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Plasticity of central mechanisms for cough.

Cough is associated with plasticity of putative cough afferent fibres, but whether plasticity in the brainstem network contributes is less well understood. A key site in the CNS network is the nucleus tractus solitarius (NTS), the first synaptic contact of the primary afferent fibres. We sought to develop a conscious guinea pig model to detect enhanced cough, to focus on the NTS as a potential site for plasticity, and to test a role for substance P in the NTS since the neuropeptide has been implicated in plasticity of the vagal afferent fibres. Guinea pigs were exposed to second-hand tobacco smoke (SHS) or filtered air (FA) from 1-6 weeks of age. At 5 weeks, cannulae were implanted in the NTS. At 6 weeks, either vehicle or a neurokinin 1 (NK-1) receptor antagonist was injected into the NTS of the conscious guinea pigs who were then exposed to citric acid aerosol. SHS exposure significantly enhanced citric acid-induced cough (56%, P<0.05), an effect attenuated by NTS NK-1 receptor blockade (P<0.05). The findings suggest that one possible mechanism for plasticity in cough is related to substance P effects in the NTS. Future studies will be required to investigate the possible mechanisms underlying the role of substance P as well as other mechanisms in generating SHS-induced cough.

Animals↗

Interplay between DNA and RNA methylation shapes cancer cell plasticity.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Humans↗

Plastic containers and the whole-blood clotting test: glass remains the best option.

This is the first study to identify normal whole-blood clotting times in various plastic containers and to identify the effect of the addition of various concentrations of Pseudechis australis (Mulga snake) venom on the clotting time in glass and plastic. Polycarbonate was identified as a potential alternative to glass as a testing container owing to a whole-blood clotting time within acceptable limits for a bedside test (mean 29.5 min) and equivalent performance to glass in the presence of P. australis venom. Other plastic containers (such as polypropylene and polyethylene) were found to be unsuitable owing to very prolonged clotting times (>60 min) or impaired performance in the presence of venom. Overall, owing to the variation between the performance of different plastics and the difficulty in differentiating between them, plastic containers cannot be recommended as an alternative to glass when performing the whole-blood clotting test for envenomed patients.

Analysis of Variance↗

DNA probe attachment on plastic surfaces and microfluidic hybridization array channel devices with sample oscillation.

DNA probe immobilization on plastic surfaces and device assembly are both critical to the fabrication of microfluidic hybridization array channel (MHAC) devices. Three oligonucleotide (oligo) probe immobilization procedures were investigated for attaching oligo probes on four different types of plastic surfaces (polystyrene, polycarbonate, poly(methylmethacrylate), and polypropylene). These procedures are the Surmodics procedure, the cetyltrimethylammonium bromide (CTAB) procedure, and the Reacti-Bind procedure. To determine the optimal plastic substrate and attachment chemistry for array fabrication, we investigated plastic hydrophobicity, intrinsic fluorescence, and oligo attachment efficiency. The Reacti-Bind procedure is least effective for attaching oligo probes in the microarray format. The CTAB procedure performs well enough to use in array fabrication, and the concentration of CTAB has a significant effect on oligo immobilization efficiency. We also found that use of amine-modified oligo probes resulted in better immobilization efficiency than use of unmodified oligos with the CTAB procedure. The oligo probe immobilization on plastic surfaces by the Surmodics procedure is the most effective with regard to probe spot quality and hybridization sensitivity. A DNA hybridization assay on such a device results in a limit of detection of 12pM. Utilizing a CO(2) IR laser machining and adhesive layer approach, we have developed an improved procedure for realizing a DNA microarray inside a microfluidic channel. This device fabrication procedure allows for more feasible spot placement in the channel and reduced sample adsorption by adhesive tapes used in the fabrication procedure. We also demonstrated improved hybridization kinetics and increased detection sensitivity in MHAC devices by implementing sample oscillation inside the channel. A limit of detection of 5pM has been achieved in MHAC devices with sample oscillation.

Carbocyanines↗

MAP2 phosphorylation and visual plasticity in Xenopus.

