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At least 1,189 records · Page 66Linked to original sources
PubMed1997

Fractionated stereotactic radiotherapy for choroidal melanoma.

Stereotactic radiotherapy used for the treatment of choroidal melanoma made use of a 6-MeV linac with built-in multileaf collimators and a simple plastic head mold. The latter provided excellent head and ocular immobilization. The system resulted in highly localized dose distributions with a maximum 2-mm targeting error during fractionated treatments. Based on these techniques, sixteen patients with choroidal melanoma have so far been treated. Majority of patients received a total dose of 48 Gy in 8 fractions. Fourteen patients who presented with small- to moderate-sized tumors have remained free of relapse or major complications during the follow-up period of 3-42 months. Two patients who presented with an extensive tumor eventually required enucleation after irradiation. Technical precision required for stereotactic radiotherapy and reproducibility for fractionation appear adequate. Encouraging preliminary results justify further studies to evaluate its efficacy as an alternative to other conventional therapeutic approaches.

Adult↗
PubMed2003

Functional magnetic resonance imaging in stroke recovery.

A better understanding of brain reorganization following stroke may have value in predicting outcome defining the targets of restorative therapies, measuring the physiology of recovery, and in serving as a biologic marker in studies targeting stroke recovery. Measures of brain organization may provide insights as to which patients retain relevant substrate for therapies that target restorative events. Brain reorganization can be studied with many different methods that often have complementary value. Functional MR imaging provides insights into brain plasticity after stroke and remains a valuable tool in the study of motor recovery after stroke.

Brain↗
PubMed2025

Multicompartment Quantitative Proteomics Revealing Potential Mechanisms Underlying the Treatment Effects of Mesenchymal-Derived Extracellular Vesicles in a Monkey Model of Cortical Injury.

Previous studies have demonstrated that mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) enhance functional recovery after cortical injury in rhesus monkeys by reducing chronic microglial inflammation, neuronal damage, and myelination deficits. However, the signaling pathways underlying these therapeutic effects remain largely unexplored. In this study, employing a reliable quantitative proteomics platform UHR-IonStar, we identified the protein cargo of MSC-EVs infused intravenously to rhesus monkeys 24 h and 2 weeks post-injury to the motor cortex. We then analyzed global protein expression changes across cerebrospinal fluid (CSF), plasma, and brain tissue of MSC-EV-treated versus vehicle-treated female, aged rhesus monkeys. A total of 1241/431/4124 monkey proteins were reliably quantified in CSF/plasma/tissue samples, respectively. Longitudinal analysis of CSF and plasma samples highlighted a shift from MSC-EV modulation of inflammatory and metabolic proteins in plasma at early recovery (2 weeks), toward modulation of plasticity-related proteins in CSF and brain tissue at later stages (4 weeks). Further protein-protein interaction analysis identified potential MSC-EV targets related to complementary signaling, proteolysis, and aminoglycan stability, which aligned with our previous findings. This comprehensive, multicompartment monkey proteomics study advances understanding of MSC-EV contents and treatment effects, paving the way for novel treatment of cortical injury.

Animals↗
PubMed2003

Merlin links to the cAMP neuronal signaling pathway by anchoring the RIbeta subunit of protein kinase A.

The cAMP-protein kinase A (PKA) pathway, important in neuronal signaling, is regulated by molecules that bind and target PKA regulatory subunits. Of four regulatory subunits, RIbeta is most abundantly expressed in brain. The RIbeta knockout mouse has defects in hippocampal synaptic plasticity, suggesting a role for RIbeta in learning and memory-related functions. Molecules that interact with or regulate RIbeta are still unknown. We identified the neurofibromatosis 2 tumor suppressor protein merlin (schwannomin), a molecule related to the ezrin-radixin-moesin family of membrane-cytoskeleton linker proteins, as a binding partner for RIbeta. Merlin and RIbeta demonstrated a similar expression pattern in central nervous system neurons and an overlapping subcellular localization in cultured hippocampal neurons and transfected cells. The proteins were coprecipitated from brain lysates by cAMP-agarose and coimmunoprecipited from cellular lysates with specific antibodies. In vitro binding studies verified that the interaction is direct. The interaction appeared to be under conformational regulation and was mediated via the alpha-helical region of merlin. Sequence comparison between merlin and known PKA anchoring proteins identified a conserved alpha-helical PKA anchoring protein motif in merlin. These results identify merlin as the first neuronal binding partner for PKA-RIbeta and suggest a novel function for merlin in connecting neuronal cytoskeleton to PKA signaling.

