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At least 595 records · Page 33Linked to original sources
PubMed2006

The kv4.2 potassium channel subunit is required for pain plasticity.

A-type potassium currents are important determinants of neuronal excitability. In spinal cord dorsal horn neurons, A-type currents are modulated by extracellular signal-regulated kinases (ERKs), which mediate central sensitization during inflammatory pain. Here, we report that Kv4.2 mediates the majority of A-type current in dorsal horn neurons and is a critical site for modulation of neuronal excitability and nociceptive behaviors. Genetic elimination of Kv4.2 reduces A-type currents and increases excitability of dorsal horn neurons, resulting in enhanced sensitivity to tactile and thermal stimuli. Furthermore, ERK-mediated modulation of excitability in dorsal horn neurons and ERK-dependent forms of pain hypersensitivity are absent in Kv4.2(-/-) mice compared to wild-type littermates. Finally, mutational analysis of Kv4.2 indicates that S616 is the functionally relevant ERK phosphorylation site for modulation of Kv4.2-mediated currents in neurons. These results show that Kv4.2 is a downstream target of ERK in spinal cord and plays a crucial role in pain plasticity.

Action Potentials↗
PubMed2005

Fragmentation studies of relativistic iron ions using plastic nuclear track detectors.

We measured fluence and fragmentation of high-energy (1 or 5 A GeV) 56Fe ions accelerated at the Alternating Gradient Synchrotron or at the NASA Space Radiation Laboratory (Brookhaven National Laboratory, NY, USA) using solid-state CR-39 nuclear track detectors. Different targets (polyethylene, PMMA, C, Al, Pb) were used to produce a large spectrum of charged fragments. CR-39 plastics were exposed both in front and behind the shielding block (thickness ranging from 5 to 30 g/cm2) at a normal incidence and low fluence. The radiation dose deposited by surviving Fe ions and charged fragments was measured behind the shield using an ionization chamber. The distribution of the measured track size was exploited to distinguish the primary 56Fe ions tracks from the lighter fragments. Measurements of projectile's fluence in front of the shield were used to determine the dose per incident particle behind the block. Simultaneous measurements of primary 56Fe ion tracks in front and behind the shield were used to evaluate the fraction of surviving iron projectiles and the total charge-changing fragmentation cross-section. These physical measurements will be used to characterize the beam used in parallel biological experiments.

Aluminum↗
PubMed2000

Ballistic characterization of the Remington Premier Copper Solid sabot shotgun slug.

We evaluated the impact and penetration characteristics of the Remington Copper Solid sabot shotgun slug with standardized ballistic tests and used this information to predict tissue wounding patterns. This unique ammunition, first distributed in 1993, is composed of a solid copper, hollow-point slug with longitudinal slots cut into the nose. The slug is fitted into a hard plastic sabot with 8 finger-like projections and loaded into a shotgun shell with two plastic wads separating it from the underlying gunpowder charge. The ammunition was fired through a 12-gage shotgun using a rifled barrel, a smooth-bore barrel with rifled choke, and a smooth-bore barrel with a smooth modified choke into targets consisting of poster board and 10% ballistic gelatin at a variety of distances. The copper slug and plastic sabot created single 8-fingered asterisk-shaped defects in the poster board when fired at distances of less than 7 to 9 ft (approximately 2 to 3 m). All three barrel types performed similarly. At greater distances, the sabot impacted the targets separately from the slugs and created variably shaped defects that reflected base-first, nose-first, and side-first impacts. Increasing muzzle-to-target distances generally increased the impact distances between the slug and sabot. There was no predictable relationship between the sabot and slug impact points for any of the three barrel types. With each barrel tested, the wads created separate defects from the slug at distances greater than 5 ft (1.5 m). The distances between the slug and the wad impact points increased with increasing muzzle-to-target distances up to 40 ft (12 m), after which the wads generally no longer struck the targets. The slug created atypical defects at distances between 7 and 150 ft (approximately 2 to 45 m), probably due to yawing or tumbling. When the slug impacted the gelatin block in a nose-first orientation, the slotted nose portion tended to fragment and radially deposit pieces in the gelatin that were visible on radiographs. When the slug struck the gelatin target in a side-first orientation, it passed through the gelatin intact. The slug, sabot, and wads of this unique projectile separate and create independent impact points in a stereotypical manner independent of barrel type. This pattern of separation allows estimates to be made of ranges of fire. Wounds created in human tissues by this ammunition would likely have similar asterisk-shaped configurations, and nose fragments may be deposited in tissues and seen radiographically. Rectangular wounds created by the tumbling or yawing slug might be mistaken for intermediate target wounds.

