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At least 1,333 records · Page 74Linked to original sources
PubMed2006

The striatal-enriched protein tyrosine phosphatase gates long-term potentiation and fear memory in the lateral amygdala.

BACKGROUND: Formation of long-term memories is critically dependent on extracellular-regulated kinase (ERK) signaling. Activation of the ERK pathway by the sequential recruitment of mitogen-activated protein kinases is well understood. In contrast, the proteins that inactivate this pathway are not as well characterized. METHODS: Here we tested the hypothesis that the brain-specific striatal-enriched protein tyrosine phosphatase (STEP) plays a key role in neuroplasticity and fear memory formation by its ability to regulate ERK1/2 activation. RESULTS: STEP co-localizes with the ERKs within neurons of the lateral amygdala. A substrate-trapping STEP protein binds to the ERKs and prevents their nuclear translocation after glutamate stimulation in primary cell cultures. Administration of TAT-STEP into the lateral amygdala (LA) disrupts long-term potentiation (LTP) and selectively disrupts fear memory consolidation. Fear conditioning induces a biphasic activation of ERK1/2 in the LA with an initial activation within 5 minutes of training, a return to baseline levels by 15 minutes, and an increase again at 1 hour. In addition, fear conditioning results in the de novo translation of STEP. Inhibitors of ERK1/2 activation or of protein translation block the synthesis of STEP within the LA after fear conditioning. CONCLUSIONS: Together, these data imply a role for STEP in experience-dependent plasticity and suggest that STEP modulates the activation of ERK1/2 during amygdala-dependent memory formation. The regulation of emotional memory by modulating STEP activity may represent a target for the treatment of psychiatric disorders such as posttraumatic stress disorder (PTSD), panic, and anxiety disorders.

Acoustic Stimulation↗
PubMed2005

Cognitive aging: recapturing the excitation of youth?

The electrical excitability of cortical neurons changes significantly during normal ageing. A recent study found that targeted deletion of a gene encoding a potassium channel-modifier subunit can restore to aged mice, not only normal neuronal firing, but also normal learning and synaptic plasticity.

Action Potentials↗
PubMed2026

Navigated repetitive transcranial magnetic stimulation for post-stroke recovery: A systematic review and meta-analysis of randomized controlled trials.

Repetitive transcranial magnetic stimulation (rTMS) is a subcategory of non-invasive brain stimulation (NIBS), used to modulate brain plasticity and improve post-stroke recovery. Neuronavigation is used to improve the accuracy of stimulation with the aim of achieving a superior clinical outcome than with conventional targeting. The objective of this review is to evaluate the efficacy of navigated rTMS in subacute and chronic stroke patients in comparison to sham stimulation. We conducted a systematic-review and meta-analysis of randomized controlled trials (RCTs) identified from Pubmed, Scopus and Cochrane CENTRAL. Trials employing neuronavigated rTMS were included of these five types; high and low frequency rTMS, intermittent and continuous theta-burst stimulation (TBS) and Hebbian-type stimulation. 13 RCTs were included after a screening of 1900 studies. 606 patients receiving either active (n = 360) or sham stimulation (n = 246) were assessed. The pooled standardized mean difference (SMD) favored rTMS over sham SMD = 0.4 (95 %CI: 0.11-0.69), with moderate heterogeneity I2 = 55 %. Among stimulation modalities, continuous TBS showed the largest pooled effect. rTMS was also associated with significant improvements in disability-related outcomes, SMD = 0.61 (95 % CI 0.14-1.08). Navigated rTMS is associated with modest but significant improvements in motor and disability outcomes in subacute and chronic stroke. Large comparative trials are required to clarify the potential added value over conventional targeting approaches.

Humans↗
PubMed2004

Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator.

Sensory experience physically rewires the brain in early postnatal life through unknown processes. Here, we identify a robust anatomical consequence of monocular deprivation (MD) in layer II/III of visual cortex that corresponds to the rapid, functional loss of responsiveness preceding any changes in axonal input. Protrusions on pyramidal cell apical dendrites increased steadily after eye opening, but were transiently lost through competitive mechanisms after brief MD only during the physiological critical period. Proteolysis by tissue-type plasminogen activator (tPA) conversely declined with age and increased with MD only in young mice. Targeted disruption of tPA release or its upstream regulation by glutamic acid decarboxylase (GAD65) prevented MD-induced spine loss that was pharmacologically rescued concomitant with critical period plasticity. An extracellular mechanism for structural remodeling that is limited to the binocular zone upon proper detection of competing inputs thus links early sensory experience to visual function.

