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At least 1,027 records · Page 57Linked to original sources
PubMed2001

Simultaneous activation and opioid modulation of long-term potentiation in the dentate gyrus and the hippocampal CA3 region after stimulation of the perforant pathway in freely moving rats.

Recent investigations indicate monosynaptic activation by the perforant pathway (pp) of the dentate gyrus and the CA3 region. While short-term potentiation and long-term potentiation (LTP) and its opioid modulation are frequently described for the dentate gyrus, data for the CA3 region are rare. Therefore, evoked potentials and opioid modulation of LTP were directly compared in both target regions of the pp. Male Wistar rats were chronically implanted with a bipolar stimulation electrode in the pp (angular bundle) and two recording electrodes in the dorsal dentate gyrus and the CA3 region. Stimulation of the pp in the freely behaving animals induced short-latency evoked potentials in both target structures which were compared with respect to waveform, latency, amplitude and signs of short- and long-term neuronal plasticity. The short-latency potential in the CA3 region seemed to be a monosynaptic potential which displayed LTP sensitive to the N-methyl-D-aspartate receptor antagonist, MK 801, and depotentiating stimulation. After application of specific opioid antagonists at the mu-, delta- and kappa-opioid receptor subtypes, naloxone, funaltrexamine, naltrindole and binaltorphimine, different effects on induction and maintenance of LTP of the population spike were found both within the dentate gyrus and between the dentate gyrus and the CA3 region. The results show marked diminution of LTP in the dentate gyrus only for naloxone and naltrindole and only small, if any, effects of naloxone on LTP in the CA3 region. Thus, neuronal plasticity in the direct perforant pathway input to the CA3 region seems not to be under such substantial opioidergic control. LTP would be inducible in that region even when LTP in the input formation, the dentate gyrus, and transsynaptic LTP via the mossy fibres are blocked.

Animals↗
PubMedDate not supplied

Preliminary evaluation of the prototype stereoscopic endoscope: precise three-dimensional measurement system.

A prototype stereoscopic endoscope (incorporating two charged-coupled devices), developed for the accurate three-dimensional measurement of gastrointestinal tract lesions, was initially evaluated with two-dimensional target grids and in vitro measurement of 15 objects of known size (marbles, cubes, and rectangular prisms) placed in a plastic model of the sigmoid colon. Images of the objects were captured and stored in a computer. Stereoscopic measurements were compared with results from the standard (open biopsy forceps) method by a blinded endoscopist. The volume measured with the stereoscope did not differ significantly from the true volume, whereas the volume obtained with the open biopsy forceps method differed significantly from the actual volume, consistently underestimating the actual size. The aberration ratios (percentage deviation between the measured and true volume, expressed as mean +/- SD) obtained with the stereoscopic endoscope were superior (9.2% +/- 9.5%) to those obtained with the open biopsy forceps method (-34.0% +/- 26.8%). These preliminary in vitro results with the stereoscope show considerable promise for the simple and precise three-dimensional measurement of gastrointestinal lesions and warrant human clinical trials.

Endoscopes, Gastrointestinal↗
PubMed2000

Cell death of spinal interneurones.

The occurrence of neuronal death during development is well documented for some neuronal populations, such as motoneurones and dorsal root ganglion cells, whose connecting pathways are clearly defined. Cell survival is thought to be regulated largely by target and input connections, a process that serves to match the size of synaptically linked neuronal populations. Far less is known about interneurones. It is assumed that most interneurone populations are excluded from this process because their connections are more diffuse. Recent studies on the rat spinal cord have indicated that interneurone death does occur, both naturally during development and induced following peripheral nerve injury. Here the evidence for spinal interneurone death is reviewed and the factors influencing it are discussed. There are many functional types of interneurones in the spinal cord that may differ in vulnerability to cell death, but it is concluded that for most spinal interneurones the traditional view of target regulation is unlikely. Instead it is proposed that developmental interneurone death in the spinal cord forms part of a plastic response to altered sensory activation rather than a size-matching exercise. There is also emerging evidence that interneurone death may play a more direct role in some neurodegenerative diseases than hitherto considered.

Animals↗
PubMed2002

From synaptic errors to thalamocortical circuitry.

Recent data indicate that newly grown synapses in the brain are not guaranteed to innervate their desired target, but can form instead on nearby targets. Such 'errors' introduce representational inaccuracies but improve representational flexibility. Optimizing accuracy and flexibility requires detecting correlated activity and disabling plasticity, explaining the structure of the thalamocortical circuit.

