myelin-derived molecules. Our findings illustrate the pivotal role of p75(NTR) in spinal axonal plasticity and identify it as a potential therapeutic target for spinal cord injury.

Afferent Pathways↗
PubMed2006

Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites.

Mammalian target of rapamycin (mTOR) is implicated in synaptic plasticity and local translation in dendrites. We found that the mTOR inhibitor, rapamycin, increased the Kv1.1 voltage-gated potassium channel protein in hippocampal neurons and promoted Kv1.1 surface expression on dendrites without altering its axonal expression. Moreover, endogenous Kv1.1 mRNA was detected in dendrites. Using Kv1.1 fused to the photoconvertible fluorescence protein Kaede as a reporter for local synthesis, we observed Kv1.1 synthesis in dendrites upon inhibition of mTOR or the N-methyl-d-aspartate (NMDA) glutamate receptor. Thus, synaptic excitation may cause local suppression of dendritic Kv1 channels by reducing their local synthesis.

3' Untranslated Regions↗
PubMedDate not supplied

Cdk5: a novel role in learning and memory.

Learning and memory are processes by which organisms acquire, retain and retrieve information. They result in modifications of behavior in response to new or previously encountered stimuli thereby enabling adaptation to a permanently changing environment. Protein phosphorylation has long been known to play a key role in triggering synaptic changes underlying learning and memory. Although intracellular phosphorylation and dephosphorylation is orchestrated by a complex network of interactions between a number of protein kinases and phosphatases, significant advances in the understanding of neuronal mechanisms underlying learning and memory have been achieved by investigating the actions of individual molecules under defined experimental conditions, brain areas, neuronal cells and their subcellular compartments. On the basis of these approaches, the cyclic AMP protein kinase (PKA), protein kinase C (PKC) and extracellularly regulated protein kinases 1 and 2 (Erk-1/2) have been identified as the core signaling pathways in memory consolidation. Here we review recent findings demonstrating an important novel role for Cdk5 in learning and memory. We suggest that some of the well-characterized roles of Cdk5 during neurodevelopmental processes, such as interactions with distinct cytoplasmic and synaptic target molecules, may be also involved in synaptic plasticity underlying memory consolidation within the adult central nervous system.

Animals↗
PubMed2007

Development of cortical maps: perspectives from the barrel cortex.

One approach to examining how higher sensory, motor, and cognitive faculties emerge in the neocortex is to elucidate the underlying wiring principles of the brain during development. The mammalian neocortex is a layered structure generated from a sheet of proliferating ventricular cells that progressively divide to form specific functional areas, such as the primary somatosensory (S1) and motor (M1) cortices. The basic wiring pattern in each of these functional areas is based on a similar framework, but is distinct in detail. Functional specialization in each area derives from a combination of molecular cues within the cortex and neuronal activity-dependent cues provided by innervating axons from the thalamus. One salient feature of neocortical development is the establishment of topographic maps in which neighboring neurons receive input relayed from neighboring sensory afferents. Barrels, which are prominent sensory units in the somatosensory cortex of rodents, have been examined in detail, and data suggest that the initial, gross formation of the barrel map relies on molecular cues, but the refinement of this topography depends on neuronal activity. Several excellent reviews have been published on the patterning and plasticity of the barrel cortex and the precise targeting of ventrobasal thalamic axons. In this review, the authors will focus on the formation and functional maturation of synapses between thalamocortical axons and cortical neurons, an event that coincides with the formation of the barrel map. They will briefly review cortical patterning and the initial targeting of thalamic axons, with an emphasis on recent findings. The rest of the review will be devoted to summarizing their understanding of the cellular and molecular mechanisms underlying thalamocortical synapse maturation and its role in barrel map formation.

Animals↗
PubMed2005

Early and rapid targeting of eye-specific axonal projections to the dorsal lateral geniculate nucleus in the fetal macaque.