Microtubule-associated protein 2 (MAP2) has been implicated in activity-dependent structural changes in dendrites. MAP2 regulates the assembly of cytoskeletal proteins such as microtubules and actin, and its function is phosphorylation-dependent. In hippocampus, MAP2 has been reported to be dephosphorylated by activation of the NMDA-type glutamate receptor, a key player in synaptic plasticity. In this work, we used a phospho-specific MAP2 antibody (Ab 305) that recognizes epitopes close to the microtubule-binding domain to investigate the possible role of MAP2 in the Xenopus visual system. The binocular system in Xenopus exhibits activity-dependent synapse rearrangement during a critical period of development. We have found that, in critical period animals, NMDA receptor activation leads to the dephosphorylation of MAP2 at sites recognized by Ab 305 in a dose-dependent manner. We compared the responses of MAP2 to NMDA treatment in animals with high binocular plasticity (critical period juveniles and dark-reared adults) and low plasticity (normal adults). Our results show that, in all groups, NMDA treatment induces the dephosphorylation of MAP2. Tecta from frogs with different degrees of plasticity show no differences in the baseline level of MAP2 phosphorylation or in the NMDA-induced MAP2 dephosphorylation response. These results suggest that activity may modify dendrite structure via the NMDA receptor--MAP2-cytoskeletal protein pathway, but this pathway does not seem to be a determinant of the degree of plasticity.

Aging↗

Neuroendocrine plasticity in GnRH release during rat estrous cycle: correlation with molecular markers of synaptic remodeling.

Morphological changes in the gonadotropin releasing hormone (GnRH) neurons in the preoptic area (POA) and their terminals in the median eminence-arcuate (ME-ARC) region are reported to occur during ovarian cycle that may be involved in the GnRH release into the portal blood during preovulatory surge. However, the neuronal substrates participating in altered GnRH neuronal plasticity are poorly understood. The present study was designed to determine whether morphological changes occurring in the GnRH neuron cell bodies in the POA and their terminals in the ME-ARC region of hypothalamus with pulsatile GnRH release in cycling female rats are associated with expression of intrinsic determinants of neuronal plasticity. The plasticity markers studied are polysialylated neural cell adhesion molecule (PSA-NCAM), high molecular weight isoforms of NCAM, growth associated protein (GAP-43), glial fibrillary acidic protein (GFAP) and synaptophysin. Regularly cycling female rats were sacrificed at diestrous, i.e., when GnRH release is low, and at proestrous, i.e., when preovulatory GnRH surge occurs, using perfusion fixation method for immunohistochemical staining of GnRH cells. GnRH cell bodies and their terminals from the POA and ME-ARC region respectively, were localized using immunohistochemical technique in proestrous and diestrous phase of estrous cycle and our results showed a marked increase in the GnRH nerve terminals length and immunoreactivity in the ME-ARC region from proestrous phase rats as compared to diestrous rats. Immunoblot analyses of the POA and ME-ARC region of the hypothalamus revealed a significant increase in the content of PSA-NCAM, NCAM-180, NCAM-140, GAP-43 and synaptophysin from proestrous phase rats as compared to diestrous phase rats. The ME-ARC region showed more pronounced increase in the protein expression of these markers of neuronal plasticity as compared to the POA, whereas, hippocampal region did not show any significant change in the content of these markers showing specificity of the changes to the GnRH system. GFAP content was significantly decreased in the POA with a marginal increase in the GFAP level from the ME-ARC region. These results demonstrate the involvement of synaptic proteins in the dynamic plasticity of the ME-ARC region of hypothalamus, allowing GnRH nerve terminals to release the neurohormone into the pituitary portal blood on the day of proestrous.

Animals↗

Perception and reality-a study of public and professional perceptions of plastic surgery.

A questionnaire survey of the perception of plastic surgery amongst 1567 members of the public, general practitioners and medical students is presented. Closed-ended format questions were designed to assess understanding of the range of conditions managed by plastic surgeons. Respondents were asked to match nine surgical specialists with 40 conditions or procedures. To investigate understanding of the multidisciplinary nature of some surgery, respondents were asked which type of surgeon might have a supplementary role. Completed questionnaires from 1004 members of the public, 335 general practitioners, and 228 medical students are presented (responses rate>65%). Significant differences were identified between public respondents and other groups. Plastic surgery was associated with reconstruction for trauma and cancer and procedures with a strong aesthetic element by all three groups. The public were poorly informed about some core plastic surgery including burns, melanoma and hand surgery. General practitioner and student respondents had a better understanding of the diversity of the specialty. However, both groups considered orthopaedic surgeons and not plastic surgeons to be hand surgeons. The strengths and weaknesses of this study are discussed together with potential areas for education and promotion.

Adolescent↗

Paediatric plastic surgery in the University Teaching Hospital, Lusaka, Zambia: a 13-year audit.

