Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Target plasticity”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,405 records · Page 78Linked to original sources
PubMed2002

Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure.

Neurotrophins are key regulators of neuronal survival and function. Here we show that TrkB, the receptor for brain-derived neurotrophic factor (BDNF), is located at parallel fiber to Purkinje cell (PF/PC) synapses of the cerebellum. To determine the effects of TrkB receptor activation on synapse formation and function, we examined the parallel fiber to Purkinje cell synapses of mice with a targeted deletion of the BDNF gene. Although Purkinje cell dendrites are abnormal in BDNF -/- mice, PF/PC synapses are still able to form. Immunohistochemical analysis of mutant animals revealed the formation of numerous PF/PC synapses with the appropriate apposition of presynaptic and postsynaptic proteins. These synapses are functional, and no differences were detected in the waveform of evoked EPSCs, the amplitude of spontaneous mini-EPSCs, or the response to prolonged 10 Hz stimulus trains. However, paired-pulse facilitation, a form of short-term plasticity, is significantly decreased in BDNF -/- mice. Detailed ultrastructural analysis of the presynaptic terminals demonstrated that this change in synaptic function is accompanied by an increase in the total number of synaptic vesicles in mutant mice and a decrease in the proportion of vesicles that are docked. These data suggest that BDNF regulates both the mechanisms that underlie short-term synaptic plasticity and the steady-state relationship between different vesicle pools within the terminal.

Animals↗
PubMed2026

Genetic Mutation and Epigenetic Silencing Drive Antigen-Negative Relapse in CD7 CAR T-Treated T-cell Lymphoid Malignancies.

UNLABELLED: CD7 is a promising target for chimeric antigen receptor (CAR) T-cell therapy in T-cell lymphoid malignancies; however, antigen loss-mediated relapse has emerged as a major challenge. In this study, we systematically analyzed the genetic and epigenetic alterations of paired specimens (pretreatment and relapsed) from 10 patients with T-cell lymphoma/leukemia receiving CD7 CAR T cells. Overall, we identified three distinct mechanisms underlying CD7 loss: first, frameshift insertion (patient 4; c.164dupG:p.R55fs) or deletion (patient 7; c.122delG:p.G41Efs*19) resulting in truncation of the CD7 transmembrane domain in two of 10 patients; second, hypermethylation of the CD7 promoter in seven of 10 patients without CD7 mutation; third, simultaneous occurrence of promoter region hypermethylation and multiple in-frame mutations with predicted functional interference in one of 10 patients (patient 2). Collectively, these findings demonstrate that both clonal heterogeneity and epigenetic plasticity drive antigen-negative relapse in T-cell lymphoid malignancies under the selective pressure of CD7 CAR T-cell therapy. SIGNIFICANCE: Understanding mechanisms of antigen-negative relapse is critical for developing effective CD7-targeting CAR-T therapies against T-cell lymphoid malignancies. Our study identifies both genetic truncation mutations and epigenetic silencing as contributors to CD7-negative relapse. Monitoring and preventing these events is warranted to improve treatment outcomes.

Humans↗
PubMed1983

The effect of forebrain lesions in the neonatal rat: survival of midbrain dopaminergic neurons and the crossed nigrostriatal projection.

Lesions were placed in the striatum and the olfactory tubercle of 1-day-old rat pups. Control and experimental animals were raised to adulthood. Efferent projections of mesencephalic neurons were examined by injecting the retrograde tracers horseradish peroxidase or Fast Blue into the undamaged striata of some experimental animals. The survival of the mesencephalic dopaminergic neurons was monitored by using immunocytochemical localization of tyrosine hydroxylase. Small lesions in the caudate-putamen had no appreciable effect on the survival of tyrosine hydroxylase-containing neurons in the mesencephalon, but the density of dopaminergic terminals adjacent to the lesion increased in the remaining caudate-putamen. Striatal lesions that involved an estimated area of more than one-third resulted in loss of dopamine neurons of the substantia nigra compacta. Rostral lesions in the striatum affected mostly rostrally positioned neurons in the substantia nigra. Dorsal lesions of the caudate-putamen resulted in disappearance of dorsal A9 neurons. Reduction of the A10 and A8 dopamine neuron groups occurred if the neonatal lesions involved the olfactory tubercle and nucleus accumbens. Some tyrosine hydroxylase-containing neurons persisted even after the largest lesions. These dopaminergic neurons formed a crossed nigrostriatal pathway which was confirmed by retrogradely transported tracers. The density of this crossed projection in the adult appeared unaffected by the neonatal lesion. We concluded that dopaminergic neurons form topographically ordered projections with their targets in the newborn rat. Rearrangement of these fibers appeared limited, but compensatory increase of axon terminal density was evident in partially lesioned target areas.