Animals↗
PubMed2026

Comparative phylogenomics and transcriptional regulatory networks of AQPs, HSPs, and LEA proteins in salt-stressed Portulaca oleracea.

Soil salinization severely threatens global food security, necessitating systematic investigations of halophytes like Portulaca oleracea to decode the molecular mechanisms of environmental resilience. Utilizing an integrated framework of deep learning-based genome annotation (58,817 predicted genes; 96.5% BUSCO completeness), multi-tissue RNA-Seq, phylogenomics, and gene regulatory network (GRN) inference, the synergistic orchestration of 78 aquaporins (AQPs), 525 heat shock proteins (HSPs), and 119 late embryogenesis abundant (LEA) proteins was elucidated. The active transcriptome, encompassing 39,065 expressed loci, revealed a systemic growth-defense trade-off. Tissues displayed distinct adaptive mechanisms: leaves modulated intracellular water balance via specialized AQPs, whereas adult roots maintained proteostasis through robust HSP20/HSP70 induction. Phylogenomic clustering across 154 species demonstrated that salinity tolerance constitutes an evolutionary mosaic, identifying 81 halophyte-exclusive orthogroups and 1129 species-specific clusters. Comparative topology across six independent GRNs (4.2M-5.3 M edges) unmasked a highly modular transcriptional reprogramming strategy governed by a core apparatus of 22 stress-exclusive regulators, with functional enrichment heavily prioritizing protein dimerization and chromatin remodeling. Theoretically, the distinct convergence of Trihelix transcription factors with guard cell differentiation pathways offers a candidate transcriptomic framework to explain the plant's characteristic C4-CAM photosynthetic plasticity under severe osmotic pressure. Practically, these evolutionary blueprints and specific master switches transcend single-gene transgenic limitations. Utilizing these root-sustained and stress-inducible targets under localized promoters provides a naturally optimized, network-level precision engineering roadmap to transfer robust, compartmentalized halotolerance to sensitive glycophytic crops.

Gene Regulatory Networks↗
PubMed2006

Role of the AP-1 transcription factor c-Jun in developing, adult and injured brain.

The transcription factor activator protein-1 (AP-1) consists of a variety of dimers composed of members of the Jun and Fos families of proteins. However, it is the up-regulation of c-jun that is a particularly common event in the developing, adult as well as in injured nervous system that serves as a model of transcriptional control of brain function. In view of the long list of excellent in depth overviews on the different members of the Jun family and associated molecules, the primary focus of the current paper is to focus on c-Jun specifically and discuss the evidence on the involvement of this transcription factor in ischaemia and stroke, in seizures, during learning and memory, or following axonal injury and during successful regeneration. Functional studies employing in vivo strategies using gene deletion, targeted expression of dominant negative isoforms and pharmacological inhibitors all suggest a bipotential role of c-Jun, in mediating neurodegeneration and cell death, as well as in plasticity and repair. Phosphorylation of c-Jun, and the activation of its upstream kinases (Jun N-terminal Kinase (JNK) 1-3, JNK kinases (JNKK)) is required in many but not in all forms of these events, with only a partial overlap of the Jun-, JNK- or JNKK(n)-dependent functions. Moreover, a better understanding of the non-overlapping roles could considerably increase the potential of pharmacological agents to improve neurological outcome following trauma, neonatal encephalopathy and stroke, or neurodegenerative disease.

Animals↗
PubMed2003

Working with Xenopus spinal neurons in live cell culture.

Neurons from the Xenopus spinal cord are highly versatile and easily manipulated, making them an ideal model system to answer questions regarding the cellular and molecular basis of early neural development and function. Xenopus has been a productive model system in studies ranging from axon growth and guidance to synaptic plasticity. Exogenous molecules, such as proteins, fluorescent tracers, and nucleic acids, can be injected into early blastomeres to load tracers in all neurons or into late blastomeres to target specific classes of neurons based on established lineage maps. Xenopus spinal neurons also provide an excellent culture system, as neurons extend processes on a variety of substrata and develop at room temperature in minimal salt solutions. Live fluorescent neurons can be imaged for hours with fluorescence microscopy at room temperature in static cultures without neurotrophic support or serum. This highly reduced culture system minimizes variables that can confound interpretation of results. Cultures can be prepared at various stages of development as dissociated neurons or as spinal cord explants. Both excitatory and inhibitory neurons develop in culture, and synaptic contacts among neurons and between neurons and nonneuronal targets form naturally. The simple anatomy and rapid rostral-to-caudal development of the Xenopus spinal cord also make this an excellent in vivo model system to analyze axon guidance by identifiable classes of neurons. This chapter focuses on techniques that exploit both in vitro and in vivo qualities of this system.