Journal Article↗
PubMed2000

Structure-based discovery of small molecule inhibitors targeted to protein tyrosine phosphatase 1B.

Protein tyrosine phosphatases (PTPases) are involved in the control of tyrosine phosphorylation levels in the cell and are believed to be crucial for the regulation of a multitude of cellular functions. A detailed understanding of the role played by PTPases in various signaling pathways has not yet been achieved, and potent and selective PTPase inhibitors are essential in the quest to determine the functionality of individual PTPases. Using the DOCK methodology, we have carried out a structure-based, computer-assisted search of an available chemical database in order to identify low molecular weight, nonpeptidic PTP1B inhibitors. We have identified several organic molecules that not only possess inhibitory activity against PTP1B but which also display significant selectivity for PTP1B. This indicates that although structural features important for pTyr recognition are conserved among different PTPases, it is possible to generate selective inhibitors targeted primarily to the catalytic site. Kinetic analysis and molecular modeling experiments suggest that the PTP1B active site possesses significant plasticity such that substituted and extended aromatic systems can be accommodated. The newly identified molecules provide a molecular framework upon which therapeutically useful compounds can ultimately be based, and systematic optimization of these lead compounds is likely to further enhance their potency and selectivity.

Catalytic Domain↗
PubMed2026

Single-cell multiomics reveals exosome-mediated reprogramming and clonotypic remodeling of T cells in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive and immunogenic subtype lacking targeted therapies. While tumor-derived exosomes are known to modulate immune function, their direct impact on human T cell plasticity and antigen specificity remains poorly defined. Here, we conducted a comprehensive single-cell multiomic analysis of primary human T cells exposed to exosomes derived from 17 genomically diverse TNBC cell lines and 35 patient samples. Integrating single-cell RNA-seq, V(D)J sequencing, non-coding RNA profiling, bulk and single-cell cytokine analyses, we uncovered conserved and subtype-specific immunomodulatory programs induced by TNBC exosomes. Exosome-treated T cells displayed skewing toward regulatory and dysfunctional phenotypes, including Th17-like, Treg, and PD-1⁺/PD-L1⁺ Tfh cells. Functional profiling revealed suppression of early activation markers and cytokine responses, alongside selective preservation of cytotoxic features in γδ T and NKT subsets. Transcriptomic and miRNA network analyses demonstrated widespread downregulation of immune effector genes (e.g., HBEGF and TNFSF9) mediated by exosome-delivered regulatory miRNAs (has-miR-98-5p). Notably, exosome-stimulated T cells displayed distinct clonotypic expansions, characterized by the emergence of five tumor-specific γδ TCR clonotypes and 30 unique αβ TCR CDR3 sequences that were absent in mock-treated controls, underscoring the role of exosomes in shaping TCR repertoire dynamics.

Humans↗
PubMed2004

Glutamate regulates Oct-2 DNA-binding activity through alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in cultured chick Bergmann glia cells.

Ionotropic glutamate receptors in cerebellar Bergmann glial cells are linked to transcriptional regulation and, by these means, are thought to play an important role in plasticity, learning and memory and in several neuropathologies. Within the CNS, the transcription factors of the POU family bind their target DNA sequences after a growth factor-dependent phosphorylation-dephosphorylation cascade. Exposure of cultured Bergmann glial cells to glutamate leads to a time- and dose-dependent increase in Oct-2 DNA-binding activity. The use of specific pharmacological tools established the involvement of Ca2+-permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors. Furthermore, the signaling cascade includes phosphatidyl inositol 3-kinase as well as protein kinase C activation. Interestingly, transcriptional as well as translational inhibitors abolish the glutamate effect, suggesting a transcriptional up-regulation of the oct-2 gene. These data demonstrate that Oct-2 expression is not restricted to neurons and further strengthen the notion that the glial glutamate receptors participate in the modulation of glutamatergic cerebellar neurotransmission.

Animals↗
PubMed1991

Lack of neuropathological changes in rats after exposure to butyl benzyl phthalate.

Butyl benzyl phthalate (BBP; Santicizer 160 Plasticizer) was fed to 3 groups of 10 male and 10 female Charles River CD rats for 6 wk at target doses of 500, 1500, and 3000 mg/kg/d. Control groups of 6 males and 6 females received untreated diets for the same period. Body weight gains were decreased at the 1500 and 3000 mg/kg/d levels. Hindlimb stiffness was noted at the 3000 mg/kg/d level and was more prevalent in males. Stiffness was apparently reversed after withdrawal from BBP exposure for 2 d. Microscopic examination of central and peripheral nervous system tissues did not reveal any compound-related pathological changes. Thus, there were no morphological changes in the nervous system that could be related to the apparently reversible hindlimb stiffness.