Journal Article↗
PubMed2003

Retention of NMDA receptor NR2 subunits in the lumen of endoplasmic reticulum in targeted NR1 knockout mice.

Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system, and the N-methyl-D-aspartate-selective glutamate receptor (NR) consisting of the NR1 subunit and an NR2 or NR3 subunit plays crucial roles in synaptic transmission, plasticity, and learning and memory. By using a knockout mouse strain, in which the NR1 gene deletion is primarily targeted to the CA1 pyramidal cells of the hippocampus, we investigated the in vivo effect of the loss of the NR1 subunit on the cellular expression and intracellular distribution of the NR2 subunits. The NR1 gene deletion had no apparent effect on the levels of NR2A or NR2B mRNA but led to severe reductions of NR2A and NR2B protein in dendrites of CA1 pyramidal cells. This reduced dendritic distribution of the NR2 subunits accompanied their robust accumulation in perikarya, where they were condensed in the lumen of the endoplasmic reticulum as electron-dense granules. These granules were also observed in CA1 pyramidal cells of the control mice but they were much fewer and contained no detectable levels of the NR2 subunit. The effect of the NR1 knockout on intracellular localization of the NR2 subunits was specific in that no such effect was observed for the GluR1 and PSD-95, two other major postsynaptic proteins. These results suggest that the NR1 subunit plays a crucial role in the release of the NR2 subunit from the endoplasmic reticulum in hippocampal pyramidal cells in vivo, and when the NR1 subunit is unavailable, the NR2 subunits are retained and aggregate into intracisternal granules.

Aging↗
PubMed2006

NMDA-dependent facilitation of corticostriatal plasticity by the amygdala.

Emotions generally improve memory, and the basolateral amygdala (BLA) is believed to mediate this effect. After emotional arousal, BLA neurons increase their firing rate, facilitating memory consolidation in BLA targets. The enhancing effects of BLA activity extend to various types of memories, including motor learning, which is thought to involve activity-dependent plasticity at corticostriatal synapses. However, the underlying mechanisms are unknown. Here we show that the NMDA-to-AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) ratio is nearly twice as high at BLA as compared with cortical synapses onto principal striatal neurons and that activation of BLA inputs greatly facilitates long-term potentiation induction at corticostriatal synapses. This facilitation was NMDA-dependent, but it occurred even when BLA and cortical stimuli were 0.5 s apart during long-term potentiation induction. Overall, these results suggest that BLA activity opens long time windows during which the induction of corticostriatal plasticity is facilitated.

Amygdala↗
PubMed2006

Kainate receptors.

Kainate receptors form a family of ionotropic glutamate receptors that appear to play a special role in the regulation of the activity of synaptic networks. This review first describes briefly the molecular and pharmacological properties of native and recombinant kainate receptors. It then attempts to outline the general principles that appear to govern the function of kainate receptors in the activity of synaptic networks under physiological conditions. It subsequently describes the way that kainate receptors are involved in synaptic integration, synaptic plasticity, the regulation of neurotransmitter release and the control of neuronal excitability, and the manner in which they might play an important role in synaptogenesis and synaptic maturation. These functions require the proper subcellular localization of kainate receptors in specific functional domains of the neuron, necessitating complex cellular and molecular trafficking events. We show that our comprehension of these mechanisms is just starting to emerge. Finally, this review presents evidence that implicates kainate receptors in pathophysiological conditions such as epilepsy, excitotoxicity and pain, and that shows that these receptors represent promising therapeutic targets.