Animals↗
PubMed2003

Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction.

Dendritic cells (DCs) are uniquely well-equipped antigen-presenting cells (APCs) regarded classically as sentinels of the immune response, which induce and regulate T-cell reactivity. They play critical roles in central tolerance and in the maintenance of peripheral tolerance in the normal steady state. Following cell or organ transplantation, DCs present antigen to T cells via the direct or indirect pathways of allorecognition. These functions of DCs set in train the rejection response, but they also serve as potential targets for suppression of alloimmune reactivity and promotion of tolerance induction. Much evidence from various model systems now indicates that DCs can induce specific T-cell tolerance. Although underlying mechanisms have not been fully elucidated, the capacity to induce T-regulatory cells may be an important property of tolerogenic or regulatory DCs. Efforts to generate "designer" DCs with tolerogenic properties in the laboratory using specific cytokines, immunologic or pharmacologic reagents, or genetic engineering approaches have already met with some success. Alternatively, targeting of DCs in vivo (e.g. by infusion of apoptotic allogeneic cells) to take advantage of their inherent tolerogenicity has also demonstrated exciting potential. The remarkable heterogeneity and plasticity of these important APCs present additional challenges to optimizing DC-based therapies that may lead to improved tolerance-enhancing strategies in the clinic.

Animals↗
PubMed1997

Minimum alveolar concentration of sevoflurane for tracheal extubation in children.

BACKGROUND: One advantage of tracheal extubation during deep anaesthesia is that respiratory complications are reduced. Sevoflurane is a suitable anaesthetic agent for children. This study was conducted to determine the minimum alveolar concentration of sevoflurane required to prevent cough or movement during and after tracheal extubation (MACextubation). METHODS: We studied 30 nonpremedicated children, aged 2-10 yr, undergoing plastic surgery. They were allocated randomly to five groups (end-tidal sevoflurane concentrations: 2.0, 2.5, 3.0, 3.5, 4.0%). After surgery, 60% nitrous oxide was discontinued and the target concentration of sevoflurane was maintained for at least 10 min in 100% oxygen, then the trachea was extubated to determine MACextubation. Logistic regression was used to estimate MACextubation of sevoflurane. RESULTS: MACextubation was 2.3 (0.2; standard error)% (95% confidence limits: 1.2% and 2.7%). CONCLUSIONS: Tracheal extubation in 50% of anaesthetized children age 2-10 yr may be accomplished without coughing or moving at 2.3% end-tidal concentration of sevoflurane.

Anesthetics, Inhalation↗
PubMed2003

Putative targets of CNS melanocortin receptor activity.

Chronic antagonism of hypothalamic melanocortin receptors, primarily melanocortin-4 receptor (MC4R), is the molecular basis for "agouti obesity syndrome," whereas suppression of MC4R gene activity due to genetic mutations induces obesity in both rodents and humans. However, little is known about the neurocircuitry of MC4R-mediated control of energy balance, the regulation of MC4R gene expression, or how suppression of MC4R activity leads to differential expression of potential downstream central nervous system (CNS) targets or effectors of melanocortin signaling. This paper focuses on strategies for mapping CNS melanocortin circuits using transgenic mouse models for conditional expression of MC4R and MC3R as well as progress in characterizing the murine MC4R promoter. Additionally, preliminary studies that focus on putative targets of melanocortinergic signaling will include a discussion of CD81, a gene identified using the polymerase chain reaction-based method of suppression subtractive hybridization. CD81, first described as TAPA-1 (target of antiproliferative antibody), is a member of the tetraspanin family of cell surface proteins believed to function in cell-cell adhesion, signal transduction, and possibly neuronal plasticity. Elevated expression of CD81 mRNA in hypothalamic regions of obese yellow mice suggests that loss of MC4R activity may lead to altered neuronal function via modulation of the cell surface protein CD81.

Animals↗
PubMed2005

Adult neurogenesis in the mammalian central nervous system.