Animals↗
PubMed2001

Changing synaptic connections on cell bodies of growing identified spinal motoneurons of the eel, Anguilla.

As the target musculature they innervate grows throughout life, certain segmental motoneurons from the spinal cord of Anguilla, readily identified on the basis of their form and position, also increase in size. In doing so, they present a steadily increasing target to the spinal and supraspinal neurons that innervate them. How the afferent neurons respond was assessed by measuring features of their synaptic boutons contacting the motoneuronal perikarya, as seen with electron microscopy. About 60% of the perimeter of the perikaryal profile of each motoneuron was found to be covered with synaptic bouton profiles, a value that is independent of the size of the motoneuron. Furthermore, the distances between synaptic profiles, their contact sizes (measured as apposition length) and the number and size of the vesicles each profile contains were all found to be relatively constant and also independent of motoneuronal size. In contrast, the number of synaptic profiles contacting a motoneuron correlated well with its perikaryal size. Our findings indicate that the challenge of a growing neuronal target is met by a steady increase in the number of contacting boutons, the form and spacing of which are held relatively constant; this strategy will require continual synaptic realignment at the target.

Anguilla↗
PubMed2003

Endothelial-pericyte interactions in angiogenesis.

It takes two to make blood vessels-endothelial cells and pericytes. While the endothelial cells are the better characterized of the two, pericytes are now coming into focus as important regulators of angiogenesis and blood vessel function, and as potential drug targets. However, pericytes are still surrounded by much controversy. They are difficult to define, they constitute a heterogeneous population of cells, and their ontogeny is not well understood. They are plastic and have the capacity to differentiate into other mesenchymal cell types, such as smooth muscle cells, fibroblasts and osteoblasts. Recent interest in pericytes also stems from their potential involvement in diseases such as diabetic microangiopathy, tissue fibrosis, cancer, atherosclerosis and Alzheimer's disease. The present review focuses on the role of pericytes in physiological angiogenesis. The currently favored view states that the initial endothelial tubes form without pericyte contact, and that subsequent acquisition of pericyte coverage leads to vessel remodeling, maturation and stabilization. Improved means of identifying and visualizing pericytes now challenge this view and show that high numbers of pericytes invest in actively sprouting and remodeling vessels. Genetic data demonstrate the critical importance of pericytes for vascular morphogenesis and function, and imply specific roles for the cell type in various aspects of angiogenesis.

Animals↗
PubMed2006

GABA(B) receptors and synaptic modulation.

GABA(B) receptors modulate transmitter release and postsynaptic membrane potential at various types of central synapses. They function as heterodimers of two related seven-transmembrane domain receptor subunits. Trafficking, activation and signalling of GABA(B) receptors are regulated both by allosteric interactions between the subunits and by the binding of additional proteins. Recent studies have shed light on the roles of GABA(B) receptors in plasticity processes at excitatory synapses. This review summarizes our knowledge of the localization, structure and function of GABA(B) receptors in the central nervous system and their use as drug targets for neurological and psychiatric disorders.

Allosteric Regulation↗
PubMed1988

Excessive numbers of axons after early enucleation and blockade of metamorphosis in the oculomotor nerve of Xenopus laevis.

The number of axons in the oculomotor (OM) nerve of Xenopus laevis tadpoles was counted in unoperated and in unilaterally enucleated animals, raised in 0.4 g/l thiourea (TU), a thyroid-blocking agent, which arrested their development at premetamorphosis. In unoperated animals the number of axons starts to decrease with metamorphosis. When raised in TU, the tadpoles do not metamorphose and show no axon loss; rather, there is a moderate increase in axon number (13%) after 6 months of thiourea-treatment. Thus metamorphosis is necessary for the initiation of axon loss. In unilaterally enucleated tadpoles, increased axon loss occurs at metamorphosis in the OM nerve of the operated side, but the contralateral OM nerve shows no loss at all. When these animals are treated with TU, there is, as compared with the effects of the TU-treatment in unoperated animals, an increase of 7% in the ipsilateral side and of 28% in the contralateral one. Thus thyroxine blockade prevents the effects of unilateral enucleation and induces an excessive number of axons during the period observed. We postulate that through blockade of metamorphosis, axon elimination is arrested, while their production continues, and that these effects are accentuated by manipulation of the axonal target.

