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At least 1,513 records · Page 84Linked to original sources
PubMed1982

Effect of various immunoregulatory substances on the growth inhibitory activity (GIA) of human monocytes against lymphoblastoid cell lines.

Human peripheral blood monocytes, isolated by adherence to plastic surfaces or elutriation by size, were tested for growth inhibitory activity (GIA) against human and mouse lymphoblastoid cell lines. Cells isolated by either method inhibited incorporation of 3H-thymidine of both target cells, but did not affect phytohemagglutinin-induced blasts. GIA was appreciably higher when the assays were performed in medium with human serum rather than fetal calf serum. Interferon significantly augmented GIA at a 10:1 effector:target (E/T) radio in a 24 hr assay, and at an E/T ratio of 30:1 in a 48 hr assay. Preincubation with phorbol myristate acetate (PMA) caused a threefold or greater increase in GIA by monocytes. Prostaglandins or indomethacin, as well as corticosteroids, did not influence GIA. Superoxide dismutase and catalase were not found to affect GIA when added to the assay. cytostatic activity by human monocytes is apparently subject to positive regulation, but not to suppression by prostaglandins. The mechanism responsible for GIA remains undetermined, but appears to be independent of superoxide radical generation.

Cell Line↗
PubMed1983

Hormonal regulation of sympathetic neuron development. The effects of neonatal castration.

The effects of neonatal castration on neuronal ontogeny were examined in peripheral sympathetic ganglia in male Sprague-Dawley rats. Tyrosine hydroxylase (T-OH) activity, the rate-limiting enzyme in catecholamine biosynthesis and a marker of noradrenergic maturation, was examined in the hypogastric (HG) and superior cervical ganglion (SCG). Initial studies characterized the normal development of T-OH activity in HG ganglia. Neonatal castration at 10-11 days of age prevented the normal ontogeny of HG T-OH activity: T-OH activity failed to develop normally and was 17% of sham-operated littermate controls when examined at 8 weeks of age, and less than 5% when studied 10 weeks after surgery. In contrast to the effects in HG, there was no change in enzyme activity in the SCG. Replacement therapy with testosterone decanoate completely reversed the developmental alteration in enzyme activity. These observations suggest that hormonal factors modulate noradrenergic ontogeny in peripheral sympathetic ganglia but these effects appear restricted to ganglia whose targets include hormonally dependent sex organs.

Animals↗
PubMed2026

CNNM2 in schizophrenia: multilevel evidence of genetic susceptibility, magnesium homeostasis, neurodevelopment and cognitive dysfunction.

Schizophrenia (SCZ) is a common psychiatric disorder with a complex, genetically and environmentally influenced etiology, but the specific pathogenesis remains unclear. In recent years, the SCZ susceptibility gene CNNM2 (encoding cyclin M2) located at the 10q24.32-33 locus has received widespread attention. The well-validated SCZ risk interval 10q24.32-33 harbors two independent risk variants: rs11191580 in NT5C2 (significantly associated with CNNM2 mRNA and protein levels) and rs7914558 in CNNM2. Results from functional genomic analyses indicate that lower CNNM2 expression is significantly associated with SCZ. Imaging genetics studies have demonstrated that carriers of risk alleles of CNNM2 SNPs exhibit alterations in brain structure. Animal model studies have revealed that Cnnm2 downregulation in mice leads to impairments in sensorimotor gating and cognitive function. As an Mg2+ transporter, CNNM2 primarily maintains systemic Mg2+ homeostasis. According to clinical studies, a proportion of patients with SCZ exhibit reduced Mg2+ concentrations in plasma and cerebrospinal fluid. CNNM2 dysfunction may contribute to the pathology of SCZ by disrupting Mg2+ homeostasis, thereby affecting neurodevelopment and synaptic plasticity. A systematic consolidation of current evidence supporting the involvement of CNNM2 in SCZ pathogenesis provides a direction for further investigation of the pathological mechanisms underlying this disease, and for identification of novel targets for clinical intervention..

Schizophrenia↗
PubMed2006

Complex functional interaction between integrin receptors and ion channels.

Integrin receptors mediate adhesion of the cell to the extracellular matrix and thereby regulate cell motility, proliferation, differentiation and apoptosis. These processes are frequently accompanied by alterations in ion flow. Recent evidence suggests that integrins can regulate ion channels and form macromolecular complexes, thus contributing to the localization of the channel onto the plasma membrane. The integrin-channel complex regulates downstream signaling proteins, such as tyrosine kinases and GTPases. This process could occur in plasma membrane microdomains, such as caveolae. It seems that ion channels sometimes transmit their signals through conformational coupling, instead of change in ion fluxes. Finally, the channel protein is not merely a final target, because it often feeds back by controlling integrin activation and/or expression. These findings have important implications for the physiology of normal and neoplastic cells and suggest interesting perspectives for studies of synaptic plasticity.