Administration, Oral↗
PubMed2003

Ribosomal protein S15 represses its own translation via adaptation of an rRNA-like fold within its mRNA.

The 16S rRNA-binding ribosomal protein S15 is a key component in the assembly of the small ribosomal subunit in bacteria. We have shown that S15 from the extreme thermophile Thermus thermophilus represses the translation of its own mRNA in vitro, by interacting with the leader segment of its mRNA. The S15 mRNA-binding site was characterized by footprinting experiments, deletion analysis and site-directed mutagenesis. S15 binding triggers a conformational rearrangement of its mRNA into a fold that mimics the conserved three-way junction of the S15 rRNA-binding site. This conformational change masks the ribosome entry site, as demonstrated by direct competition between the ribosomal subunit and S15 for mRNA binding. A comparison of the T.thermophilus and Escherichia coli regulation systems reveals that the two regulatory mRNA targets do not share any similarity and that the mechanisms of translational inhibition are different. Our results highlight an astonishing plasticity of mRNA in its ability to adapt to evolutionary constraints, that contrasts with the extreme conservation of the rRNA-binding site.

Bacterial Proteins↗
PubMed2001

Size of myelinated nerve fibres is not increased by expansion of the peripheral field in cats.

This study tests the hypothesis that target size regulates the size of myelinated sensory and motor fibres in peripheral nerves. Cat medial gastrocnemius (MG) muscles were partially denervated and the size of the remaining nerve fibres that sprouted was examined 6.4 +/- 0.9 months later to determine whether nerve fibre size increased with target size. Electrophysiological and morphometric analyses were used to quantify myelinated nerve fibre size. Charge measurements from dorsal and ventral roots were used to electrophysiologically quantify the relative number of cut nerve fibres and the average size of the remaining intact sensory and motor nerve fibres. Medial gastrocnemius muscle and motor unit forces provided indirect measurements of the increase in target size. Conduction velocities and amplitude of unitary action potentials of motor nerve fibres innervating single motor units were also measured after partial denervation. Electrophysiological measurements of nerve fibre size and morphometric measurements of outer fibre perimeters and fibre areas concurred and demonstrated that myelinated nerve fibres supplying partially denervated MG muscles did not increase in size in parallel with the increase in the target size. Thus, unlike non-myelinated nerve fibres, the size of myelinated nerve fibres does not increase as target size increases. Retrograde control of size in non-myelinated but not in myelinated nerve fibres demonstrates differences in plasticity of neurons in the somatic and autonomic nervous systems.

Action Potentials↗
PubMed2006

Imaging tumor angiogenesis.

Since the discovery of vascular-specific growth factors with angiogenic activity, there has been a significant effort to develop cancer drugs that restrict tumorigenesis by targeting the blood supply. In this issue of the JCI, Mancuso et al. use mouse models to better understand the plasticity of the tumor vasculature in the face of antiangiogenic therapy (see the related article beginning on page 2610). They describe a rapid regrowth of the tumor vasculature following withdrawal of VEGFR inhibitors, emphasizing the importance of fully understanding the function of these and similar treatments used in the clinic at the cellular and molecular level.

Angiogenesis Inhibitors↗
PubMed2006

Dopamine presynaptically and heterogeneously modulates nucleus accumbens medium-spiny neuron GABA synapses in vitro.

BACKGROUND: The striatal complex is the major target of dopamine action in the CNS. There, medium-spiny GABAergic neurons, which constitute about 95% of the neurons in the area, form a mutually inhibitory synaptic network that is modulated by dopamine. When put in culture, the neurons reestablish this network. In particular, they make autaptic connections that provide access to single, identified medium-spiny to medium-spiny neuron synaptic connections. RESULTS: We examined medium-spiny neuron autaptic connections in postnatal cultures from the nucleus accumbens, the ventral part of the striatal complex. These connections were subject to presynaptic dopamine modulation. D1-like receptors mediated either inhibition or facilitation, while D2-like receptors predominantly mediated inhibition. Many connections showed both D1 and D2 modulation, consistent with a significant functional colocalization of D1 and D2-like receptors at presynaptic sites. These same connections were subject to GABAA, GABAB, norepinephrine and serotonin modulation, revealing a multiplicity of modulatory autoreceptors and heteroreceptors on individual varicosities. In some instances, autaptic connections had two components that were differentially modulated by dopamine agonists, suggesting that dopamine receptors could be distributed heterogeneously on the presynaptic varicosities making up a single synaptic (i.e. autaptic) connection. CONCLUSION: Differential trafficking of dopamine receptors to different presynaptic varicosities could explain the many controversial studies reporting widely varying degrees of dopamine receptor colocalization in medium-spiny neurons, as well as more generally the diversity of dopamine actions in target areas. Longer-term changes in the modulatory actions of dopamine in the striatal complex could be due to plasticity in the presynaptic distribution of dopamine receptors on medium-spiny neuron varicosities.

