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At least 199 records · Page 11Linked to original sources
PubMed2006

Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets.

All BH3-only proteins, key initiators of programmed cell death, interact tightly with multiple binding partners and have sequences of low complexity, properties that are the hallmark of intrinsically unstructured proteins (IUPs). We show, using spectroscopic methods, that the BH3-only proteins Bim, Bad and Bmf are unstructured in the absence of binding partners. Detailed sequence analyses are consistent with this observation and suggest that most BH3-only proteins are unstructured. When Bim binds and inactivates prosurvival proteins, most residues remain disordered, only the BH3 element becomes structured, and the short alpha-helical molecular recognition element can be considered to behave as a 'bead on a string'. Coupled folding and binding is typical of many IUPs that have important signaling roles, such as BH3-only proteins, as the inherent structural plasticity favors interaction with multiple targets. This understanding offers promise for the development of BH3 mimetics, as multiple modes of binding are tolerated.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Vicarious function of remote cortex following stroke: recent evidence from human and animal studies.

Following a lesion, the adult central nervous system undergoes dramatic structural and physiological reorganization in diverse subcortical and cortical areas. Our knowledge of the events that parallel recovery within the tissue surrounding the lesion and other distant cortical areas has evolved greatly in the past few years. Particularly, recent efforts have increased our understanding of the potential implication of premotor areas in recovery from lesions disturbing the primary motor cortex (M1) and its corticospinal outputs. Because these areas share extensive connections with M1 and have direct access to the spinal cord through corticospinal projections, they are particularly well positioned to take over the role of M1 in a vicarious manner and thus compensate for the neuronal loss resulting from M1 lesions. The impressive postlesional reorganization known to occur in many areas of the CNS including the premotor cortex traditionally has been assumed to play a beneficial role in recovery. However, recent experiments suggest that in some cases, reorganization of distant cortical areas correlates with poor recovery, raising the concept of maladaptive vicarious process. This concept might be particularly critical in the development of new treatment approaches favoring postlesion plasticity and even more so for interventions targeting specific area(s). Here, the author reviews human and animal studies that show the plastic potential of the adult CNS after stroke, highlighting the vicarious role of the premotor cortex in the recovery of motor control.

Animals↗
PubMed2004

NCAM mimetic peptides: Pharmacological and therapeutic potential.

The neural cell adhesion molecule (NCAM) plays an important role in neuronal differentiation and synaptic plasticity, making it an attractive target for the development of drugs for the treatment of neurodegenerative disorders. NCAM binds to itself (homophilic binding) and to a series of counter-receptors, including the fibroblast growth factor receptor (FGFR), other adhesion molecules, and various extracellular matrix components (heterophilic binding). By means of combinatorial chemistry and based on the unraveling of the structure of NCAM, it has been possible to develop a number of peptides that mimic NCAM homophilic binding. These peptides interfere with cell adhesion and promote differentiation and cell survival. Recently, a peptide mimicking the heterophilic binding to FGFR has also been identified. It binds and activates the receptor, thereby modulating neurite extension and synaptic plasticity.

Animals↗
PubMed1997

Translational research models in neuro-oncology.

Tumor development and progression in the nervous system are poorly understood. Consequently, even though there seems to be little possibility of major advances in existing clinical modalities used to treat malignant brain tumors, no targeted molecular therapies have risen to take their place. The variability and plasticity of brain neoplasms make them an illusive target for study and therapeutic intervention. Further complicated by infiltration of vital nervous tissue, clinical studies have serious practical limitations and the ability to assess tumor progression in vivo is still a developing technology. Evaluation of potential new therapies for brain tumors is heavily dependent on the development of more informative and cognate experimental models. To develop and validate new models, it is particularly important to integrate clinical, pathological, and cell biological characterizations of malignant brain tumors. This discussion provides an overview of developments in tumor cell culture and the impact of animal models on brain tumor research. Studies of malignant glial neoplasms associated with a dismal prognosis in patients receive particular attention.

Animals↗
PubMed1993

Plasticity in chromosome number and testing of essential genes in Leishmania by targeting.