Animals↗
PubMed2005

In vivo inhibition of hippocampal Ca2+/calmodulin-dependent protein kinase II by RNA interference.

Hippocampal alpha-Ca2+/calmodulin-dependent protein kinase II (alpha-CaMKII) has been implicated in spatial learning, neuronal plasticity, epilepsy, and cerebral ischemia. In the present study, an adeno-associated virus (AAV) vector was designed to express green fluorescent protein (GFP) from the CBA promoter and a small hairpin RNA targeting alpha-CaMKII (AAV-shCAM) driven from the U6 promoter. The AAV-shCAM or control vector was microinfused into the rat hippocampus and behavioral testing conducted 19-26 days following surgery. Expression of the marker gene and alpha-CaMKII was evaluated 31 days following AAV infusion. GFP expression was localized to the hippocampus and extended +/-2 mm rostral and caudal from the injection site. Hippocampal alpha-CaMKII was significantly reduced following AAV-shCAM treatment as demonstrated using immunohistochemical and Western analysis. This suppression of alpha-CaMKII was associated with changes in exploratory behavior (open field task) and impaired place learning (water maze task). These results demonstrate the efficacy of a viral-based delivered shRNA to produce gene suppression in a specific circuit of the brain.

Animals↗
PubMed1998

Induction and transient suppression of long-term potentiation in the peri- and postrhinal cortices following theta-related stimulation of hippocampal field CA1.

During behavioral events associated with periods of likely mnemonic processing, CA1 pyramidal cells in rats typically discharge repetitively in either high-frequency bursts ('complex spikes') or single spikes, both of which are tightly phase-locked to the hippocampal theta rhythm. Interestingly, patterned stimulation which mimics the repetitive, learning-related complex spike discharges are optimal for inducing long-term potentiation (LTP) of excitatory field potentials in CA1, and patterned stimulation which mimics the theta-related single action potentials results in a robust and lasting depotentiation at these same synapses. The aim of the present study was to determine the extent to which these physiologically-relevant patterns of hippocampal stimulation have similar effects on synaptic efficacy in the monosynaptic projection from CA1 to the perirhinal and postrhinal cortices (PRh), areas thought to play a prominent role in many forms of learning and memory. Single-pulse stimulation of CA1 evoked a small amplitude, short latency population excitatory postsynaptic potential (EPSP) in the PRh. Theta-burst stimulation (TBS; n = 8) delivered to CA1 reliably potentiated the PRh EPSP slope for at least 30 min. Theta-pulse stimulation (TPS; 5 Hz; n = 4) delivered to CA1 5 min after TBS substantially but transiently suppressed EPSP slope relative to that of potentiated control preparations. Collectively these data suggest that theta-related patterns of hippocampal activation can reliably induce and transiently suppress LTP in PRh, and are consistent with the notion that behaviorally-relevant, theta-modulated patterns of CA1 unit activity may result in both long- and short-term alterations of synaptic strength within their rhinal cortical targets.

Action Potentials↗
PubMed2000

Enhanced accuracy of needle placement in horizontal stereotactic core biopsy by a plastic slot.

Horizontal stereotactic core biopsy can be used in the investigation of clinically occult mammographic abnormalities especially when breast thickness is less than 3 cm. We designed a 6-mm plastic slot that can be inserted between the bushing and the biopsy gun to enhance the accuracy of needle placement within the lesion. With this device, the centre of the lesion can be targeted at the centre of the biopsy trough. We advocate the use of this piece of small, simple and inexpensive instrument in every case of horizontal stereotactic core biopsy.

Biopsy, Needle↗
PubMed2001

Vision research: losing sight of eye dominance.

Most people prefer to use their right eye for viewing. New evidence reveals that this dominance is much more plastic than that for one hand or foot: it changes from one eye to the other depending on angle of gaze. Remarkably, sighting dominance depends on the hand being directed towards the visual target.

Dominance, Ocular↗
PubMed2003

Growth factors and stem cells as treatments for stroke recovery.