Animals↗
PubMed2006

Development and characterization of a tissue equivalent plastic scintillator based dosimetry system.

High precision techniques in radiation therapy, such as intensity modulated radiation therapy, offer the potential for improved target coverage and increased normal tissue sparing compared with conformal radiotherapy. The complex fluence maps used in many of these techniques, however, often lead to more challenging quality assurance with dose verification being labor-intensive and time consuming. A prototype dose verification system has been developed using a tissue equivalent plastic scintillator that provides easy-to-acquire, rapid, digital dose measurements in a plane perpendicular to the beam. The system consists of a water-filled Lucite phantom with a scintillator screen built into the top surface. The phantom contains a silver coated plastic mirror to reflect scintillation light towards a viewing window where it is captured using a charge coupled device camera and a personal computer. Optical photon spread is removed using a microlouvre optical collimator and by deconvolving a glare kernel from the raw images. A characterization of the system was performed that included measurements of linear output response, dose rate dependence, spatial linearity, effective pixel size, signal uniformity and both short- and long-term reproducibility. The average pixel intensity for static, regular shaped fields between 3 cm X 3 cm and 12 cm x 12 cm imaged with the system was found to be linear in the dose delivered with linear regression analysis yielding a correlation coefficient r2 > 0.99. Effective pixel size was determined to be 0.53 mm/pixel. The system was found to have a signal uniformity of 5.6% and a long-term reproducibility/stability of 1.7% over a 6 month period. The system's ability to verify a dynamic treatment field was evaluated using 60 degrees dynamic wedged fields and comparing the results to two-dimensional film dosimetry. Results indicate agreement with two-dimensional film dosimetry distributions within 8% inside the field edges. With further development, this system promises to provide a fast, directly digital, and tissue equivalent alternative to current dose verification systems.

Biomimetic Materials↗
PubMed2006

Chaperoning oncogenes: Hsp90 as a target of geldanamycin.

Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, and/or over-expressed signaling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the inactivation, destabilization, and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in preclinical model systems. One Hsp90 inhibitor, 17-AAG, has completed Phase I clinical trial and several Phase II trials of this agent are in progress. Hsp90 inhibitors are unique in that, although they are directed toward a specific molecular target, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival. Further, by inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, a combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer.

Angiogenesis Inhibitors↗
PubMed2004

Mitogen-activated protein kinases as potential targets for pain killers.

Pathological pain, such as inflammatory and neuropathic pain, is an expression of neural plasticity. Mitogen-activated protein kinases (MAPKs) play an important role in neural plasticity via post-translational, translational and transcriptional regulation. Under conditions of tissue and nerve damage, extracellular signal-regulated kinase (ERK) and p38 MAPK can be activated by nociceptive activity and inflammatory mediators in primary sensory neurons in the peripheral nervous system, and spinal cord neurons and glia in the central nervous system. Activation of ERK in dorsal horn neurons is nociceptive-specific and suppressed by several analgesics, and therefore has potential for the development of an assay to test the efficacy of new analgesics. Inhibition of ERK or p38 alleviates inflammatory pain and neuropathic pain in animal models. Development of specific inhibitors for these two MAPKs may lead to new therapies for pathological pain.

Analgesics↗
PubMed1993

Evaluation of various solvent systems for modeling solute sorption with plasticized polyvinyl chloride materials.

