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At least 721 records · Page 40Linked to original sources
PubMed2004

Retinoic acid reverses the PTU related decrease in neurogranin level in mice brain.

Recent data have shown that fine regulation of retinoid mediated gene expression is fundamentally important for optimal brain functioning in aged mice. Nevertheless, alteration of the thyroid hormone signalling pathway may be a limiting factor, which impedes retinoic acid (RA) from exerting its modulating effect. Mild hypothyroidism is often described in the elderly. Thus, in the present study, it was of interest to determine if RA exerts its neurological modulating effect in mild hypothyroidism. To obtain further insight into this question, mice were submitted to a low propylthiouracyl (PTU) drink (0.05%) in order to slightly reduce the serum level of triiodothyronine (T3). A quantitative evaluation of RA nuclear receptors (RAR, RXR), T3 nuclear receptor (TR) and of neurogranin (RC3, a RA target gene which codes for a protein considered as a good marker of synaptic plasticity) in PTU treated mice injected with vehicle or RA or T3 was carried out. The PTU-related decrease in expression of RAR, RXR and RC3 was restored following RA or T3 administration, as observed in aged mice. The amount of TR mRNA, which was not affected in PTU treated mice, was increased only after T3 treatment as observed in overt hypothyroidism. These results suggest that neurobiological alterations observed in aged mice are probably related to RA and T3 signalling pathway modifications associated, in part, with mild changes in thyroid function.

Animals↗
PubMed1995

Long-term potentiation and depression of synaptic transmission in rat posterior cingulate cortex.

We used stimulation of corpus callosum (CAL) and the subiculo-cingulate tract (SCT), in an in vitro brain slice preparation, to study activity-dependent changes in synaptic efficacy in posterior cingulate cortex (PCC). SCT stimulation monosynaptically excites the apical dendrites of deep laminae (V-VI) pyramidal neurons, while CAL afferents drive these same cells via synapses on their basal dendrites. In contrast, most superficial laminae (II/III-IV) pyramids appear to be driven polysynaptically via ascending axonal collaterals of deep pyramids. In slices retaining these connectivities, we contrasted characteristics of synaptic plasticity in superficial vs deep laminae field and intracellular potentials evoked by conditioning stimuli given at frequencies of 100, 20, 8, 5 and 1 Hz. Tetanic stimulation (100 Hz) of SCT or CAL yielded homosynaptic long-term potentiation (LTP) of each pathway, while stimulus trains of 8-20 Hz did not. 1-5 Hz stimulation of SCT and CAL elicited homosynaptic long-term depression (LTD) of synaptic strength in each pathway. Associative LTD was induced by interleaving 5 Hz pulses to the SCT pathway with 100 Hz theta-burst stimulation of CAL, but was not induced when these stimulus loci were switched. Heterosynaptic non-associative LTD was also observed in the alternate pathway following tetanization of either SCT or CAL. In all cases, LTP and LTD were observed only in deep laminae recordings. In contrast, superficial records showed only paired-pulse facilitation and short-term post-tetanic potentiation. In in vivo experiments in anaesthetized rats, PCC responses to SCT stimulation were contrasted with responses to stimulation of anteroventral and anterodorsal thalamic nuclei (AV/AD). SCT-elicited field potentials closely resembled those evoked in the slice, with maximal amplitude tuned to the 4-8 Hz frequency band. AV/AD stimulation elicited field potentials which were not frequency tuned. Overall, these data suggest that the acute circuit properties of PCC superficial laminae, modulated by thalamic input and synaptic plasticity in deep laminae, can transform hippocampal synaptic inflow before relaying it to extracingulate targets.

Animals↗
PubMed1987

Noradrenergic, serotonergic, and cholinergic sprouting in the hippocampus that follows partial or complete transection of the septohippocampal pathway: contributions of spared inputs.