Both polypeptide growth factors and stem cell populations from bone marrow and umbilical cord blood hold promise as treatments to enhance neurologic recovery after stroke. Growth factors may exert their effects through stimulation of neural sprouting and enhancement of endogenous progenitor cell proliferation, migration, and differentiation in brain. Exogenous stem cells may exert their effects by acting as miniature "factories" for trophic substances in the poststroke brain. The combination of growth factors and stem cells may be more effective than either treatment alone. Stroke recovery represents a new and relatively untested target for stroke therapeutics. Whereas acute stroke treatments focus on agents that dissolve blot clots (thrombolytics) and antagonize cell death (neuroprotective agents), stroke recovery treatments are likely to enhance structural and functional reorganization (plasticity) of the damaged brain. Successful clinical trials of stroke recovery-promoting agents are likely to be quite different from trials testing acute stroke therapies. In particular, the time window of effective treatment to enhance stroke recovery is likely to be far longer than that for acute stroke treatments, perhaps days or weeks rather than minutes or hours after stroke. This longer time window means that time is available for careful screening and testing of potential subjects for stroke recovery trials, both in terms of size and location of cerebral infarcts and in type and severity of neurologic deficits. Detailed baseline information can be obtained for each patient against which eventual clinical outcome can be compared. Finally, separate and detailed outcome measures can be obtained in both the sensorimotor and cognitive neurologic spheres, because it is possible that these two kinds of function may recover differently or be differentially responsive to recovery-promoting treatments. Stroke recovery represents an important and underexplored opportunity for the development of new stroke treatments.

Bone Morphogenetic Protein 7↗
PubMed2002

Treatment of neural injury with marrow stromal cells.

We describe our preclinical studies on the use of bone-marrow stromal cells (MSC; an uncharacterised mixed population of plastic-adherent cells) in the treatment of neural injury. These cells obtained from donor rats or human beings have been directly transplanted into brain or administered intra-arterially or intravenously. MSC selectively target injured tissue and promote functional recovery. Signals that target inflammatory cells to injured tissue probably direct MSC to injury sites. Although some MSC express proteins typical of neural cells, the possibility that benefit is derived by replacement of infarcted tissue with differentiated MSC is highly unlikely. MSC activate endogenous restorative responses in injured brain, which include angiogenesis, neurogenesis, and synaptogenesis. Given the robust therapeutic benefit of these cells in the treatment of experimental neural injury, and the fact that MSC have been used in the treatment of other human disease, there is justification for further preclinical studies leading to clinical trials for the treatment of neural injury such as stroke.

Animals↗
PubMed1999

A solid-phase glycosyltransferase assay for high-throughput screening in drug discovery research.

Glycosyltransferases mediate changes in glycosylation patterns which, in turn, may affect the function of glycoproteins and/or glycolipids and, further downstream, processes of development, differentiation, transformation and cell-cell recognition. Such enzymes, therefore, represent valid targets for drug discovery. We have developed a solid-phase glycosyltransferase assay for use in a robotic high-throughput format. Carbohydrate acceptors coupled covalently to polyacrylamide are coated onto 96-well plastic plates. The glycosyltransferase reaction is performed with recombinant enzymes and radiolabeled sugar-nucleotide donor at 37 degrees C, followed by washing, addition of scintillation counting fluid, and measurement of radioactivity using a 96-well beta-counter. Glycopolymer construction and coating of the plastic plates, enzyme and substrate concentrations, and linearity with time were optimized using recombinant Core 2 beta1-6-N-acetylglucosaminyltransferase (Core 2 GlcNAc-T). This enzyme catalyzes a rate-limiting reaction for expression of polylactosamine and the selectin ligand sialyl-Lewis(x) in O-glycans. A glycopolymer acceptor for beta1-6-N-acetylglucosaminyltransferase V was also designed and shown to be effective in the solid-phase assay. In a high-throughput screen of a microbial extract library, the coefficient of variance for positive controls was 9.4%, and high concordance for hit validation was observed between the Core 2 GlcNAc-T solid-phase assay and a standard solution-phase assay. The solid-phase assay format, which can be adapted for a variety of glycosyltransferase enzymes, allowed a 5-6 fold increase in throughput compared to the corresponding solution-phase assay.

Acrylic Resins↗
PubMed2001

Kainate receptor-mediated heterosynaptic facilitation in the amygdala.

Prolonged low-frequency stimulation of excitatory afferents to basolateral amygdala neurons results in enduring enhancement of excitatory synaptic responses. The induction of this form of synaptic plasticity is eliminated by selective antagonists of GluR5 kainate receptors and can be mimicked by the GluR5 agonist ATPA. Kainate receptor-mediated synaptic facilitation generalizes to include inactive afferent synapses on the target neurons, and therefore contrasts with other types of activity-dependent enduring synaptic facilitation that are input-pathway specific. Such heterosynaptic spread of synaptic facilitation could account for adaptive and pathological expansion in the set of critical internal and external stimuli that trigger amygdala-dependent behavioral responses.