The partitioning behavior of 16 chemically diverse model solutes was determined for four model solvents (octanol, hexane, heptane, and chloroform) and two components of plasticized polyvinyl chloride [PVC; PVC resin and dioctyl phthalate (DOP) plasticizer]. Interactions between these model solutes and four plasticized PVC polymers, differing in their PVC-to-DOP weight ratio, were studied. The data were used to evaluate the utility of the solvents and components to act as PVC interaction models (correlating the interaction constant of the plastic with the solvent-water partition coefficients of the solute). The ability of any single solvent to model the material-solute interaction was limited because of the multiple mechanisms by which the PVC and the solute can interact. Several bimodal solvent systems, including octanol and hexane, DOP and PVC resin, and octanol and heptane, mimic the behavior of polymers studied with a higher degree of accuracy. The success of these pairings is directly related to their ability to target different potential material-solute interaction mechanisms. The interaction properties of the test plastics are strongly impacted by the amount of plasticizer in the material. The interaction properties of the materials studied could be effectively represented as a mass-related average of the interaction properties of the major components of the material.

Absorption↗
PubMed2002

Deletion of the C-terminal domain of the NR2B subunit alters channel properties and synaptic targeting of N-methyl-D-aspartate receptors in nascent neocortical synapses.

Channel properties and synaptic targeting of N-methyl-D-aspartate (NMDA) receptors determine their importance in synaptic transmission, long-term synaptic plasticity, and developmental reorganization of synaptic circuits. To investigate the involvement of the C-terminal domain of the NR2B subunit in regulating channel properties and synaptic localization, we analyzed gene-targeted mice expressing C-terminally truncated NR2B subunits (NR2B(DeltaC/DeltaC) mice; Sprengel et al. [1998] Cell 92:279-89). Because homozygous NR2B(DeltaC/DeltaC) mice die perinatally, we studied embryonic neocortical neurons differentiating in culture. At early stages in vitro, neurons predominantly expressed NR1/NR2B receptors, as shown by the NR2B subunit-specific antagonist ifenprodil. At these nascent synapses, NMDA excitatory postsynaptic currents (EPSCs) in neurons from NR2B(DeltaC/DeltaC) mice showed a strong-amplitude reduction to 20% of control, but AMPA EPSCs were unaltered. Analysis of the MK-801 block of NMDA receptor-mediated whole-cell currents revealed a decreased peak open probability of NMDA receptor channels (to about 60%) in neurons from NR2B(DeltaC/DeltaC) mice, although their single channel conductance was unchanged. To study effects on synaptic targeting, we determined the fraction of synaptically localized NMDA receptors relative to the whole-cell NMDA receptor population. In neurons from NR2B(DeltaC/DeltaC) mice, the synaptic NMDA receptor fraction was drastically reduced, suggesting that the C-terminal domain of the NR2B subunit plays a major role in synaptic targeting of NMDA receptors at nascent synapses. With increasing time in culture, the reduction in NMDA EPSCs in neurons from NR2B(DeltaC/DeltaC) mice diminished. This is explained by the expression of additional NMDA receptor subtypes containing NR2A subunits at more mature synapses.

Animals↗
PubMed2007

Identification of a novel targeting sequence for regulated secretion in the serine protease inhibitor neuroserpin.

Ns (neuroserpin) is a member of the serpin (serine protease inhibitor) gene family that is primarily expressed within the central nervous system. Its principal target protease is tPA (tissue plasminogen activator), which is thought to contribute to synaptic plasticity and to be secreted in a stimulus-dependent manner. In the present study, we demonstrate in primary neuronal cultures that Ns co-localizes in LDCVs (large dense core vesicles) with the regulated secretory protein chromogranin B. We also show that Ns secretion is regulated and can be specifically induced 4-fold by secretagogue treatment. A novel 13-amino-acid sorting signal located at the C-terminus of Ns is identified that is both necessary and sufficient to target Ns to the regulated secretion pathway. Its deletion renders Ns no longer responsive to secretagogue stimulation, whereas PAI-Ns [Ns (neuroserpin)-PAI-1 (plasminogen activator inhibitor-1) chimaera appending the last 13 residues of Ns sequence to the C-terminus of PAI-1] shifts PAI-1 secretion into a regulated secretory pathway.