Age Factors↗
PubMed1996

Nitric oxide actions in neurochemistry.

The discovery of the role of nitric oxide (NO) as a messenger molecule in the central nervous system has radically altered our conception of neuronal communication. Information has been generated at a rapid pace in the last few years regarding the biochemistry, enzymatic activity and molecular characteristics of NO synthase (NOS) and NO synthesis, and the biological consequences of NO production. The full scope of the biological consequences of NO production is unknown but putative cellular targets of NO are rapidly being discovered as well as potential physiological and pathophysiological roles in the nervous system. Roles for NO have been identified in neurotransmitter release, morphogenesis, synaptic plasticity, regulation of gene expression, as well as mediation of inhibitory processes associated with sexual and aggressive behaviour. Inappropriate formation of NO is emerging as an important factor in the neurotoxicity associated with a variety of central nervous system disorders. The current information on the various roles of NO as a neuronal messenger molecule as well as a neurotoxin are reviewed in this article.

Animals↗
PubMed1987

Regenerating retinal fibers of the goldfish make temporary and unspecific but functional synapses before forming the final retinotopic projection.

Many investigators have examined the retinotectal projection following regeneration, but the mapping technique used in these studies mainly involved recording action potentials from presynaptic terminals. Hence it was not possible to analyse the postsynaptic phenomena underlying the target finding process of the retinal fibers. In the present study, the process of making functional synapses was examined using field potentials generated by small spots of light fixed in the visual field. The results show that regenerating retinal fibers first make functional but temporary, unspecific and diffuse synapses before reaching the target area to form a sharpened retinotopic projection. It is suggested that the formation of synapses subserves an important role in the target finding process.

Action Potentials↗
PubMed2003

[The therapeutic function of the aesthetic surgery].

By its definition and its etymology, aesthetic surgery is as much a surgery for the soul as for the body. Aesthetic surgery is a true "armed" therapy that essentially targets the psychology of the patient. This therapeutic "arsenal" preserves and/or restores the health of the patient according to its different aspects as defined by the World Health Organization. The plastic surgeon is always concerned about his patient as a whole, and as a human being, of whom he takes charge. Indeed there lies his specificity: He is as well a surgeon and a physician. We identify and analyze, in this chapter, the particular quality of patient-surgeon relationship on a surgical, psychological and juridical level. It is interesting to note that this collaboration results from a spontaneous convergence. The surgeon, the main interested figure, asserts himself mainly as a physician that is totally involved in a dialogue with his patient. He multiplies the interviews and he sharpens his clinical approach, and his own reactions, with regard to the demand for plastic surgery. The psychiatrist establishes the theoretical and practical aspects of the patient demand. The jurist, far from the barren dissertation of the law, reconsiders the environment of the demand and legitimates the generating wish: he insists on the necessary information but also on assuming responsibility. The therapeutic function of the plastic surgery appears essentially related to the success of a psychic repair solicited by the patient but that is scarcely specified by him as such, and of which he is, most probably, rarely fully aware. The process is to listen and to gather the information that guarantees mutual understanding. Plastic surgery is considered irreplaceable by many of our patients, and indisputable by us. It brings incomparable social and human fertility. It is, however, an ambitious and difficult project that is highly demanding. It is far from the impression of facility reflected by the media. Every actor of this scene, where the patient takes the center stage, must be aware of it.

Humanism↗
PubMed2025

Innate immune sensing and signaling: Co-opted for genome surveillance? Implications for tumorigenesis.

Innate immune signaling is traditionally associated with the response to pathogenic infection. However, emerging evidence suggests that nuclear innate immune sensors and their downstream pathways may also serve as a critical mechanism for genome surveillance. This review explores a model in which DNA sensors such as mouse IFI204 and IFI205 (IFI16 in humans) localize to replication forks, where they detect endogenous aberrant DNA structures and initiate an interferon-stimulated gene (ISG) transcriptional program. A key output of this transcriptional program is ISG15, which we find conjugated to fork-associated proteins and facilitates recruitment of the replication fork protection complex, thereby stabilizing replication forks under physiological conditions. We discuss how nuclear innate immune sensors mediate replication stress sensing and examine the broad consequences of downstream ISG transcription across diverse contexts-including its impact on genome stability and its dual roles in modulating tumor cell behavior and the tumor microenvironment. These findings suggest that the innate immune system, through its nuclear DNA sensing arm, may be evolutionarily co-opted for genome surveillance and may influence tumor initiation and therapy resistance. Understanding how innate immune signaling intersects with replication stress could offer mechanistic insights into tumor development and reveal novel therapeutic targets.