Amygdala↗
PubMed2005

Effects of dexmedetomidine on hippocampal focal adhesion kinase tyrosine phosphorylation in physiologic and ischemic conditions.

BACKGROUND: Dexmedetomidine is a potent and selective alpha2-adrenoceptor agonist that exhibits a broad pattern of actions, including sedation, analgesia, and neuroprotection. Some of these actions (e.g., neuroprotection) may require targets involved in long-term cellular changes. The authors hypothesized that dexmedetomidine increases the expression of active (autophosphorylated) focal adhesion kinase (FAK), a nonreceptor tyrosine kinase playing a pivotal role in cellular plasticity and survival. Therefore, we examined the cellular mechanisms involved in this effect and its sensitivity to oxygen-glucose deprivation (OGD) in rat hippocampal slices. METHODS: The effects of dexmedetomidine on phospho-tyrosine FAK phosphorylation were studied first with or without various pharmacologic agents in normoxic conditions, and second in a model of pharmacologic preconditioning of slices subjected to 30 min of OGD followed by 1 h of reperfusion. FAK phosphorylation and caspase-3 activation were examined by immunoblotting. Neuronal death was assessed by propidium iodide fluorescence. RESULTS: Dexmedetomidine produced a dose-related increase in FAK phosphorylation (187 +/- 4%, mean +/- SD, from basal level, EC50 = 0.2 microm; 95% confidence interval, 0.09-0.5 microm). This effect was stereoselective and was completely blocked by yohimbine and the combination of the cyclic monophosphate permeant analog 8 bromo cyclic monophosphate and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. It was mimicked by the protein kinase A inhibitor H 89. In contrast, prazosin and the protein kinase C inhibitors chelerythrine and bisindolylmaleimide I were ineffective. OGD induced a significant increase in immunoreactivity of the cleaved caspase-3 17-kd fragment (417 +/- 22; P < 0.001), a decrease in FAK phosphorylation (78 +/- 12% of control; P < 0.05), and production of significant neuronal death. In OGD conditions, a preconditioning application of dexmedetomidine (0.2 microm, 20-min application, 3 h before anoxia) significantly reduced neuronal death and cleaved caspase-3 expression and significantly attenuated the decrease in phosphorylated FAK content. The dexmedetomidine-induced reduction in caspase-3 expression was significantly decreased by the Src tyrosine kinase inhibitor PP2. CONCLUSION: Dexmedetomidine exhibits a preconditioning effect against ischemic injury in hippocampal slices subjected to OGD. Increase in phosphorylation of FAK via stimulation of alpha2 adrenoceptors and decrease in cleaved caspase-3 expression correlate with dexmedetomidine-induced cell survival.

Adrenergic alpha-Agonists↗
PubMed2004

Functional reorganization of the cerebral motor system after stroke.

PURPOSE OF REVIEW: Recovery of function after stroke is now widely considered to be a consequence of central nervous system reorganization. Non-invasive techniques such as functional magnetic resonance imaging, transcranial magnetic stimulation, electroencephalography and magnetoencephalography now allow the study of the working human brain. Studies in stroke patients can now address how cerebral networks in the human brain respond to focal injury and whether these changes are related to functional recovery. This understanding may in turn lead to the development of techniques that will drive cerebral reorganization in a way that promotes functional improvement. RECENT FINDINGS: The relationship between cerebral reorganization and functional recovery has been examined in both cross-sectional and longitudinal studies. It appears that the motor system reacts to damage in a way that attempts to generate motor output through surviving brain regions and networks. There are changes in cortical excitability after stroke that may provide the substrate whereby the effects of motor practice or experience can be more effective in driving long lasting changes in motor networks. This will be particularly important in intact portions of neural networks subserving motor skills learning. SUMMARY: Functionally relevant adaptive changes occur in the human brain following focal damage. A greater understanding of how these changes are related to the recovery process will allow the development of novel therapeutic techniques that are based on neurobiological principles and which are designed to minimize impairment in appropriately targeted patients suffering from stroke.

Functional Laterality↗
PubMed2000

A new beginning with new ends: linearisation of circular chromosomes during bacterial evolution.