The aminergic and cholinergic fibers innervating the hippocampus reach their target regions via the dorsal (dorsal fornix, fimbria, and cingulum) and ventral routes. The plasticity of this innervation after lesions of the dorsal pathway was investigated in the septal, medial, and temporal regions of the adult rat hippocampus. The extent and time course of sprouting was assessed by determining high-affinity uptake of [3H]noradrenaline and [3H]serotonin, and the activities of cholinergic enzymes 1 week to 6 months after partial or complete transection of the dorsal pathway. The initial decline in these terminal indices resulting from the transection of the medial or lateral half of the dorsal pathway reflected the distribution of their respective terminal sites in the three hippocampal regions. Longer survival after such lesions led to a substantial recovery of cholinergic and noradrenergic markers indicating reinnervation of the hippocampus by spared dorsal and/or by undamaged ventral afferent fibers. Whether the recovery was complete or not, the sprouting of spared dorsal fibers was maximum within a relatively shorter postlesion survival whereas that of the ventral afferents continued for a longer time. In contrast to the extent of noradrenergic and cholinergic restitution, very poor serotonergic recovery was seen in the same animal in spite of the availability of spared serotonergic afferent fibers and regardless of the duration of postlesion survival. The apparently finite capacity of spared axons for postlesion reinnervation was not increased by longer survival. Amplification of this property of central neurons by other interventions may supplement the approach of transplantation for recovery of function following injury.

Acetyl Coenzyme A↗
PubMed2006

Density and morphology of dendritic spines in mouse neocortex.

Dendritic spines of pyramidal cells are the main postsynaptic targets of cortical excitatory synapses and as such, they are fundamental both in neuronal plasticity and for the integration of excitatory inputs to pyramidal neurons. There is significant variation in the number and density of dendritic spines among pyramidal cells located in different cortical areas and species, especially in primates. This variation is believed to contribute to functional differences reported among cortical areas. In this study, we analyzed the density of dendritic spines in the motor, somatosensory and visuo-temporal regions of the mouse cerebral cortex. Over 17,000 individual spines on the basal dendrites of layer III pyramidal neurons were drawn and their morphologies compared among these cortical regions. In contrast to previous observations in primates, there was no significant difference in the density of spines along the dendrites of neurons in the mouse. However, systematic differences in spine dimensions (spine head size and spine neck length) were detected, whereby the largest spines were found in the motor region, followed by those in the somatosensory region and those in visuo-temporal region.

Animals↗
PubMed2026

Exploiting DNA damage tolerance for precision oncology.

Unresolved DNA lesions trigger replication stress, forcing cancer cells to hijack DNA damage tolerance (DDT) networks, specifically translesion synthesis (TLS) and template switching, to sustain replication. While DDT prevents lethal fork collapse, error-prone TLS drives mutagenesis, tumor evolution, chemoresistance and radioresistance. Proliferating cell nuclear antigen post-translational modifications dynamically govern pathway selection. Cancer cells exploit this plasticity, creating actionable vulnerabilities such as postreplicative single-stranded DNA gaps. Emerging inhibitors targeting TLS polymerases, upstream regulators such as ubiquitin-specific peptidase 1 (USP1), and critical protein-protein interactions offer unprecedented opportunities for precision oncology. By integrating DDT inhibition with biomarkers such as homologous recombination deficiency and tumor mutational burden, we can drive synthetic lethality, sensitize tumors to genotoxic agents, suppress treatment-induced mutagenesis, and potentially enhance responses to immunotherapy.

DDT↗
PubMed1982

Characterization of the effector cells responsible for tumour resistance in Salmonella enteritidis 11RX-immunized mice.