Amino Acid Sequence↗
PubMed2026

Proteomics-based approaches to neutrophil biology.

INTRODUCTION: Neutrophils are central effectors of innate immunity and key contributors to inflammation, host defense, and tissue injury across a wide range of physiological and pathological contexts. Due to their short lifespan, rapid activation, and extensive post-translational regulation, comprehensive molecular characterization of neutrophil function requires approaches that go beyond transcriptomics or marker-based analyses. AREAS COVERED: This review summarizes how proteomic technologies have advanced the understanding of neutrophil biology by enabling unbiased, system-wide profiling of protein abundance, subcellular organization, post-translational modifications, and functional heterogeneity. We discuss global and subcellular proteomics, PTM-centric analyses, and emerging low-input and single-cell proteomic strategies, highlighting recent studies of infection, cancer, metabolic disorders, aging, autoimmune disease, and inflammation. The literature covered includes current large-scale quantitative proteomics, targeted PTMs, and integrative multi-omics studies in both human samples and relevant experimental models. EXPERT OPINION: Proteomics has established neutrophils as highly plastic and context-dependent cells whose functions are governed by coordinated remodeling of signaling, metabolism, and effector pathways. Future progress will depend on expanding neutrophil-specific PTM maps, improving low-input workflows, and integrating single-cell and spatial proteomics. Together, these advances are expected to redefine neutrophil functional states and accelerate translation toward clinically meaningful biomarkers and therapeutic strategies.

Humans↗
PubMed1998

Neutron measurements in the stray field produced by 158 GeV c(-1) per nucleon lead ion beams.

This paper discusses measurements carried out at CERN in the stray radiation field produced by 158 GeV c(-1) per nucleon 208Pb82+ ions. The purpose was to test and intercompare the response of several detectors, mainly neutron measuring devices, and to determine the neutron spectral fluence as well as the microdosimetric (absorbed dose and dose equivalent) distributions in different locations around the shielding. Both active instruments and passive dosimeters were employed, including different types of Andersson-Braun rem counters, a tissue equivalent proportional counter, a set of superheated drop detectors, a Bonner sphere system, and different types of ion chambers. Activation measurements with 12C plastic scintillators and with 32S pellets were also performed to assess the neutron yield of high energy lead ions interacting with a thin gold target. The results are compared with previous measurements and with measurements made during proton runs.

Environmental Exposure↗
PubMed2003

Volume transmission and pain perception.

Volume transmission (VT) is the diffusion through the brain extracellular fluid of neurotransmitters released at points that may be remote from the target cells with the resulting activation of extrasynaptic receptors. VT appears to play multiple roles in the brain in normal and abnormal activity, brain plasticity and drug actions. The relevance of VT to pain perception has been explored in this review.

Animals↗
PubMed2005

Inflammation-induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage-gated ion channels.

Gastrointestinal (GI) inflammation modulates the intrinsic properties of nociceptive dorsal root ganglia neurones, which innervate the GI tract and these changes are important in the genesis of abdominal pain and visceral hyperalgesia neurones exhibit hyperexcitability characterized by a decreased threshold for activation and increased firing rate, and changes in voltages-gated Na(+) and K(+) channels play a major role in this plasticity. This review highlights emerging evidence that specific subsets of channels and signalling pathways are involved and their potential to provide novel selective therapeutics targets for the treatment of abdominal pain.