We attempted to generate homozygous dhfr-ts (dihydrofolate reductase-thymidylate synthase) knockouts in virulent Leishmania major, an asexual diploid protozoan parasite. Transfection of a neo (neomycin phosphotransferase) targeting fragment yielded heterozygous replacement lines with high efficiency. However, second transfections with a hyg (hygromycin B phosphotransferase) targeting fragment in the presence of metabolites shown to rescue homozygous knockouts in attenuated Leishmania did not yield the expected dhfr-ts- thymidine auxotrophs obtained previously with attenuated lines. Molecular karyotype, Southern blot, and flow cytometric DNA content analysis of clonal transfectants revealed three classes: (i) genomic tetraploids, containing two wild-type dhfr-ts chromosomes and one neo and one hyg replacement chromosome; (ii) aneuploid trisomic lines with one wild-type dhfr-ts and one neo and one hyg replacement chromosome; (iii) diploids bearing homologous integration of the targeting fragment without replacement. Aneuploid and tetraploid lines predominated. This confirms the common impression that natural populations of Leishmania are often aneuploid. The remarkable ability of these parasites to undergo and tolerate changes in chromosome number suggests a general method for testing whether genes are essential for growth in vitro, as the ability of Leishmania to simultaneously undergo homologous gene replacement while retaining wild-type genes by increasing chromosome number provides a diagnostic and positive experimental result. Our results show that virulent Leishmania require at least one copy of dhfr-ts and argue that DHFR-TS plays an unanticipated role in addition to its role in the de novo synthesis of thymidine. These results also have implications for genetic tests of the organization of Leishmania populations.

Alleles↗
PubMed1999

Nitric oxide and target-organ control in the autonomic nervous system: anatomical distribution, spatiotemporal signaling, and neuroeffector maintenance.

Recent neuroanatomical studies, neurochemical coding and physiological findings of multiple cotransmitter actions and/or receptor patterns, and the characterization of synaptic molecules and nitrergic (NOergic) signaling mechanisms may help for a better understanding of target-organ control in the autonomic nervous system. Thus, nitric oxide (NO) synthase, which generates the freely diffusible and short-lived messenger NO and expression of neurotrophic proteins (e.g., neurotrophins, glial cell-line-derived neurotrophic factor, fibroblast growth factors) in autonomic neural pathways or target organs suggest unique actions in autonomic neurotransmission. In central NOergic pathways, NO may serve as spatial (volume) messenger within hierarchically ordered autonomic neuron pools and convergent/divergent pathways for synchronized autonomic outflow. Likewise, NO modulates intraganglionic and interaxonal transmission and postganglionic activity including long-term potentiation. In the visceral targets, NO appears to be a spatial modulator in local intrinsic networks or at varicose terminals. In endocrine glands, NO possibly acts as synaptic coactivator or inhibitor, as a cotransmitter affecting stimulus-coupled exocytosis, or as a local vasoactive signal. The short-term neural messenger NO may also induce diffusible target-derived long-term neurotrophic signals, thereby supporting neuroeffector maintenance and plasticity, if not synaptic efficacy, in autonomic target-organ control.

Animals↗
PubMed1991

Magnetic stimulation of the human cerebral cortex, an indicator of reorganization in motor pathways in certain pathological conditions.

Basic principles of magnetic stimulation of biological tissues are reviewed. Noninvasive magnetic stimulation of the brain delivered over sensorimotor areas evokes movements and less commonly paresthesias in contralateral limbs. We have evaluated the maps of motor outputs in patients with (1) congenital mirror movements, which resulted in marked derangement of the map of outputs of distal hand muscles with enlarged and ipsilateral representations; (2) amputations, which resulted in plastic reorganization of motor outputs targeting muscles immediately proximal to the stump; (3) spinal cord injury, which also resulted in enlargement of the map of outputs targeting muscles proximal to the lesion level; and (4) hemispherectomy performed at an early age for intractable seizures, which resulted in the remaining hemisphere controlling ipsilateral arm muscles. These results demonstrate the potential for reorganization in motor systems following lesions in the peripheral as well as in the central nervous system.

Brain Mapping↗
PubMed2000

Nigrostriatal system plasticity in Parkinson's disease: effect of dopaminergic denervation and treatment.

Clinical studies suggest that the appearance of levodopa-induced dyskinesias may be partly related to changes in the dopaminergic system. This article reviews data on biochemical and morphological changes induced by treatment, the lesion, or both, in dopaminergic neurons themselves, postsynaptic striatal tissue, and afferent fibers to dopaminergic neurons in the substantia nigra. Recent studies on dopaminergic neurons suggest that levodopa therapy can induce sprouting of surviving dopaminergic neurons at their terminals in the striatum. At the postsynaptic level, treatment may trigger induction of D3 dopamine receptors and internalization of D1 receptors. Furthermore, dopaminergic denervation has been shown to be involved in plastic changes in the striatum associated with hyperactivity of glutamatergic fibers making synapses with the head of the spines of gamma-aminobutyric acidergic neurons. At the level of the dendrites of dopaminergic neurons, plasticity of excitatory cholinergic afferent fibers targeting dopaminergic neurons and an involution of noncholinergic afferent fibers have been observed. Taken together, these data suggest that dopaminergic denervation and treatment induce profound plastic changes in the nigrostriatal system. Whether such changes participate in side-effects of treatment and, in particular, the appearance of dyskinesias remains to be determined.