Bacterial circular chromosomes have sporadically become linearised during prokaryote evolution. Unrelated bacteria, including the spirochete Borrelia burgdorferi and the actinomycete Streptomyces, have linear chromosomes. Linear chromosomes may have been formed through integration of linear plasmids. Linear chromosomes use linear plasmid strategies to resolve the 'end-of-replication problem', but they have generally retained from their circular ancestors a central origin of replication. Streptomyces linear chromosomes are very unstable and at high frequency undergo amplifications and large deletions, often removing the telomeres. At least in Streptomyces, chromosome linearity is reversible: circular chromosomes arise spontaneously as products of genetic instability or can be generated artificially by targeted recombination. Streptomyces circularised chromosomes are very unstable as well, indicating that genetic instability is not confined to the linearised chromosomes. Bacterial linear chromosomes may contain telomere-linked regions of enhanced genomic plasticity, which undergo more frequent genetic exchanges and rearrangements and allow differential evolution of genes, depending on their chromosomal location.

Bacteria↗
PubMed1994

Control of thalamocortical afferent rearrangement by postsynaptic activity in developing visual cortex.

The formation of specific connections in the developing central nervous system is thought to result from mechanisms that increase the strengths of synapses at which pre- and postsynaptic activity are correlated and decrease it otherwise. In the visual cortex, initially widespread inputs normally sort out into eye-specific patches during early life. If only one eye can see during this period, its patches are much larger than normal, and patches from the occluded eye become much smaller. Anatomical experiments here show that closed-eye inputs expand within a region of cortex that is silenced, establishing that inhibition of common target cells gives less active inputs a competitive advantage.

Animals↗
PubMed2005

Effect of saccadic adaptation on localization of visual targets.

Objects flashed briefly around the time of a saccadic eye movement are grossly mislocalized by human subjects, so they appear to be compressed toward the endpoint of the saccade. In this study, we investigate spatial localization during saccadic adaptation to examine whether the focus of compression tends toward the intended saccadic target or at the endpoint of the actual (adapted) movement. We report two major results. First, that peri-saccadic focus of the compression did not occur at the site of the initial saccadic target, but tended toward the actual landing site of the saccade. Second, and more surprisingly, we observed a large long-term perceptual distortion of space, lasting for hundreds of milliseconds. This distortion did not occur over the whole visual field but was limited to a local region of visual space around the saccade target, suggesting that saccadic adaptation induces a visuo-topic remapping of space. The results imply that the mechanisms controlling saccadic adaptation also affect perception of space and point to a strong perceptual plasticity coordinated with the well-documented plasticity of the motor system.

Adaptation, Physiological↗
PubMed2006

Interplay between the p53 tumor suppressor protein family and Cdk5: novel therapeutic approaches for the treatment of neurodegenerative diseases using selective Cdk inhibitors.

Cyclin-dependent kinases (Cdks) play a key role in orchestrating the coordination of cell cycle progression in proliferating cells. The escape from the proper control of the cell cycle by the upregulation of cyclins or aberrant activation of Cdks leads to malignant transformation. In quiescent cells and/or terminally differentiated cells, the expression pattern and activity of Cdks is altered. In postmitotic neurons, expression of mitotic kinases is downregulated, whereas Cdk5 expression becomes upregulated. Similarly to other Cdks, free Cdk5 displays no enzymatic activity and requires complex formation with a specific regulatory subunit. Two activators of Cdk5 have been identified. p35 and its isoform p39 bind to, and thereby activate, Cdk5. Unlike mitotic kinases, Cdk5 does not require activating phosphorylation within the T-loop. Because p35 is a short-lived protein, the p35/Cdk5 complexes are unstable. The stability of the p35 protein is regulated by its Cdk5-mediated phosphorylation of p35. Activated p35/Cdk5 kinase phosphorylates numerous physiological targets. The proper phosphorylation of the most important substrates, such as tau protein and neurofilament H, is essential for the correct regulation of the cytoskeletal organization, thereby regulating cell adhesion, motility, and synaptic plasticity. Moreover, Cdk5 regulates the activity of the p53 tumor suppressor via phosphorylation. p53 is upregulated in multiple neuronal death paradigms, including hypoxia, ischemia, and excitotoxicity, and plays a key role in the induction of apoptosis. On the other hand, an abnormally high expression and elevated activity of Cdk5 was observed in neurodegenerative diseases, suggesting the application of Cdk inhibitors for their therapy. Considering the action of some Cdk inhibitors on the expression and activity of the p53 protein, their therapeutic efficacy must be carefully evaluated.

Animals↗