In an attempt to characterize the effector cells responsible for tumour resistance in Salmonella enteritidis 11RX-immunized mice the anti-macrophage agent trypan blue was used in both in vivo and in vitro experiments. Resistance was measured in vivo by the clearance of 125I from the peritoneal cavity of mice injected intraperitoneally with 125I-5-iododeoxyuridine labelled Ehrlich Ascites Tumour (EAT) cells. The in vitro correlate was measured by lysis of 51Cr-labelled tumour cells by peritoneal cells (PC) from 11RX-immunized mice. Pre-treatment of resistant mice with trypan blue greatly reduced both 125I clearance and 51Cr release. The in vitro cytolytic activity was non-specific. Fractionation of cytotoxic PC on the basis of adherence to plastic or nylon wool and buoyant density, coupled with the use of appropriate cell targets, showed that the bulk of cytotoxic activity resided with macrophages, with some contribution from other cells such as natural killer cells. Killing of labelled tumour cells could be inhibited by competition with unlabelled cells or by separating the PC and tumour cells by a cell impermeable membrane. This showed that close association between the effector and target cells was necessary before killing could occur.

Animals↗
PubMed2003

Real-time imaging of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor) movements in neurons.

The mechanisms that regulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) synthesis, transport, targeting and surface expression are of fundamental importance for fast excitatory neurotransmission and synaptic plasticity in the mammalian central nervous system. It has become apparent that these control processes involve complex sets of protein-protein interactions and many of the proteins responsible have been identified. We have been working to visualize AMPAR movement in living neurons in order to investigate the effects of blocking protein interactions. Here we outline the approaches used and the results obtained thus far.

Animals↗
PubMed2001

Retrograde signaling at central synapses.

Transcellular retrograde signaling from the postsynaptic target cell to the presynaptic neuron plays critical roles in the formation, maturation, and plasticity of synaptic connections. We here review recent progress in our understanding of the retrograde signaling at developing central synapses. Three forms of potential retrograde signals-membrane-permeant factors, membrane-bound factors, and secreted factors-have been implicated at both developing and mature synapses. Although many of these signals may be active constitutively, retrograde factors produced in association with activity-dependent synaptic plasticity, e.g., long-term potentiation and long-term depression, are of particular interest, because they may induce modification of neuronal excitability and synaptic transmission, functions directly related to the processing and storage of information in the nervous system.

Animals↗
PubMed2005

Monitoring tat peptide binding to TAR RNA by solid-state 31P-19F REDOR NMR.

Complexes of the HIV transactivation response element (TAR) RNA with the viral regulatory protein tat are of special interest due in particular to the plasticity of the RNA at this binding site and to the potential for therapeutic targeting of the interaction. We performed REDOR solid-state NMR experiments on lyophilized samples of a 29 nt HIV-1 TAR construct to measure conformational changes in the tat-binding site concomitant with binding of a short peptide comprising the residues of the tat basic binding domain. Peptide binding was observed to produce a nearly 4 A decrease in the separation between phosphorothioate and 2'F labels incorporated at A27 in the upper helix and U23 in the bulge, respectively, consistent with distance changes observed in previous solution NMR studies, and with models showing significant rearrangement in position of bulge residue U23 in the bound-form RNA. In addition to providing long-range constraints on free TAR and the TAR-tat complex, these results suggest that in RNAs known to undergo large deformations upon ligand binding, 31P-19F REDOR measurements can also serve as an assay for complex formation in solid-state samples. To our knowledge, these experiments provide the first example of a solid-state NMR distance measurement in an RNA-peptide complex.

Binding Sites↗
PubMed2006

A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences.

Meganucleases, or homing endonucleases (HEs) are sequence-specific endonucleases with large (>14 bp) cleavage sites that can be used to induce efficient homologous gene targeting in cultured cells and plants. These findings have opened novel perspectives for genome engineering in a wide range of fields, including gene therapy. However, the number of identified HEs does not match the diversity of genomic sequences, and the probability of finding a homing site in a chosen gene is extremely low. Therefore, the design of artificial endonucleases with chosen specificities is under intense investigation. In this report, we describe the first artificial HEs whose specificity has been entirely redesigned to cleave a naturally occurring sequence. First, hundreds of novel endonucleases with locally altered substrate specificity were derived from I-CreI, a Chlamydomonas reinhardti protein belonging to the LAGLIDADG family of HEs. Second, distinct DNA-binding subdomains were identified within the protein. Third, we used these findings to assemble four sets of mutations into heterodimeric endonucleases cleaving a model target or a sequence from the human RAG1 gene. These results demonstrate that the plasticity of LAGLIDADG endonucleases allows extensive engineering, and provide a general method to create novel endonucleases with tailored specificities.