Abdominal Pain↗
PubMed2005

Evidence for low GluR2 AMPA receptor subunit expression at synapses in the rat basolateral amygdala.

Fast excitatory synaptic responses in basolateral amygdala (BLA) neurons are mainly mediated by ionotropic glutamate receptors of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) subtype. AMPA receptors containing an edited GluR2 subunit are calcium impermeable, whereas those that lack this subunit are calcium permeable and also inwardly rectifying. Here, we sought to determine the extent to which synapses in the rat BLA have AMPA receptors with GluR2 subunits. We assessed GluR2 protein expression in the BLA by immunocytochemistry with a GluR2 subunit-specific antiserum at the light and electron microscopic level; for comparison, a parallel examination was carried out in the hippocampus. We also recorded from amygdala brain slices to examine the voltage-dependent properties of AMPA receptor- mediated evoked synaptic currents in BLA principal neurons. At the light microscopic level, GluR2 immunoreactivity was localized to the perikarya and proximal dendrites of BLA neurons; dense labeling was also present over the pyramidal cell layer of hippocampal subfields CA1 and CA3. In electron micrographs from the BLA, most of the synapses were asymmetrical with pronounced postsynaptic densities (PSD). They contained clear, spherical vesicles apposed to the PSD and were predominantly onto spines (86%), indicating that they are mainly with BLA principal neurons. Only 11% of morphological synapses in the BLA were onto postsynaptic elements that showed GluR2 immunoreactivity, in contrast to hippocampal subfields CA1 and CA3 in which 76% and 71% of postsynaptic elements were labeled (p < 0.001). Synaptic staining in the BLA and hippocampus, when it occurred, was exclusively postsynaptic, and particularly heavy over the PSD. In whole-cell voltage clamp recordings, 72% of BLA principal neurons exhibited AMPA receptor-mediated synaptic currents evoked by external capsule stimulation that were inwardly rectifying. Although BLA principal neurons express perikaryal and proximal dendritic GluR2 immunoreactivity, few synapses onto these neurons express GluR2, and a preponderance of principal neurons have inwardly rectifying AMPA-mediated synaptic currents, suggesting that targeting of GluR2 to synapses is restricted. Many BLA synaptic AMPA receptors are likely to be calcium permeable and could play roles in synaptic plasticity, epileptogenesis and excitoxicity.

Amygdala↗
PubMed2004

Three-finger alpha-neurotoxins and the nicotinic acetylcholine receptor, forty years on.

The discovery, about forty years ago, of alpha-bungarotoxin, a three-finger alpha-neurotoxin from Bungarus multicinctus venom, enabled the isolation of the nicotinic acetylcholine receptor (nAChR), making it one of the most thoroughly characterized receptors today. Since then, the sites of interaction between alpha-neurotoxins and nAChRs have largely been delineated, revealing the remarkable plasticity of the three-finger toxin fold that has optimally evolved to utilize different combinations of functional groups to generate a panoply of target specificities to discern subtle differences between nAChR subtypes. New facets in toxinology have now broadened the scope for the use of alpha-neurotoxins in scientific discovery. For instance, the development of short, combinatorial library-derived, synthetic peptides that bind with sub-nanomolar affinity to alpha-bungarotoxin and prevent its interaction with muscle nAChRs has led to the in vivo neutralization of experimental alpha-bungarotoxin envenomation, while the successful introduction of pharmatopes bearing "alpha-bungarotoxin-sensitive sites" into toxin-insensitive nAChRs has permitted the use of various alpha-neurotoxin tags to localize and characterize new receptor subtypes. More ambitious strategies can now be envisaged for engineering rationally designed novel activities on three-finger toxin scaffolds to generate lead peptides of therapeutic value that target the nicotinic pharmacopoeia. This review details the progress made towards achieving this goal.