The emergence of eye-specific axonal projections to the dorsal lateral geniculate nucleus (dLGN) is a well established model system for exploring the mechanisms underlying afferent targeting during development. Using modern tract tracing methods, we examined the development of this feature in the macaque, an Old World Primate with a visual system similar to that of humans. Cholera toxin beta fragment conjugated to Alexa 488 was injected into the vitreous of one eye, and CTbeta conjugated to Alexa 594 into the other eye of embryos at known gestational ages. On embryonic day 69 (E69), which is approximately 100 d before birth, inputs from the two eyes were extensively intermingled in the dLGN. However, even at this early age, portions of the dLGN were preferentially innervated by the right or left eye, and segregation is complete within the dorsalmost layers 5 and 6. By E78, eye-specific segregation is clearly established throughout the parvocellular division of the dLGN, and substantial ocular segregation is present in the magnocellular division. By E84, segregation of left and right eye axons is essentially complete, and the six eye-specific domains that characterize the mature macaque dLGN are clearly discernable. These findings reveal that targeting of eye-specific axonal projections in the macaque occurs much earlier and more rapidly than previously reported. This segregation process is completed before the reported onset of ganglion cell axon loss and retino-dLGN synapse elimination, suggesting that, in the primate, eye-specific targeting occurs independent of traditional forms of synaptic plasticity.

Age Factors↗
PubMed2000

[Corticosteroid receptor and stress].

Adrenal corticosteroids readily enter the brain and exert markedly diverse effects, such as stress response of the target neural cells. These effects are regulated via two receptor systems, the mineralocorticoid receptor (MR; type I corticosteroid receptor) and the glucocorticoid receptor (GR; type II corticosteroid receptor), both of which are ligand-dependent transcription factors. MR is localized mainly in the hippocampus, and GR is distributed throughout the brain. MR and GR, however, are highly colocalized in the hippocampus, which is a target of the stress hormone and an especially plastic and vulnerable region of the brain. MR has a high affinity for corticosterone/cortisol, a common endogenous ligand for MR and GR, and is extensively bound at low levels of circulating corticosterone/cortisol. GR has a lower affinity and is extensively bound at high levels of circulating corticosterone/cortisol. These findings suggest that MR plays major roles under physiological conditions, whereas GR is mainly effective at high concentrations of corticosterone/cortisol, such as stressful conditions. The interactions of MR and GR in the hippocampal regions could be important for regulating stress response in the brain.

Animals↗
PubMedDate not supplied

[Morphology and electric instability of the myocardium in chronic coronary insufficiency].

Morphology and electric instability of the myocardium in patients with chronic coronary insufficiency have been studied in experiments on animals (rabbits), using a set of histological and histochemical techniques, and electron microscopy. Main aspects of myocardium reorganization at the subcellular, cellular, and tissual levels have been traced. The performed studies testify that the basic disturbances of the electric stability of the myocardium at chronic coronary insufficiency are based not upon some individual key pathogenic factor, but upon a series of alterations developing irregularly at all structural and functional levels of organization of the myocardium. That situation can be medically effectively corrected; very perspective in that respect is a targeted influence for optimizing the secretory-and-plastic function of ventricular cardiomyocytes (cardiac hystiocytes).

Animals↗
PubMed1987

Herpes zoster ophthalmicus.

The incidence and severity of herpes zoster ophthalmicus have increased because of the growing number of immunocompromised patients. Uveitis and keratitis are the most common inflammatory complications. Corneal exposure from scarring and contraction of the upper lid may require reconstructive plastic surgery. Preliminary studies of oral acyclovir, specifically targeted at preventing ocular complications, are encouraging.

Acyclovir↗
PubMed1994

[Nitric monoxide, a new neurotransmitter in the central nervous system].

Nitric oxide (NO) is a recently discovered endogenous molecule considered as an unconventional biological messenger. Experimental evidence indicates that, in the brain, NO is produced enzymatically (calcium-dependent mechanism) in response to stimulation of postsynaptic excitatory amino cid receptors. NO activates soluble guanylate cyclase, that results in increases of cGMP levels in target cells. NO is physiologically involved in synaptic plasticity mechanisms. In situation of excessive production, NO can exert neurotoxic effects, suggesting a role in neurodegenerative disorders, including post-ischemic damage.