Forty years since the initial discovery of neurogenesis in the postnatal rat hippocampus, investigators have now firmly established that active neurogenesis from neural progenitors continues throughout life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Significant progress has been made over the past few years in understanding the developmental process and regulation of adult neurogenesis, including proliferation, fate specification, neuronal maturation, targeting, and synaptic integration of the newborn neurons. The function of this evolutionarily conserved phenomenon, however, remains elusive in mammals. Adult neurogenesis represents a striking example of structural plasticity in the mature CNS environment. Advances in our understanding of adult neurogenesis will not only shed light on the basic principles of adult plasticity, but also may lead to strategies for cell replacement therapy after injury or degenerative neurological diseases.

Animals↗
PubMed1993

Frameless stereotaxic integration of CT imaging data: accuracy and initial applications.

To evaluate the spatial accuracy of a rapid interactive method of transferring computed tomographic (CT) information between its display on a computer screen to its source (test object, operating field), a multidimensional computer combined with a six-jointed position-sensing mechanical arm was tested with a Plexiglas model consisting of 50 rods of varied height and known location, a plastic replica of the skull, and, subsequently, three patients. The median error value between image and real location was 1-2 mm (P > .95), regardless of the registration target sites. The accuracy, however, increased with the selection of widespread registration points, and 95% of all errors were below 3.70 mm (P > .95). The results compare favorably with the four most commonly used stereotaxic framed units. A misregistration error of 0.3-2.2 mm was found during intraoperative correlation between anatomy on the CT display and actual anatomic location in the operative field.

Child↗
PubMed2006

Novel agonist monoclonal antibodies activate TrkB receptors and demonstrate potent neurotrophic activities.

Tyrosine kinase receptor B (TrkB) mediates neurotrophic effects of brain-derived neurotrophic factor (BDNF) to increase neuronal survival, differentiation, synaptic plasticity, and neurogenesis. The therapeutic potential of TrkB activation using BDNF has been demonstrated well in several preclinical models of CNS diseases, validating TrkB as a promising drug target. Therefore, we aimed to develop TrkB-specific receptor agonists by using a monoclonal antibody approach. After generation of hybridoma clones and assessment of their binding and functional activity, we identified five mouse monoclonal antibodies that show highly selective binding to TrkB and that induce robust activation of TrkB signaling. Epitope mapping studies using competition analysis showed that each of the monoclonal antibodies recognizes a unique binding site on TrkB, some of which are distinct from BDNF docking sites. These antibodies behave as true agonists based on their ability to both activate proximal and secondary signaling molecules downstream of TrkB receptors and promote neuronal survival and neurite outgrowth. The binding affinities and the functional efficacy of these antibodies are comparable to those of BDNF, whereas they do not bind to the p75 low-affinity neurotrophin receptor at all. Therefore, they could represent novel reagents to explore the pathophysiological roles of TrkB and its potential therapeutic utility in treating CNS disorders.

Animals↗
PubMed2005

Activin induces tactile allodynia and increases calcitonin gene-related peptide after peripheral inflammation.

Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide important in inflammatory pain that conveys pain information centrally and dilates blood vessels peripherally. Previous studies indicate that activin A increases CGRP-immunoreactive (IR) sensory neurons in vitro, and following wound, activin A protein increases in the skin and more neurons have detectable CGRP expression in the innervating dorsal root ganglion (DRG). These data suggest some adult sensory neurons respond to activin A or other target-derived factors with increased neuropeptide expression. This study was undertaken to test whether activin contributes to inflammatory pain and increased CGRP and to learn which neurons retained plasticity. After adjuvant-induced inflammation, activin mRNA, but not NGF or glial cell line-derived neurotrophic factor, increased in the skin. To examine which DRG neurons increased CGRP immunoreactivity, retrograde tracer-labeled cutaneous neurons were characterized after inflammation. The proportion and size of tracer-labeled DRG neurons with detectable CGRP increased after inflammation. One-third of CGRP-IR neurons that appear after inflammation also had isolectin B4 binding, suggesting that some mechanoreceptors became CGRP-IR. In contrast, the increased proportion of CGRP-IR neurons did not appear to come from RT97-IR neurons. To learn whether central projections were altered after inflammation, CGRP immunoreactivity in the protein kinase Cgamma-IR lamina IIi was quantified and found to increase. Injection of activin A protein alone caused robust tactile allodynia and increased CGRP in the DRG. Together, these data support the hypothesis that inflammation and skin changes involving activin A cause some sensory neurons to increase CGRP expression and pain responses.

Activins↗
PubMed2001

Pharmacological enhancement of synaptic efficacy, spatial learning, and memory through carbonic anhydrase activation in rats.