Amino Acid Sequence↗
PubMed1995

Toxicity of endogenous and environmental estrogens: what is the role of elemental interactions?

Many naturally occurring and man-made chemicals present in the environment possess estrogenic activity. Examples include plant and fungal products, pesticides, plasticizers, and other agricultural and industrial chemicals. These environmental estrogens as well as endogenous ovarian estrogens are thought to initiate their physiological actions in target tissues largely via interactions with a nuclear receptor system. The resultant estrogen-receptor complex in turn affects transcription via its interactions with nucleotide sequences known as estrogen response elements (EREs) present in the regulatory regions of hormone responsive genes. A "consensus" ERE sequence GGTCAnnnTGACC was originally identified in the vitellogenin genes of birds and amphibians, but it is now clear that most naturally occurring EREs differ from this sequence in one or more bases. We and others have obtained both in vivo and in vitro data suggesting a differential interaction of receptor complexes containing different ligands with the multiple EREs present in mammalian systems. This raises the possibility that the toxicity of environmental estrogens may arise in part from a differential pattern of ERE activation by environmental compounds relative to endogenous ovarian estrogens. The experimental basis for such a paradigm and its toxicological implications are discussed in this paper.

Animals↗
PubMed2003

A number no greater than the sum of its parts: the use and abuse of heritability.

Though widely used in quantitative genetics, in the study of human variation perhaps no statistic is more easily misinterpreted than heritability. While the contribution of genetic heritage to complex biological and behavioral phenotypes cannot be lightly dismissed, nonetheless we remain profoundly ignorant of how that legacy plays out in any environmental context. To be sure, it is not reducible to a single number. Nor does the preference among anthropologists for analyzing biological rather than behavioral phenotypes improve what heritability can reasonably say about the sources of human variation. This paper discusses the meaning of heritability, the methods for its estimation, the fallacies underlying its misuse, and its utility for inquiries in evolutionary anthropology and epidemiology. Progress in anthropological genetics will be realized through greater sophistication in study designs, including the measurement of environmental (physical and sociocultural) variation and the judicious choice of phenotypes for study. Elucidating the ontogenetic processes underlying adaptive plasticity is particularly critical to understanding the evolution of human biological variation. Such advancements will also shed light on the feasibility of genotype-targeted biomedical treatments. Failure to appreciate the limits of such approaches can divert resources from demonstrably effective environmentally based health interventions that benefit entire populations. Simplistic notions of genetic determinism should be challenged for the sake of our theories and the well-being of larger communities. As exemplified by the work of Frank B. Livingstone, anthropological genetics is at its best when incorporating anthropology into the study of human phenotypic variation.

Genetic Variation↗
PubMed2004

In vivo and in vitro characterization of novel neuronal plasticity factors identified following spinal cord injury.

Following spinal cord injury, there are numerous changes in gene expression that appear to contribute to either neurodegeneration or reparative processes. We utilized high density oligonucleotide microarrays to examine temporal gene profile changes after spinal cord injury in rats with the goal of identifying novel factors involved in neural plasticity. By comparing mRNA changes that were coordinately regulated over time with genes previously implicated in nerve regeneration or plasticity, we found a gene cluster whose members are involved in cell adhesion processes, synaptic plasticity, and/or cytoskeleton remodeling. This group, which included the small GTPase Rab13 and actin-binding protein Coronin 1b, showed significantly increased mRNA expression from 7-28 days after trauma. Overexpression in vitro using PC-12, neuroblastoma, and DRG neurons demonstrated that these genes enhance neurite outgrowth. Moreover, RNAi gene silencing for Coronin 1b or Rab13 in NGF-treated PC-12 cells markedly reduced neurite outgrowth. Coronin 1b and Rab13 proteins were expressed in cultured DRG neurons at the cortical cytoskeleton, and at growth cones along with the pro-plasticity/regeneration protein GAP-43. Finally, Coronin 1b and Rab13 were induced in the injured spinal cord, where they were also co-expressed with GAP-43 in neurons and axons. Modulation of these proteins may provide novel targets for facilitating restorative processes after spinal cord injury.