Animals↗
PubMed2026

Balancing under constraint: Structural insights into norovirus evolution and antigenic innovation.

Norovirus is the leading cause of acute viral gastroenteritis worldwide. While genomic studies have revealed its diversity and evolutionary patterns, the structural mechanisms driving viral adaptation remain poorly understood. Here, we establish a comprehensive structural database of norovirus VP1 P-domains across nine genogroups (GI-GIX) through large-scale AlphaFold2 predictions. By integrating phylogenetic analysis of VP1 sequences and structures, we demonstrate that sequence and structural evolution show overall concordance under purifying selection, yet significant local discrepancies reveal distinct patterns of convergent evolution shaped by structural constraints and functional divergence. Focusing on the predominant GII.4 genotype, we found that compared to near-full-genome and nucleotide trees, only the VP1 amino acid tree reliably clustered GII.4 variants in chronological order as monophyletic groups. We further identify a hierarchical evolutionary strategy: positive selection may drive structural hypervariability in major antigenic epitopes D and C for immune escape, with epitope D exhibiting pronounced structural flexibility that complicates its structural characterization, whereas coevolutionary analysis uncovers a broad network of compensatory interactions spanning multiple epitopes, with striking enrichment in epitope A. These epitopes exhibited a pattern of "sequence plasticity with structural conservation", maintained by coevolutionary constraints that preserve conformational integrity. Together, these findings suggest that norovirus vaccine strategies targeting the structurally conserved conformations of epitopes A and G could overcome the limitations of traditional strain-specific approaches, offering a pathway toward broad protection against evolving viral diversity.

Norovirus↗
PubMed2001

Emerging targets for the treatment of depressive disorder.

New agents offering novel mechanisms of action are required in the treatment of depressive disorder. Established agents targeting monoamine systems are unsatisfactory because of full and partial treatment resistance, delay in the onset of their effect and the occurrence of side effects. The monoamine hypothesis of depression is now recognised to provide an incomplete explanation of the pathophysiology of depression. New theories have recently developed and new targets for treatment have emerged. We briefly review some important candidate systems and therapeutic targets in depression: the hypothalamic-pituitary-adrenal axis (HPA) and the glucocorticoid and corticotrophin-releasing factor receptors, synaptic plasticity and neurotrophins and the N-methyl-D-aspartate (NMDA) receptor. The putative role of the neuropeptides substance P and neuropeptide Y, the nicotinic system and the potential therapeutic benefits of cannabinoids are also reviewed. Vagal nerve stimulation (VNS) and transcranial magnetic stimulation, serendipitous advances in treatment, are discussed briefly.

Journal Article↗
PubMed1976

Cytotoxicity in graft-versus-host reaction. II. Lysis of target cells of parental genotyppe by F1 hybrid macrophages.

Graft-versus-host (GVH) reactions were induced in adult F1 hybrid mice with the i.p. injection of parental strain spleen cells. Peritoneal exudate and spleen cells of the F1 hybrids taken 8 days after the induction of GVH reaction had a nonspecific in vitro cytotoxic effect which was measured by using 51Cr-labeled target cells of parental genotype. The cytotoxic cells in the peritoneal exudates were shown to be macrophages which adhered to plastic surfaces and were sensitive to the toxic action of crystalline silica particles. Moreover, the injection of partially purified syngeneic macrophages into the F1 hybrids undergoing GVH reactions increased the cytotoxic activity of the peritoneal exudate cells obtained from these animals. These results suggest that during GVH reaction host macrophages are activated into a state of nonspecific cytotoxicity.

Animals↗
PubMed1980

Natural cytotoxicity on tumour cells of human macrophages obtained from diverse anatomical sites.