Humans↗
PubMed2006

Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation.

The ERK/MAP kinase cascade is important for long-term memory formation and synaptic plasticity, with a myriad of upstream signals converging upon ERK activation. Despite this convergence of signaling, neurons routinely activate appropriate biological responses to different stimuli. Scaffolding proteins represent a mechanism to achieve compartmentalization of signaling and the appropriate targeting of ERK-dependent processes. We report that kinase suppressor of Ras (KSR1) functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Specificity of KSR1-dependent signaling also extends to specific downstream targets of ERK. Behaviorally and physiologically, we found that the absence of KSR1 leads to deficits in associative learning and theta burst stimulation-induced LTP. Our report provides novel insight into the endogenous scaffolding role of KSR1 in controlling kinase activation within the nervous system.

Adrenergic beta-Agonists↗
PubMed2004

Reparative mechanisms in the cerebellar cortex.

In the adult brain, different neuronal populations display different degrees of plasticity. Here, we describe the highly different plastic properties of inferior olivary neurones and Purkinje cells. Olivary neurones show a basal expression of growth-associated proteins, such as GAP-43 and Krox24/EGR-1, and remarkable remodelling capabilities of their terminal arbour. They also regenerate their transected neurites into growth-permissive territories and may reinnervate the lost target. Sprouting and regrowing olivary axons are able to follow specific positional information cues to establish new connections according to the original projection map. In addition, they set a strong cell body reaction to injury, which in specific olivary subsets is regulated by inhibitory target-derived cues. In contrast, Purkinje cells do not have a constitutive level of growth-associated genes, and show little cell body reaction, no axonal regeneration after axotomy, and weak sprouting capabilities. Block of myelin-derived signals allows terminal arbour remodelling, but not regeneration, while selective over-expression of GAP-43 induces axonal sprouting along the axonal surface and at the level of the lesion. We suggest that the high constitutive intrinsic plasticity of the inferior olive neurones allows their terminal arbour to sustain the activity-dependent ongoing competition with the parallel fibres in order to maintain the post-synaptic territory, and possibly underlies mechanisms of learning and memory. Such a plasticity is used also as a reparative mechanism following axotomy. In contrast, in Purkinje cells, poor intrinsic regenerative capabilities and myelin-derived signals stabilise the mature connectivity and prevent axonal regeneration after lesion.

Animals↗
PubMed1976

The role of adherent cells in the secondary cell-mediated response in vitro to a natural poxvirus pathogen.

The role of adherent cells in an in vitro secondary response to ectromelia virus infection was investigated. Spleen cells from ectromelia-primed mice ("responder" cells) depleted of adherent cells by either carbonyl iron treatment, adherence to plastic or passage through cotton wool columns had a markedly decreased capacity to produce a secondary response, as indicated by decreased T cell-mediated cytotoxicity against virus-infected target cells, when cultured with virus-infected "stimulator" cells. The secondary response was restored by the addition of peritoneal cells from either normal or ectromelia-immune mice. Small numbers of peritoneal cells completely reconstituted the response within a certain dose range but larger numbers produced a marked inhibition of the response. Spleen cells were less effective in restoring the response. The peritoneal cells were not merely acting as additional, infected "stimulator" or antigen-presenting cells, since they could be added as late as 3 days after culture. Reconstituting activity was not affected by pretreatment with anti-theta serum and complement and cell separation studies showed that the activity was associated mainly with Ig-negative cells and that the active cell probably bears Ia antigens on its surface. These results indicate that the adherent cells involved are probably macrophages and that they act non-specifically to produce optimum conditions for the specific response of T cells.

Animals↗
PubMed2004

Theta frequency stimulation up-regulates the synaptic strength of the pathway from CA1 to subiculum region of hippocampus.