Animals↗
PubMed1997

Synaptic clustering of Fascilin II and Shaker: essential targeting sequences and role of Dlg.

Previous studies have shown that both the Fasciclin II (Fas II) cell adhesion molecule and the Shaker potassium channel are localized at the Drosophila neuromuscular junction, where they function in the growth and plasticity of the synapse. Here, we use the GAL4-UAS system to drive expression of the chimeric proteins CD8-Fas II and CD8-Shaker and show that the C-terminal sequences of both Fas II and Shaker are necessary and sufficient to drive the synaptic localization of a heterologous protein. Moreover, we show that the PDZ-containing protein Discs-Large (Dlg) controls the localization of these proteins, most likely through a direct interaction with their C-terminal amino acids. Finally, transient expression studies show that the pathway these proteins take to the synapse involves either an active clustering or a selective stabilization in the synaptic membrane.

Amino Acid Sequence↗
PubMed2005

What can a neuron learn with spike-timing-dependent plasticity?

Spiking neurons are very flexible computational modules, which can implement with different values of their adjustable synaptic parameters an enormous variety of different transformations F from input spike trains to output spike trains. We examine in this letter the question to what extent a spiking neuron with biologically realistic models for dynamic synapses can be taught via spike-timing-dependent plasticity (STDP) to implement a given transformation F. We consider a supervised learning paradigm where during training, the output of the neuron is clamped to the target signal (teacher forcing). The well-known perceptron convergence theorem asserts the convergence of a simple supervised learning algorithm for drastically simplified neuron models (McCulloch-Pitts neurons). We show that in contrast to the perceptron convergence theorem, no theoretical guarantee can be given for the convergence of STDP with teacher forcing that holds for arbitrary input spike patterns. On the other hand, we prove that average case versions of the perceptron convergence theorem hold for STDP in the case of uncorrelated and correlated Poisson input spike trains and simple models for spiking neurons. For a wide class of cross-correlation functions of the input spike trains, the resulting necessary and sufficient condition can be formulated in terms of linear separability, analogously as the well-known condition of learnability by perceptrons. However, the linear separability criterion has to be applied here to the columns of the correlation matrix of the Poisson input. We demonstrate through extensive computer simulations that the theoretically predicted convergence of STDP with teacher forcing also holds for more realistic models for neurons, dynamic synapses, and more general input distributions. In addition, we show through computer simulations that these positive learning results hold not only for the common interpretation of STDP, where STDP changes the weights of synapses, but also for a more realistic interpretation suggested by experimental data where STDP modulates the initial release probability of dynamic synapses.

Action Potentials↗
PubMed1988

Additive and synergistic antiproliferative effects of cyclosporin A and gamma interferon on cultured human keratinocytes.

To examine whether keratinocytes (KC) may be a cellular target for the action of cyclosporin A (CsA) in psoriasis and other skin diseases, the direct antiproliferative effect of CsA was examined on rapidly proliferating KCs grown on plastic in serum-free media. CsA at concentrations of 1-10 micrograms/ml directly inhibited KC proliferation over an 8-day incubation period. CsH, an immunologically inert stereoisomer, also inhibited KC proliferation at 5-10 micrograms/ml. When CsA (1 microgram/ml) was combined with gamma-interferon (gamma-IFN; 100 units/ml), there was an additive cytostatic effect on KC proliferation. The potentiating properties of gamma-IFN (100 U/ml) were additive when combined with CsA (1 microgram/ml) and synergistic at a higher concentration of CsA (5 micrograms/ml). The cytostatic effect of CsA (5 micrograms/ml) on KC proliferation was reversible after removal of the drug. Exposure of KCs to CsA resulted in numerous lipid-laden cytoplasmic vacuoles, which began to appear after 24 hours of CsA treatment. The fact that previous reports have documented 1-3 micrograms/ml of CsA and 100 U/ml of gamma-IFN in skin lesions of psoriasis patients suggests that our in vitro results were obtained with the use of physiologically relevant concentrations of these molecules. The direct antiproliferative effects by CsA on KCs suggest that both KCs and lymphocytes may be cellular targets in vivo for the mechanism of action of CsA in psoriasis.