DNA↗
PubMed2003

CaMKII, an enzyme on the move: regulation of temporospatial localization.

Calcium-calmodulin-dependent protein kinase II (CaMKII) is an important regulator of neuronal and behavioral plasticity. Studies in which the subcellular distribution of CaMKII has been altered argue that targeting of this enzyme to specific subcellular compartments is crucial to many of its roles. Understanding how a very abundant enzyme can achieve specificity of action over time and space requires an understanding of the functional diversity of the enzyme and its distribution. In this review we will discuss how structurally distinct isozymes, splice isoforms, and autophosphorylation states of CaMKII can affect kinase activity and localization. We will focus on the fast activity-dependent synaptic localization of the kinase and its association with postsynaptic proteins. The ability of enzyme activation to regulate protein-protein interactions with these binding partners and the potential for such binding interactions to regulate CaMKII activity in novel ways may represent new paradigm for CaMKII regulation.

Animals↗
PubMed2003

Making image guidance work: understanding control of accuracy.

Use of image-guided surgery is becoming increasingly common in both sinus surgery and neuro-otologic applications. The purpose of this study was to determine the effect of fiducial distribution and mean fiducial error on point accuracy. Using a plastic model, we determined that optimal navigation accuracy was achieved by surrounding the operative target with a widespread field of fiducials. True accuracy was always highest when we targeted a surface point. Accuracy was decreased at points removed from the center of the registration target zone created by the fiducials. Inaccurate registration resulted in increased mean fiducial error and lower accuracy at the target point. Understanding the registration process will enhance the utility of image-guided surgery in otolaryngology and skull base surgery.

Cranial Fossa, Middle↗
PubMed1981

Visual-vestibular interaction in multiple sclerosis.

Visual modulation of the vestibuloocular reflex (VOR) was analyzed in 20 patients with multiple sclerosis who had no vestibular or ocular motor symptoms. Visual suppression of the VOR was impaired in 75% of patients. VOR gains in darkness were elevated in 35% of patients. Elevated VOR gain in darkness is attributed to vestibular adaptation to defective smooth pursuit. This vestibular plasticity achieved retinal image stability by matching eye velocity to head velocity when stationary targets were viewed. The high incidence of impaired visual suppression of the VOR rivals the sensitivity of other physiologic tests used to identify multiple sclerosis.

Adult↗
PubMed2005

Regulation of alpha-synuclein expression in limbic and motor brain regions of morphine-treated mice.

Chronic exposure to opiates produces dependence and addiction, which may result from neuroadaptations in the dopaminergic reward pathway and its target brain regions. The neuronal protein alpha-synuclein has been implicated in neuronal plasticity and proposed to serve as a negative regulator of dopamine neurotransmission. Thus, alpha-synuclein could mediate some effects of opiates in the brain. The present study investigated the influence of acute and chronic morphine administration on alpha-synuclein mRNA and protein expression in the brains of mice. Downregulation of alpha-synuclein mRNA was observed in the basolateral amygdala, dorsal striatum, nucleus accumbens, and ventral tegmental area of mice withdrawn from chronic morphine treatment. The changes were the most pronounced after longer periods of withdrawal (48 h). In contrast, levels of alpha-synuclein protein, as assessed by Western blotting, were significantly increased in the amygdala and striatum/accumbens (but not in the mesencephalon) of morphine-withdrawn mice. In both brain regions, levels of alpha-synuclein were elevated for as long as 2 weeks after treatment cessation. Because alpha-synuclein is a presynaptic protein, the detected opposite changes in its mRNA and protein levels are likely to take place in different populations of projection neurons whose somata are in different brain areas. Axonal localization of alpha-synuclein was confirmed by immunofluorescent labeling. An attempt to identify postsynaptic neurons innervated by alpha-synuclein-containing axon terminals revealed their selective apposition to calbindin D28K-negative projection neurons in the basolateral amygdala. The observed changes in alpha-synuclein levels are discussed in connection with their putative role in mediating suppression of dopaminergic neurotransmission during opiate withdrawal.