Corpus Striatum↗
PubMedDate not supplied

Higher seizure susceptibility and enhanced tyrosine phosphorylation of N-methyl-D-aspartate receptor subunit 2B in fyn transgenic mice.

Earlier work has suggested that Fyn tyrosine kinase plays an important role in synaptic plasticity. To understand the downstream targets of Fyn signaling cascade in neurons, we generated transgenic mice expressing either a constitutively activated form of Fyn or native Fyn in neurons of the forebrain. Transgenic mice expressing mutant Fyn exhibited higher seizure activity and were prone to sudden death. Mice overexpressing native Fyn did not show such an obvious epileptic phenotype, but they exhibited accelerated kindling in response to once-daily stimulation of the amygdala. Tyrosine phosphorylation of at least three proteins was enhanced in the forebrains of both native and mutant fyn transgenic mice; tyrosine phosphorylation of these three proteins was reduced in fyn knockout mice, suggesting that they are substrates of Fyn. One of these proteins was identified as the subunit 2B (NR2B) of the N-methyl-D-aspartate (NMDA) receptor. Administration of MK-801, a noncompetitive NMDA receptor antagonist, retarded kindling in mice overexpressing native Fyn, as well as wild-type mice, suggests that the accelerated kindling in mice overexpressing Fyn is also mediated by the NMDA receptor activity. Our results thus suggest that tyrosine phosphorylation by Fyn might be involved in regulation of the susceptibility of kindling, one form of the NMDA receptor-mediated neuronal plasticity.

Amino Acid Sequence↗
PubMed2005

[Paralyzed face. Ansa-cervicalis-nervi-hypoglossi].

INTRODUCTION: For 100 years hypoglossal-facial nerve anastomosis (HFA) has been a common surgical procedure for reanimation of paralyzed mimic muscles of the face after axotomy of the facial nerve. However, the denervation and subsequent scarred degeneration of the target muscles of the hypoglossal nerve often results in unfavorable late effects for speech and swallowing. Therefore, the ansa cervicalis nervi hypoglossi-facial nerve anastomosis (ACHFA) can be an alternative to avoid such late effects. As a branch of the hypoglossal nerve the ansa cervicalis innervates the infrahyoidal muscles. Neck dissection surgery proved that resection of the ansa cervicalis causes no side effects for swallowing because of several nerve anastomoses to the cervical plexus. PATIENTS AND METHOD: We compared our clinical results of eight cases following a delayed ACHFA with our own experiences after HFA and results from the literature. RESULTS: We found a reanimation rate lower than usually seen after HFA only in the target muscles of the forehead. This may be caused by a reduced neuronal plasticity of the ansa cervicalis. However, in the target muscles of the other two facial nerve branches we observed the same good results one would expect after HFA. There were no late side effects for swallowing and speech though.

Adult↗
PubMed1984

[Detection and isolation of antibody-forming clones by means of local cytolysis in gel].

A method is suggested combining the screening and cloning of hybridomas producing cytotoxic antibodies. The method is based on the Erne local hemolysis principles. The cells from the preformed hybridoma line NATF 9.9 secreted monoclonal antibodies (McAb) against murine T lymphocyte differentiation antigen Lyt-3.2. A mixture of hybridoma cells and target cells was attached to the plastic Petri dish surface pretreated with Poly-L-lysine and covered with agarose. McAb production by hybridoma cells was elicited by complement-dependent lysis of target cells. The lysis was detected by incorporation in dead cells of the fluorescent dye ethidium bromide. Subsequent studies made it possible to evaluate the clonogenic capacity of McAb production and isolate active clones.

Animals↗
PubMed1999

Aging impairs axonal sprouting response of dentate granule cells following target loss and partial deafferentation.