Amino Acid Sequence↗
PubMed1982

Depression of natural killer activity and mitogen responsiveness in mice treated with pristane.

In BALB/c mice, the injection of pristane resulted in a severe decrease in splenic T and B cell proliferative responses to mitogens and in a depression of natural killer (NK) activity. The effects of T and B cells, which persisted for at least 5 mo, were mediated by different mechanisms. T cell responsiveness to PHA dropped significantly below control levels 1 wk after the first of three monthly pristane injections, whereas B cell proliferation in response to LPS did not decrease until 4 wk after the first injection. The removal of plastic-adherent suppressor cells completely restored T cell proliferative capacity, but had no effect on B cells. NK activity against YAC-1 tumor targets was reduced 1 mo after the first pristane injection and remained depressed for at least 3 mo. This depression was not mediated by plastic-adherent suppressor cells. Spleen cell NK activity from pristane-treated mice could not be augmented by the interferon inducer Poly I:C to the same extent as that of control mice. This suggests an effect of pristane on either pre-NK cells or on cells that regulate NK activity.

Animals↗
PubMed1983

Characterization of the target cell for a thymocyte specific growth factor in guinea pigs.

A growth factor prepared from calf thymus has been described previously (Thymus 3, 289, 1981). The factor was shown to stimulate the DNA synthesis in thymic cells but not in peripheral lymphocytes in guinea pigs. We now present a further analysis of the target cell. Thymus cells were fractionated into subpopulations based on their different adherence to plastic, buoyant density and agglutinability by peanut agglutinin (PNA) and the influence of the growth factor on DNA synthesis was studied. The results showed that the responding cell was enriched in the population of non-adherent PNA-positive (PNA +) cells of low buoyant density. This cell population showed high spontaneous DNA synthesis in vitro, but did not contain the phytohemagglutinin-responsive thymocyte, which resided in the PNA-negative (PNA -) population of low density. The results strongly indicated that the target cell of the thymic growth factor is the immunologically immature proliferating thymocyte of the thymic cortex.

Animals↗
PubMed2006

Expression of stress inducible protein 1 (Stip1) in the mouse testis.

Phthalate esters are considered endocrine disruptors that interfere with the endocrine balance and development of the mammalian testis. Mono-2-ethylhexyl phthalate (MEHP), the active metabolite of the ubiquitously used plasticizer di-2-ethylhexyl phthalate (DEHP), acts upon Sertoli cells as initial target. By subtractive cDNA libraries we identified genes deregulated as response to MEHP in primary cultures of mouse Sertoli cells. The expression of mouse stress inducible protein 1 (Stip1) was detected as upregulated as a result of MEHP exposure. Stip1 is a cochaperone protein that is homologous to the human heat shock cognate protein 70 (hsc70)/heat shock protein 90 (hsp90)-organizing protein (Hop). To assess the presence and localization of Stip1 in mouse testis and its potential role in stress defense, we studied the expression pattern of the Stip1 protein by immunohistochemistry and of the mRNA by in situ hybridization. Both the protein and the mRNA of Stip1 were mainly found in the cytoplasm of all types of spermatogonia and spermatocytes up till zygotene, the expression decreased during late pachytene and was very weak in diplotene spermatocytes and round spermatids. Interestingly, this expression pattern resembled the pattern of stress sensitivity of spermatogenic cells in that the most sensitive cell types show the weakest expression of Stip1. This suggests an important role for Stip1 in the ability of germ cells to survive in stress conditions including high temperatures.

Animals↗
PubMed2006

Lesion-induced axonal sprouting in the central nervous system.