Animals↗
PubMed2003

Cdk5 in the adult non-demented brain.

Cyclin-dependent kinase 5 (Cdk5), a Ser/Thr kinase, regulates the phosphorylation of neuronal proteins and thereby influences neuronal morphology, migration and axon growth. Tightly coordinated interactions between Cdk5 and its activator proteins p35 and p39 are critical for the developmental processes of post-mitotic neurons as well as functioning of the adult CNS. Excessive up-regulation of Cdk5 activity leading to hyperphosphorylation of cytoskeletal proteins has been linked to neurodegenerative disorders, such as Alzheimer's disease (AD). On this basis it was proposed that Cdk5 might be a promising drug target. The physiologic role of Cdk5 in the adult CNS has been addressed recently. It was demonstrated that Cdk5 is involved in striatal and hippocampal neuronal plasticity and long-term behavioral changes associated with these processes. On the basis of the newly identified role of Cdk5 in synaptic plasticity, learning and memory the view that Cdk5 represents a good drug target in AD accompanied by cognitive dysfunctions may have to be revisited. Alternatively, targeting the mechanisms up-stream of Cdk5 leading to deregulation of Cdk5 activity, such as proteolytic cleavage of its activating subunits may prove to be more beneficial as a therapeutical approach.

Animals↗
PubMed2007

DNA detection on plastic: surface activation protocol to convert polycarbonate substrates to biochip platforms.

A mild and efficient surface activation protocol to convert polycarbonate (PC) substrates, e.g., plastic bases of compact disks, to biochip platforms for DNA probe immobilization and target detection is described. The preparation procedure (activation, patterning, and coupling) is simple and effective; the on-chip hybridization is sensitive and selective. Particularly, UV/ozone treatment of PC sheets produces a hydrophilic surface with a high density of reactive carboxylic acid groups [(4.8 +/- 0.2) x 10-10 mol/cm2] in less than 10 min at ambient conditions, and no significant aging or physical damage to the substrate is observed. Covalent immobilization of DNA probes via both passive (reagent-less photopatterning and coupling in bulk solution phase) and flow-through (creation of microarrays with microfluidic channel plates) procedures has been demonstrated. Subsequent hybridization shows uniform and strong fluorescent signals for complementary target DNA and allows clear discrimination between fully complementary targets and strands with a single base-pair mismatch. The surface chemistry described herein will facilitate the development of disposable plastic biochips (not limited to DNA microarrays) and the fabrication of biomedical devices that are readable with conventional optical drives.

DNA↗
PubMed1993

Ageing in the autonomic nervous system: a result of nerve-target interactions? A review.

There are few generalisations that can be made regarding the changes that occur in autonomic nerves during ageing. Old age has different effects, including loss of neurones, loss of axon branches and alterations in neurotransmitters and other intracellular features. However, these age-related events are associated with particular and often small groups of neurones and are frequently species specific. Changes occur at different periods during development and maturity without any obvious age-stage at which neurodegenerative changes come to predominate. Some of the observations regarding neuronal changes in old age can be interpreted as the result of altered interactions between neurones and their peripheral target tissues. Recent studies in my laboratory support this contention. The neurotrophic theory has been used to explain such interactions during early development and it seems possible that, for example, alterations in the access of neurones to target-derived growth factors may underlie some of the changes that have been observed in old age. Plasticity in the mature autonomic nervous system may also be governed by similar relationships between nerves and their target tissues.

Aging↗
PubMed1998

Auditory attention in the congenitally blind: where, when and what gets reorganized?