The subiculum (SB) is the principal target of the axons of the CA1 pyramidal cells and serves as the final relay in the trisynaptic loop between the entorhinal cortex and the hippocampus. We have examined synaptic plasticity in the synaptic pathway between the CA1 pyramidal cells and the SB in hippocampal slices and compared it under the same experimental condition with the synaptic plasticity in Shaffer collateral pathway (CA3-CA1). We find that the frequency response curve of synaptic strength induced by prolonged low-frequency stimulation (1-5 Hz) is systematically up-shifted from Shaffer collateral to the CA1-SB pathway. The up-regulation of synaptic strength is mediated by the activity-dependent modulation by beta-adrenergic transmission. Because the CA3-CA1 and the CA1-SB synaptic pathways are in series and the beta-adrenergic modulation is region-specific, this modulation seems to be involved in the selective control of signal transmission between the different regions of hippocampus.

Animals↗
PubMed1995

Transient protein kinase C activation primes long-term depression and suppresses long-term potentiation of synaptic transmission in hippocampus.

Activity-dependent long-lasting plasticity in hippocampus and neocortex includes long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength. Recent studies have confirmed theoretical predictions that the sensitivity of LTP- and LTD-inducing mechanisms is dynamically regulated by previous synaptic history. In particular, prior induction of either repeated short-term potentiations or LTP lowers the threshold for induction of LTD and raises the threshold for LTP. In the current study, transient activation of protein kinase C with phorbol 12,13-diacetate was able to substitute for synaptic activity in priming synapses to exhibit enhanced homosynaptic LTD and to suppress the induction of LTP at Schaffer collateral synapses in area CA1 of hippocampal slices. This priming lasted 30 min, but not 3 hr, following phorbol 12,13-diacetate bath application. These data suggest that a protein kinase C-sensitive phosphorylation site may be an activity-sensitive target mediating the rapid expression of LTP and LTD.

Animals↗
PubMed2003

Tissue engineering in otorhinolaryngology.

Tissue engineering is a field of research with interdisciplinary cooperation between clinicians, cell biologists, and materials research scientists. Many medical specialties apply tissue engineering techniques for the development of artificial replacement tissue. Stages of development extend from basic research and preclinical studies to clinical application. Despite numerous established tissue replacement methods in otorhinolaryngology, head and neck surgery, tissue engineering techniques opens up new ways for cell and tissue repair in this medical field. Autologous cartilage still remains the gold standard in plastic reconstructive surgery of the nose and external ear. The limited amount of patient cartilage obtainable for reconstructive head and neck surgery have rendered cartilage one of the most important targets for tissue engineering in head and neck surgery. Although successful in vitro generation of bioartificial cartilage is possible today, these transplants are affected by resorption after implantation into the patient. Replacement of bone in the facial or cranial region may be necessary after tumor resections, traumas, inflammations or in cases of malformations. Tissue engineering of bone could combine the advantages of autologous bone grafts with a minimal requirement for second interventions. Three different approaches are currently available for treating bone defects with the aid of tissue engineering: (1) matrix-based therapy, (2) factor-based therapy, and (3) cell-based therapy. All three treatment strategies can be used either alone or in combination for reconstruction or regeneration of bone. The use of respiratory epithelium generated in vitro is mainly indicated in reconstructive surgery of the trachea and larynx. Bioartificial respiratory epithelium could be used for functionalizing tracheal prostheses as well as direct epithelial coverage for scar prophylaxis after laser surgery of shorter stenoses. Before clinical application animal experiments have to prove feasability and safety of the different experimental protocols. All diseases accompanied by permanently reduced salivation are possible treatment targets for tissue engineering. Radiogenic xerostomia after radiotherapy of malignant head and neck tumors is of particular importance here due to the high number of affected patients. The number of new diseases is estimated to be over 500,000 cases worldwide. Causal treatment options for radiation-induced salivary gland damage are not yet available; thus, various study groups are currently investigating whether cell therapy concepts can be developed with tissue engineering methods. Tissue engineering opens up new ways to generate vital and functional transplants. Various basic problems have still to be solved before clinically applying in vitro fabricated tissue. Only a fraction of all somatic organ-specific cell types can be grown in sufficient amounts in vitro. The inadequate in vitro oxygen and nutrition supply is another limiting factor for the fabrication of complex tissues or organ systems. Tissue survival is doubtful after implantation, if its supply is not ensured by a capillary network.

Animals↗