Human mononuclear phagocytes were isolated from peripheral blood, peritoneal exudate and early lactation milk by adherence on microexudate-coated plastic and exposure to ethylene diamine tetracetic acid. Their cytolytic activity was measured as 3H-thymidine release from prelabelled target cells over 48-72 hr and cytostasis was evaluated in a spectrophotometric 72-hr assay. The murine SV40-transformed mKSA-TU5 line and the human E cell line, derived from an ovarian carcinoma, were employed as targets. Peripheral blood monocytes, in vitro-matured monocyte-derived macrophages, peritoneal macrophages and milk macrophages were all significantly cytolytic and cytostatic on these target cells at attacker to target cell ratios ranging from 5:1 to 40:1. When monocytes were cultivated in vitro, no loss of cytocidal capacity occurred over the first 10 days of culture, whereas later on, when epithelioid and giant cells predominate in the cultures, mononuclear phagocytes had little cytotoxic activity. Adherent cells obtained from cord blood or from the peripheral blood of old donors had natural cytotoxicity similar to monocytes obtained from young adult volunteers. Peripheral blood monocytes and peritoneal macrophages showed enhanced cytolytic activity after exposure to partially purified human fibroblast interferon. These experiments suggest that in the human mononuclear phagocyte series cytotoxicity on tumour cells is not restricted to circulating monocytes but is also expressed by macrophages obtained from diverse anatomical sites.

Adult↗
PubMed2002

SCG10-related neuronal growth-associated proteins in neural development, plasticity, degeneration, and aging.

Neuronal growth-associated proteins (nGAPs) are in general neuron-specific gene products whose expression correlates tightly with neuronal process outgrowth and/or regeneration, and are mostly good downstream targets of neurotrophin stimulation. Expression of genes encoding nGAPs such as GAP-43, SCG10, and stathmin is upregulated following lesioning of cortical and hippocampal regions of the adult rat brain. In the brains of aged animals, however, the magnitude of the response is reduced, whereas the time course of the response is mostly unchanged when compared with that for brains of young ones. Expression of GAP-43 and stathmin is reduced by aging, and is also changed in age-related neurodegenerative conditions such as Alzheimer's disease in humans. Certain nGAPs are induced during long-term potentiation (LTP) and also during critical periods of song-learning and ocular dominance column formation in birds and cats, respectively. Recent evidence further supports the idea that functional synaptic modulation is often associated with remodeling of synaptic structures. These results suggest that neurotrophin-responsive nGAPs serve as molecular markers of neuronal plasticity during development and aging, and that the neuronal plasticity decreases, at least in certain neuronal circuits, in the aged brain and neurodegenerative diseases. Recent findings on the roles of stathmin and SCG10-related proteins in microtubule destabilization and its functional block by phosphorylation further support the importance of the SCG10 family proteins in neuronal cytoskeletal regulation, particularly as to microtubule dynamics. We summarize here a decade of research on SCG10 and its related molecules with special interests to brain aging and disease.

Aging↗
PubMed2004

Therapeutic targeting of prostate cancer.

An inaugural conference in Tucson Arizona on May 6-9, 2004 brought together more than 70 clinical and basic scientists to discuss recent research advances in understanding and targeting the progression of the human prostate cancer. The informal meeting was unique in that it provided the opportunity for discussion and interaction between these different groups of scientists whose paths rarely cross. The goal of the meeting was to develop new and novel approaches in understanding the human prostate cancer in order to uncover therapeutic targets. Faculty from six different cancer centers were represented including Memorial Sloan-Kettering Cancer Center (New York, NY); Arizona Cancer Center (Tucson, AZ); Fred Hutchinson Cancer Center (Seattle, WA); Chao Family Comprehensive Cancer Center (Irvine, CA); the Sydney Kimmel Cancer Center (San Diego, CA); Jonsson Comprehensive Cancer Center, University of California (Los Angeles, CA); and University of Massachusetts Memorial Cancer Center (Worcester, MA). Several important concepts emerged from this meeting as a result of the basic and clinical science interface. These concepts include: (1) Human prostate cancer has unique biological features as compared to other human epithelial malignancies; (2) Tumor plasticity is evident early in prostate cancer progression as evidenced by alterations in the extracellular matrix; (3) New therapeutic strategies should include the co-targeting of the stroma and prostate cancer; (4) Cell-cell and cell-ECM adhesion switching are reversible phenotypes evident early in human prostate tumor progression; (5) The discovery of molecular signatures including genomic or proteomic patterns for the discrimination of indolent versus aggressive disease is a potentially powerful tool and requires multifactorial approaches for success; and (6) New biomarkers and innovative tissue specific imaging modalities for human prostate cancer are being developed that may aid in a more accurate assessment of prostate cancer in patients.

Animals↗