Analysis of Variance↗
PubMed1992

[Immunological status of alveolar macrophages in patients with lung cancer and benign pulmonary diseases].

This is a report of the study on the immunological status of alveolar macrophages (aM phi) in patients with lung cancer (LC, n = 27) and benign pulmonary diseases (BD, n = 26). Patients were undergone bronchoalveolar lavage by fiberoptic bronchoscopy. aM phi in the lavage fluid isolated by adherence on plastic surface were examined in vitro for their cytostatic and cytolytic activities against tumor target cells, secretion of interleukin 1 (IL-1) and tumor necrosis factor (TNF), intracellular IL-1 activity and mRNA expression of IL-1 beta and TNF-alpha. aM phi, both non-activated and activated, were shown to be highly cytostatic against P815 cells by 3H-TdR post-labelling assay. There was no statistical difference between the LC and BD group. As shown by isotope release assay, regardless of being activated or not, aM phi were not cytolytic against P815 and NS-1 cells in both groups of patients. TNF activity could be demonstrated in the culture supernatants of aM stimulated with LPS. Statistically, the TNF activity was not different in the two groups of patients. Spontaneous release of TNF activity was occasionally detected in unstimulated aM phi. While both intracellular and extracellular IL-1 activity of unstimulated aM phi was demonstrated in the two patient groups, the former activity was 1 to 5 times as high as the latter. When stimulated with LPS, there was some increase in extracellular but not intracellular IL-1 activity. mRNA expression of IL-1 beta and TNF-alpha by dot blot hybridization was demonstrable in aM phi from both patient groups irrespective of activation. These results indicate that the immune status of aM phi in lung cancer patients examined does not differ from that in patients with benign pulmonary diseases.

Adenocarcinoma↗
PubMed1993

Quantitative analysis of erythrocyte velocity in rat liver after acute ethanol administration.

Hepatic microcirculation is thought to be closely associated with the liver function. The present study was aimed to quantify changes in hepatic microcirculation after acute ethanol administration using a photometric device. Male Wistar rats were anesthetized with pentobarbital sodium (35 mg/kg) intraperitoneally. After laparotomy, a lobe of the liver was exposed and placed on the cover glass at the window of plastic stage, and observed using inverted intravital fluorescence microscopy assisted by a silicon intensified target camera. Erythrocytes were labeled with fluorescein isothiocyanate (FITC) according to the method of Zimmerhackl et al, and injected from the catheter placed at the aortic arch. FITC-labeled red blood cells (FITC-RBCs) recirculated continuously and resembled native cells in their flow properties. Ethanol (20%; 3 g/kg, 30%; 4.5 g/kg, 40%; 6 g/kg) was administered through the stomach tube. The microfluorograph of hepatic microcirculation was then recorded on a videotape. The velocity of FITC-RBCs in sinusoids was measured with a multipurpose computerized image analyzing system by replaying the video images. Portal pressure, mean arterial pressure, and central venous pressure were also monitored. The velocity of FITC-RBCs in the sinusoid increased by 54% at 10-20 min after 20% ethanol administration and remained at higher than the basal level throughout the period of the experiment. The velocity after 30% ethanol administration increased in some experiments and decreased in the others at the end of the experiment (60 min after acute ethanol administration). However, the velocity decreased by 26% at 60 min after 40% ethanol administration. Portal pressure increased by 16% at 45-60 min after 20% ethanol administration, and increased by 23% at 30 min after 40% ethanol administration, while mean arterial pressure and central venous pressure had no significant change. The method in this study is the first approach to visualize hepatic microcirculation by FITC-RBCs and measure erythrocyte velocity in the sinusoid using a multipurpose computerized image analysis system. The current results suggest that high concentration of ethanol may disturb hepatic microcirculation at the sinusoidal level.