Compared to other brain regions, the hippocampus shows considerable susceptibility to the aging process. Aging may impair the compensatory plastic response of hippocampal neurons following lesions, target loss, and/or deafferentation. We hypothesize that sprouting of dentate granule cell axons (mossy fibers) in response to target loss and partial deafferentation diminishes with age. We quantified mossy fiber sprouting into the dentate supragranular layer (DSGL) following intracerebroventricular kainic acid administration in young adult, middle-aged, and aged rats, using Timm's histochemical method. Mossy fiber ingrowth into the DSGL was assessed in the septal hippocampus at 2- and 4 months postlesion by measuring both the average width and the relative density of sprouted terminals. Kainic acid lesions produced degeneration of CA3 pyramids with sparing of CA1 and dentate granule cells in all age groups. Although young adults demonstrated robust DSGL mossy fiber sprouting, sprouting was significantly reduced in both middle-aged and aged rats. Compared to the case in young adults, the overall sprouting in middle-aged animals was reduced by 52% at 2 months and 50% at 4 months postlesion, whereas in aged rats the sprouting was reduced by 53% at 2 months and 64% at 4 months postlesion. Aged animals also showed an overall reduction of 28% compared to middle-aged animals at 4 months postlesion. Dramatically reduced sprouting in aged animals may represent a deficit in recognition of target loss and partial deafferentation by aged granule cells and/or an impaired up-regulation of factors that stimulate neurite outgrowth in the aged brain.

Aging↗
PubMed2003

Rapid task-related plasticity of spectrotemporal receptive fields in primary auditory cortex.

We investigated the hypothesis that task performance can rapidly and adaptively reshape cortical receptive field properties in accord with specific task demands and salient sensory cues. We recorded neuronal responses in the primary auditory cortex of behaving ferrets that were trained to detect a target tone of any frequency. Cortical plasticity was quantified by measuring focal changes in each cell's spectrotemporal response field (STRF) in a series of passive and active behavioral conditions. STRF measurements were made simultaneously with task performance, providing multiple snapshots of the dynamic STRF during ongoing behavior. Attending to a specific target frequency during the detection task consistently induced localized facilitative changes in STRF shape, which were swift in onset. Such modulatory changes may enhance overall cortical responsiveness to the target tone and increase the likelihood of 'capturing' the attended target during the detection task. Some receptive field changes persisted for hours after the task was over and hence may contribute to long-term sensory memory.

Acoustic Stimulation↗
PubMed2002

Control of developmental timing by micrornas and their targets.

In Caenorhabditis elegans the timing of many developmental events is regulated by heterochronic genes. Such genes orchestrate the timing of cell divisions and fates appropriate for the developmental stage of an organism. Analyses of heterochronic mutations in the nematode C. elegans have revealed a genetic pathway that controls the timing of post-embryonic cell divisions and fates. Two of the genes in this pathway encode small regulatory RNAs. The 22 nucleotide (nt) RNAs downregulate the expression of protein-coding mRNAs of target heterochronic genes. Analogous variations in the timing of appearance of particular features have been noted among closely related species, suggesting that such explicit control of developmental timing may not be exclusive to C. elegans. In fact, some of the genes that globally pattern the temporal progression of C. elegans development, including one of the tiny RNA genes, are conserved and temporally regulated across much of animal phylogeny, suggesting that the molecular mechanisms of temporal control are ancient and universal. A very large family of tiny RNA genes called microRNAs, which are similar in structure to the heterochronic regulatory RNAs, have been detected in diverse animal species and are likely to be present in most metazoans. Functions of the newly discovered microRNAs are not yet known. Other examples of temporal programs during growth include the exquisitely choreographed temporal sequences of developmental fates in neurogenesis in Drosophila and the sequential programs of epidermal coloration in insect wing patterning. An interesting possibility is that microRNAs mediate transitions on a variety of time scales to pattern the activities of particular target protein-coding genes and in turn generate sets of cells over a period of time. Plasticity in these microRNA genes or their targets may lead to changes in relative developmental timing between related species, or heterochronic change. Instead of inventing new gene functions, even subtle changes in temporal expression of pre-existing control genes can result in speciation by altering the time at which they function.

Animals↗
PubMed2003

Discrimination of peptides by using a molecularly imprinted piezoelectric biosensor.

Based on the direct formation of a molecularly imprinted polymer on gold electrodes, we have developed a peptide sensor for the detection of low-molecular-weight peptides. A new cross-linking monomer, (N-Acr-L-Cys-NHBn)(2), was employed to attach the surface of the chip and to copolymerize with other monomers. Interestingly, N-benzylacrylamide participates in the polymerization and recognition is carried out in an aqueous environment. By using quartz crystal microbalance detection, short peptides can be monitored by their interaction with plastic antibodies specific for the target peptides. The selectivity of molecularly imprinted polymers and the sensitivity of such artificial biosensors have been combined to differentiate between traces of oxytocin and vasopressin to the ng mL(-1) scale.