CA1 pyramidal cells were recorded in rat hippocampal slices. In the presence of carbonic anhydrase activators, comicrostimulation of cholinergic inputs from stratum oriens and gamma-aminobutyric acid (GABA)ergic inputs from stratum pyramidale at low intensities switched the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials to depolarizing responses. In the absence of the activators, however, the same stimuli were insufficient to trigger the synaptic switch. This synaptic switch changed the function of the GABAergic synapses from excitation filter to amplifier and was prevented by carbonic anhydrase inhibitors, indicating a dependence on HCO. Intralateral ventricular administration of these same carbonic anhydrase activators caused the rats to exhibit superior learning of the Morris water maze task, suggesting that the GABAergic synaptic switch is critical for gating the synaptic plasticity that underlies spatial memory formation. Increased carbonic anhydrase activity might, therefore, also enhance perception, processing, and storing of temporally associated relevant signals and represents an important therapeutic target in learning and memory pharmacology.

Acetazolamide↗
PubMed2003

[A case of eosinophilic pancreatitis].

Eosinophilic pancreatitis is a rare disorder that may only be diagnosed after pancreatic resection under the suspection of a pancreatic tumor. We experienced a 65-year-old female patient whose initial presentation suggested pancreatic cancer. Radiologic evaluation revealed a pancreatic mass-like lesion which was obstructing the main pancreatic duct. Endoscopic retrograde cholangiopancreatography (ERCP) showed double duct strictures involving the distal common bile duct and the main pancreatic duct. Serum IgE level was elevated. Percutaneous core needle biopsy with an 18-gauge needle was performed targeting the pancreatic lesion. The biopsy specimen revealed fibrotic interlobular septum and intralobular fibrosis with prominent eosinophilic infiltration. The patient was treated with oral prednisolone (40 mg/day). A plastic stent was inserted into the narrowed common bile duct. After three months of oral steroid therapy, symptoms and signs improved rapidly and serum IgE level was decreased. Abdominal computed tomography and ERCP revealed remission of pancreatic mass-like lesion.

Aged↗
PubMed1990

Saturation site-directed mutagenesis of thymidylate synthase.

We have subjected 12 different codons of a synthetic Lactobacillus casei thymidylate synthase (TS) gene to saturation site-directed mutagenesis to create amino acid "replacement sets" at each of those positions. The target residues were chosen because they are highly conserved and because they are important for the structure and function of the protein as indicated by solution and structural studies. The mutagenesis procedure involved excision of a fragment of the synthetic gene containing the target codon, followed by its replacement with a mixture of oligonucleotides which code for all 20 amino acids and the amber stop codon. TS mutants were identified by DNA sequencing, and catalytically active mutants were identified by genetic complementation using a Thy- strain of Escherichia coli. Only 3 of the 12 target amino acids examined were essential for TS activity; and of the 125 total mutants identified, 57 were catalytically active. These results point to a high degree of plasticity of TS in accommodating function with structural change.

Amino Acid Sequence↗
PubMed1988

Antibody-mediated killing of human tumor cells by attached effector cells.

Cultured human melanoma, lung carcinoma, and colon carcinoma cells were isotope labeled and incubated with a combination of effector cells and mouse monoclonal antibodies to tumor-associated cell surface antigens. The former were derived from the peritoneal cavity of mice or from peripheral blood of healthy human subjects. Monoclonal antibodies MG-21, 96.5, and L6, which are IgG3, IgG2a, and IgG2a, respectively, were all cytolytic when added in the presence of mouse effector cells to target cells expressing the relevant antigens. MG-21 and L6 were cytolytic also with human effector cells, while monoclonal antibody 96.5 was not. The effector cells attached to plastic surfaces, stained with neutral red, were peroxidase positive and mediated their effect over a 24- to 72-h time period as compared to the 4 h generally sufficient for antibody-dependent cellular cytotoxicity by natural killer cells. In tests on human effector cells with a fluorescence-activated cell sorter, they stained with antibody LCM-3C10 to the CD14 antigen, as well as with antimonocyte antibody 61D3. The cytolytic effect of human effector cells and antitumor antibody was not abolished by incubation with antibodies FC2 or 60.3 to CD16 and CD18, respectively, known to interfere with the antibody-dependent cellular cytotoxicity activity and natural killing of natural killer cells. This suggests, together with the other findings, that the effector cells were macrophages.

Animals↗