Injury or neuronal death often come about as a result of brain disorders. Inasmuch as the damaged nerve cells are interconnected via projections to other regions of the brain, such lesions lead to axonal loss in distal target areas. The central nervous system responds to deafferentation by means of plastic remodeling processes, in particular by inducing outgrowth of new axon collaterals from surviving neurons (collateral sprouting). These sprouting processes result in a partial reinnervation, new circuitry, and functional changes within the deafferented brain regions. Lesioning of the entorhinal cortex is an established model system for studying the phenomenon of axonal sprouting. Using this model system, it could be shown that the sprouting process respects the pre-existing lamination pattern of the deafferented fascia dentata, i. e., it is layer-specific. A variety of different molecules are involved in regulating this reorganization process (extracellular matrix molecules, cell adhesion molecules, transcription factors, neurotrophic factors, growth-associated proteins). It is proposed here that molecules of the extracellular matrix define the boundaries of the laminae following entorhinal lesioning and in so doing limit the sprouting process to the deafferented zone. To illustrate the role of axonal sprouting in disease processes, special attention is given to its significance for neurodegenerative disorders, particularly Alzheimer's disease (AD), and temporal lobe epilepsy. Finally, we discuss both the beneficial as well as disadvantageous functional implications of axonal sprouting for the injured organism in question.

Alzheimer Disease↗
PubMed2026

Overcoming cancer resistance in pancreatic cancer: toward dynamic precision oncology.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, largely because of its profound and evolving therapeutic resistance. Resistance is not determined by a single molecular alteration but arises from interconnected mechanisms, including intrinsic resistance, treatment-induced adaptive resistance, acquired resistance, genomic evolution, clonal selection, cancer stemness, phenotypic plasticity, metabolic adaptation, and tumor microenvironment-mediated effects. Emerging therapeutic approaches targeting KRAS/RAS signaling, stromal and immune components, metabolic dependencies, and DNA damage repair pathways offer opportunities to address these mechanisms, although durable efficacy remains limited by biological heterogeneity and adaptive responses. In this review, we examine therapeutic resistance as an evolutionary and multidimensional process and summarize emerging strategies for overcoming resistance. We further propose a Dynamic Precision Oncology (DPO) framework that extends conventional precision oncology beyond baseline molecular profiling by integrating longitudinal assessment of tumor genomics, circulating tumor DNA, CA19-9, imaging, radiomics, and clinical characteristics. This framework emphasizes iterative detection and characterization of emerging resistance, mechanism-informed treatment adaptation, and subsequent reassessment rather than automatic treatment modification based on a single biomarker. DPO may provide a conceptual framework for integrating evolving tumor biology into treatment decision-making, while prospective studies are needed to validate biomarkers, define actionable thresholds, and determine whether longitudinal resistance-guided strategies improve clinical outcomes in PDAC.

Humans↗
PubMed2006

Structure-function relationship of estrogen receptor alpha and beta: impact on human health.

17Beta-estradiol (E2) controls many aspects of human physiology, including development, reproduction and homeostasis, through regulation of the transcriptional activity of its cognate receptors (ERs). The crystal structures of ERs with agonists and antagonists and the use of transgenic animals have revealed much about how hormone binding influences ER conformation(s) and how this conformation(s), in turn, influences the interaction of ERs with co-activators or co-repressors and hence determines ER binding to DNA and cellular outcomes. This information has helped to shed light on the connection between E2 and the development or progression of numerous diseases. Current therapeutic strategy in the treatment of E2-related pathologies relies on the modulation of ER trancriptional activity by anti-estrogens; however, data accumulated during the last five years reveal that ER activities are not only restricted to the nucleus. ERs are very mobile proteins continuously shuttling between protein targets located within various cellular compartments (e.g., membrane, nucleus). This allows E2 to generate different and synergic signal transduction pathways (i.e., non-genomic and genomic) which provide plasticity for cell response to E2. Understanding the structural basis and the molecular mechanisms by which ER transduce E2 signals in target cells will allow to create new pharmacologic therapies aimed at the treatment of a variety of human diseases affecting the cardiovascular system, the reproductive system, the skeletal system, the nervous system, the mammary gland, and many others.

Amino Acid Sequence↗