Animals↗
PubMed1997

[A breakthrough in the research on pain. Survey of the synaptic network may result in new analgesics].

Increased pain fibre activity in response to tissue injury results in changes in gene expression, and prolonged changes in nerves and their environment. The resulting hyperalgesia and prolonged spontaneous pain are due both to increased sensitivity of peripheral nociceptors (primary hyperalgesia) and to facilitated spinal cord transmission (secondary hyperalgesia, receptive field expansion and allodynia). Hyperexcitability of dorsal horn neurones is first triggered by increased neuronal barrage into the central nervous system ('wind-up'), and later by retrograde chemical influences from the peripheral inflammation (central sensitisation). Central transmission and hyperexcitability are mediated by excitatory amino acids (aspartate and glutamate) and by tachykinins (substance P). Normally, the net effect of the activity in a complex network of inhibitory neurones in the spinal cord ('gate control'), driven by descending projections from brain stem sites, is to dampen and counteract the spinal cord hyperexcitability produced by tissue or nerve injury. Thus, peripherally evoked pain impulses pass through a filtering process involving gamma-aminobutyric acid, glycine and enkephalins. The activity of these substances in the spinal cord usually attenuates and limits the duration of pain. In the case of persistent pain, there is evidence of pathological reduction of the supraspinal net inhibitory actions in combination with ectopic afferent input in damaged nerves. Hence, the pathology of chronic pain (neuropathic pain) differs from that of nociceptive pain, and conventional pharmacological treatment of chronic central pain is usually less successful than treatment of inflammation-related pain. The many newly discovered mechanisms for the transmission and modulation of pain impulses are characterised by complex activity-dependent plasticity, which means that therapeutic strategies for persistent pain must be adapted to changing targets--either at the site of injury or at other sites in the central nervous system.

Analgesics↗
PubMed1998

[Breakthrough in pain research. Charting of the synaptic network may lead to new analgesics].

Increased pain fibre activity in response to tissue injury results in changes in gene expression and prolonged changes in nerves and their environment. The resulting hyperalgesia and prolonged spontaneous pain are due both to increased sensitivity of peripheral nociceptors (primary hyperalgesia) and to faciliated spinal cord transmission (secondary hyperalgesia, receptive field expansion and allodynia). Hyperexcitability of dorsal horn neurones is first triggered by increased neuronal barrage into the central nervous system ("wind-up"), and later by retrograde chemical influences from the peripheral inflammation (central sensitisation). Central transmission and hyperexcitability are mediated by excitatory amino acids (aspartate and glutamate) and by tachykinins (substance P). Normally, the net effect of the activity in a complex network of inhibitory neurones in the spinal cord ("gate control"), driven by descending projections from brain stem sites, is to dampen and counteract the spinal cord hyperexcitability produced by tissue or nerve injury. Thus, peripherally evoked pain impulses pass through a filtering process involving gamma-aminobutyric acid, glycine and enkephalins. The activity of these substances in the spinal cord usually attenuates and limits the duration of pain. In the case of persistent pain, there is evidence of pathological reduction of the supraspinal net inhibitory actions in combination with ectopic afferent input in damaged nerves. Hence, the pathology of chronic pain (neuropathic pain) differs from that of nociceptive pain and conventional pharmacological treatment of chronic central pain is usually less successful than treatment of inflammation-related pain. The many newly discovered mechanisms for the transmission and modulation of pain impulses are characterised by complex activity-dependent plasticity, which means that therapeutic strategies for persistent pain must be adapted to changing targets--either at the site of injury or at other sites in the central nervous system.

Analgesics↗