Amino Acid Sequence↗
PubMed1990

Cell death of corticospinal neurons is induced by axotomy before but not after innervation of spinal targets.

The response of corticospinal neurons to axotomy at postnatal ages from 5 days to adulthood was studied in the golden hamster (Mesocricetus auratus). Corticospinal neurons were retrogradely labeled with fluorescent rhodamine latex beads injected into the cervical or lumbar spinal cord. A unilateral lesion of the medullary pyramidal tract was made 1-2 days later and the brains fixed 1-30 days after axotomy. Comparisons of labeled axotomized corticospinal neurons with labeled normal corticospinal neurons in the contralateral cortex showed that axotomy at 14 days or later caused cell shrinkage but not cell death. Axotomy prior to 14 days caused cell death of corticospinal neurons. More neurons died the earlier the lesion was made, culminating in virtual complete cell death of corticospinal neurons following axotomy at 5 days. Axotomy at a given age did not affect all corticospinal neurons uniformly. Lumbar projection neurons underwent cell death ranging from slight to complete following axotomy at 13 and 9 days, respectively. Cervical projection neurons, in contrast, survived axotomy after a lesion at 9 days but underwent complete cell death if the lesion occurred at 5 days. Since corticospinal axons innervate the cervical cord from postnatal days 4-8 and the lumbar cord from 10-14 days (Reh and Kalil, '81; J. Comp. Neurol. 200:55-67), the ability of corticospinal neurons to survive axotomy appears to be temporally well correlated with their innervation of spinal targets. These neurons die if their axons are cut prior to target innervation but are able to survive if axotomy occurs after their axons innervate spinal targets. The results show that plasticity in the corticospinal pathway documented in previous reports cannot take the form of regrowth of severed axons, since early lesions cause extensive corticospinal cell death. Aberrant corticospinal pathways resulting from early lesions must therefore arise from undamaged axons. Additional retrograde labeling experiments showed that the opposite cortex responded to contralateral pyramidotomy by sprouting into denervated areas of the spinal cord. Thus another source of plasticity after early pyramidal tract lesions is sprouting from corticospinal axons arising from the intact cortex.

Aging↗
PubMed1994

Long-term action of lithium: a role for transcriptional and posttranscriptional factors regulated by protein kinase C.

Lithium, a simple monovalent cation, represents one of psychiatry's most important treatments and is the most effective treatment for reducing both the frequency and severity of recurrent affective episodes. Despite extensive research, the underlying biologic basis for the therapeutic efficacy this drug remains unknown, and in recent years, research has focused on signal transduction pathways to explain lithium's efficacy in treating both poles of manic-depressive illness. Critical to attributions of therapeutic relevance to any observed biochemical effect, however, is the observation that the characteristic prophylactic action of lithium in stabilizing the profound mood cycling of bipolar disorder requires a lag period for onset and is not immediately reversed upon discontinuation of treatment. Biochemical changes requiring such prolonged administration of a drug suggest alterations at the genomic level but, until recently, little has been known about the transcriptional and posttranscriptional factors regulated by chronic drug treatment, although long-term changes in neuronal synaptic function are known to be dependent upon the selective regulation of gene expression. In this paper, we will present evidence to show that chronic lithium exerts significant transcriptional and posttranscriptional effects, and that these actions of lithium may be mediated via protein kinase C (PKC)-induced alterations in nuclear transcription regulatory factors responsible for modulating the expression of proteins involved in long-term neural plasticity and cellular response. Such target sites for chronic lithium may help unravel the processes by which a simple monovalent cation can produce a long-term stabilization of mood in individuals vulnerable to bipolar illness.

Animals↗
PubMed2003

Induction of kf-1 after repeated electroconvulsive treatment and chronic antidepressant treatment in rat frontal cortex and hippocampus.

It has been proposed that signaling pathways involved in adaptive neural plasticity are long-term targets for the action of electroconvulsive treatment (ECT), which is widely used in the treatment of drug-resistant depression. We have previously performed EST analysis to identify some molecular machinery responsible for antidepressant effect. One of the cDNA fragments identified as antidepressant related genes/ESTs was identified as kf-1 which has a RING-H2 finger motif at the carboxy-terminus. In the present study, we have demonstrated the induction of kf-1 in rat frontal cortex and hippocampus not only after chronic antidepressant treatment, but also after a single and repeated ECT. RING finger proteins are proposed to play some important roles in the ubiquitin-proteasome system. In conclusion, the current investigation has identified kf-1 as a novel molecular target for antidepressants and ECT.

Animals↗