Functional reorganization of auditory attention was studied in 12 congenitally blind subjects and 12 controls using high-density event-related potentials during a highly focused dichotic listening task. Reaction times for the attend-ear intensity-deviant targets were markedly faster for the blind. Brain activity associated with sustained attention (N1 effect, Nd), and with the automatic detection of deviants in an unattended channel (MMN), did not exhibit reorganization. In contrast, marked plasticity changes were reflected in late auditory attentional processing (attend-ear targets), in the form of a prolonged negativity (200-450 ms post-stimulus) that was absent in the sighted subjects. The plasticity changes in the blind had a time course indicating progressive recruitment of parietal and then occipital regions, providing new evidence for cross-modal sensory reorganization in the blind.

Adult↗
PubMed2001

Localization of low affinity nerve growth factor receptor in the rat inferior olivary complex during development and plasticity of climbing fibres.

The rat olivocerebellar pathway has a precise topography from an inferior olive (IOC) to Purkinje cells in the contralateral hemicerebellum. While its development and plasticity have been documented, the molecular mechanisms underlying these events are not fully elucidated. Neurotrophins are a family of growth factors with diverse roles in development and neuronal plasticity, acting through a two-receptor system, including a low affinity receptor (LNGFR) which binds all neurotrophins with similar affinity. Since neurotrophins are present in the cerebellum during early postnatal development when LNGFR is synthesized in the IOC, they may act as target-derived trophic agents for climbing fibres during development and plasticity. To assess this, standard immunohistochemistry was used to document the distribution of LNGFR in the rat IOC during climbing fibre development and until cerebellar development was complete at postnatal day 28 (P28). LNGFR immunoreactivity (LNGFR-IR) was detected in the IOC from P0 until P15, however after P7 it diminished in intensity and distribution, a change which indicates a relationship between cerebellar neurotrophins and climbing fibre development. After denervation of the left hemicerebellum, there was an apparent increase in inferior olivary LNGFR-IR that was concurrent with climbing fibre re-innervation. Thus the results of this study support the hypothesis that neurotrophins are involved in climbing fibre development and suggest a possible contribution to the plasticity of the olivocerebellar pathway.

Animals↗
PubMed2002

Age-related sympathetic ganglionic neuropathology: human pathology and animal models.

Systematic studies of the autonomic nervous system of human subjects and development of well-defined animal models have begun to substantially improve our understanding of the pathogenesis of autonomic dysfunction in aging and may eventually provide strategies for intervention. Neuropathological studies of the sympathetic ganglia of aged human subjects and rodent models have demonstrated that neuroaxonal dystrophy involving intraganglionic terminal axons and synapses is a robust, unequivocal and consistent neuropathological finding in the aged sympathetic nervous system of man and animals. Quantitative studies have demonstrated that markedly swollen argyrophilic dystrophic axon terminals develop in the prevertebral superior mesenteric (SMG) and coeliac, but to a much lesser degree in the superior cervical ganglia (SCG) as a function of age, sex (males more than females) and diabetes. Dystrophic axons were immunoreactive for neuropeptide Y, tyrosine hydroxylase, dopamine-beta-hydroxylase, trkA and p75NTR, an immunophenotype consistent with their origin from postganglionic sympathetic neurons, and contained large numbers of highly phosphorylated neurofilaments or tubulovesicular elements. The sympathetic ganglia of aged rodents also showed the hallmark changes of neuroaxonal dystrophy as a function of age and location (many more in the SMG than in the SCG). Plasticity-related synaptic remodeling could represent a highly vulnerable target of the aging process. The fidelity of animal models to the neuropathology of aged humans suggests that similar pathogenetic mechanisms may be involved in both and that therapeutic advances in animal studies may have human application.

Aging↗
PubMed1990

Cross-modal plasticity in cortical development: differentiation and specification of sensory neocortex.

Early developmental manipulations can induce sensory afferents of one modality to project to central targets of a different sensory modality. We and other investigators have used such cross-modal plasticity to examine the role of afferent inputs and their patterns of activity in the development of sensory neocortex. We suggest that the afferent rewiring can significantly influence the internal connectivity or microcircuitry of sensory cortex, aspects of which appear to be determined or specified relatively late in development, but that they cannot influence, or influence only to a minor extent, the laminar characteristics and external connectivity patterns of cortex, which appear to be specified earlier.

Animals↗