Cell Division↗
PubMed2002

Differential responses of olfactory neurons to axotomy at embryonic and postnatal stages.

In the nervous system, apoptosis is a major process during embryonic and postnatal stages. In chick, experimental cell death can be obtained by axotomy. We have compared the responses of olfactory neurons to axotomy at embryonic stage E17 and postnatal stages.Forty-three chicken embryos and 32 young chickens less than 3 weeks old were used. We combined optic microscopy, electronic microscopy, terminal (TdT)-mediated dUTP-nick end labeling (TUNEL) method and gel electrophoresis of genomic DNA to analyze cell death. Cells in synthetic phase were labeled by bromodeoxyuridine injected i.p. and detected by immunohistochemistry. Apoptotic index and 5-bromo-2'-deoxyuridine (BrdU) labeling index were calculated for each stage. The Wilcoxon test was used for statistical analysis. A P value <0.05 was considered significant. Within 3 days following axotomy in E17 chicken embryos, there was no significant increase of apoptosis on the lesion side analyzed 3, 6, 12, 18, 24, 48 or 56 h later. A slight increase of bromodeoxyuridine incorporation appeared at 3 h, was weakly significant at 24 h (P=0.045) and the return to basal rate took place at 48 h. In postnatal stages, an apoptotic wave appeared 12 h after axotomy, reached a maximum at 24 h, and then decreased between 48 h and 72 h. A significant elevation of bromodeoxyuridine incorporation occurred on 48 h with a 24 h delay after the peak of apoptotic death. This differential response to axotomy in embryos and postnatal chickens might be due to a less complete maturation and higher plasticity of embryonic olfactory neurons corresponding to different requirement for survival and differentiation factors. Thus the embryonic or immature neurons would depend more on local epithelial environment and mature or postnatal neurons would require target-derived survival factors and die from apoptosis after their shortage resulting from axotomy.

Aging↗
PubMed1994

Morphology of retinal axons induced to arborize in a novel target, the medial geniculate nucleus. I. Comparison with arbors in normal targets.

Ferret retinal axons can be induced to innervate the medial geniculate nucleus (MGN) by a combination of brain lesions early in development. Our previous work suggests that the retinal ganglion cells responsible for this plasticity are W cells. The present study continues this work with a morphological investigation of normal retinal ganglion-cell axons and retinal ganglion-cell axons induced to arborize in the MGN. Retinal axons were bulk filled with horseradish peroxidase placed in the optic tract, and individual axons were serially reconstructed from sagittal sections. The control population consisted of fine-caliber axons arborizing in the superior colliculus (SC) and in the ventral C laminae of the lateral geniculate nucleus (LGN) of normal ferrets. We also compared the axons in the MGN of lesioned ferrets to intracellularly filled X and Y axons from normal ferrets as reported by Roe et al. ([1989] J. Comp. Neurol. 288:208). We have found that the retino-MGN axons in the lesioned ferrets do not resemble X or Y axons in normal ferrets in axon diameter, arbor volume, bouton number, or bouton density. However, they do resemble the fine-caliber, presumed W axons arborizing in the C laminae of the LGN and in the SC of normal ferrets. Thus, this study, in combination with previous studies, suggests strongly that W retinal ganglion cells are responsible for the retinal input to the MGN in lesioned animals. In addition, we find that the retino-MGN axons are of two types, branched and unbranched, which may correspond to different subtypes of retinal W cells.

Animals↗