An audit of paediatric plastic surgical procedures performed over a period of 13 years (1981-1993) at the University Teaching hospital, Lusaka, Zambia is presented. There are few publications of precise data from developing countries and no audit of this nature has been published from the area of Africa encompassed by this study. The purpose of the audit was to analyse the number and pattern of paediatric plastic surgical cases and to identify problems associated with their management. The pattern could be considered representative of the whole of sub-Saharan Africa. In addition to the audit, the basic principles of management and associated problems of some of the conditions have been outlined with particular respect to the local circumstances. It is hoped that an audit such as this will serve to upgrade the plastic surgical services and lead to the subject being incorporated into the undergraduate and postgraduate curriculums. It might also form the basis for establishing regional and provincial paediatric plastic surgical units. A balanced improvement in the provision of both general and plastic surgery within the health care services of the African continent is seen as important. Finally, this audit might enable surgeons in more developed nations to understand the pattern of disease and need in Africa and familiarise those who intend to work in the continent with the situation.

Burns↗

Group I mGlu receptors regulate the expression of the neuronal calcium sensor protein VILIP-1 in vitro and in vivo: implications for mGlu receptor-dependent hippocampal plasticity?

Metabotropic glutamate (mGlu) receptors are involved in several forms of synaptic plasticity in the rat hippocampus. Agonists which activate group I mGlu receptors induce slow-onset potentiation without prior tetanization in the hippocampal area CA1. Activation of group I mGlu receptors induces protein synthesis which may contribute to mGlu receptor-dependent forms of long-term plasticity. Calcium-binding proteins are widely considered to comprise key elements for synaptic plasticity. Therefore, we investigated whether the calcium sensor protein VILIP-1 is associated with group I mGlu receptor-mediated plasticity in the dentate gyrus (DG) in vivo.Application of either the group I and II mGlu agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (ACPD) or the selective group I agonist (R,S)-3,5-dihydroxyphenylglycine (DHPG) resulted in slow-onset potentiation in the DG of adult rats. In hippocampal cell cultures both agonists elicited an enhanced expression of VILIP-1. In situ hybridization revealed strong hippocampal expression of VILIP-1 and intracerebral application of DHPG to adult rats significantly enhanced hippocampal VILIP-1 expression. The DHPG effects in both, hippocampal cultures and in vivo, were prevented by the group I mGlu receptor antagonist 4-Carboxyphenylglycine (4CPG). Calcium sensor proteins thus appear to be regulated by mGlu receptors in an activity-dependent manner. A specific role for group I mGlu receptors is evident. Furthermore, the sensor proteins may function as molecular switches for the long-term regulation of synaptic plasticity.

Animals↗

Plasticity and behavior: new genetic techniques to address multiple forms and functions.

As the best-studied form of vertebrate synaptic plasticity, NMDA-receptor dependent long-term potentiation (NMDAR-LTP) has long been considered a leading candidate for a cellular locus for some aspects of learning and memory. However, assigning a specific role for this form of plasticity in learning and memory has proven surprisingly difficult. Two issues have contributed to this difficulty. First, a large number of molecules have been shown to in some way mediate or modulate not only NMDAR-LTP but also many forms of plasticity. Indeed, it is increasingly clear that multiple induction and maintenance mechanisms for plasticity exist, often at the same synapse. Second, linking cellular events to behavioral function has been hindered by a lack of sufficiently precise tools. In this review, we will discuss some of the proposed mechanisms of induction and maintenance of changes in synaptic efficacy and their regulation in the context of an attempt to understand their roles in animal behavior. Further, we will discuss recently developed genetic techniques, specifically, inducible transgenic models, which now allow more precise manipulations in the study of the roles plasticity plays in learning and memory.

Animals↗

Mitochondria, synaptic plasticity, and schizophrenia.

The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.

Animals↗

The yielding, plastic flow, and fracture behavior of ultra-high molecular weight polyethylene used in total joint replacements.

The yielding, plastic flow, and fracture behavior of UHMWPE plays an important role in wear and failure mechanisms of total joint replacement components. The primary objective of this study was to compare the yielding, plastic flow, and fracture behavior of two implantable grades of UHMWPE (GUR 1120 vs 4150 HP). The first part of this work explored the hypothesis that up to the polymer yield point, the monotonic loading behavior of UHMWPE displays similar true stress strain behavior in tension and compression. Uniaxial tension and compression tests were conducted to compare the equivalent true stress vs strain response of UHMWPE up to 0.12 true strain. During monotonic loading, the equivalent true stress strain behavior was similar in tension and compression up to the yield point. However, investigation of the unloading behavior and permanent plastic deformations showed that classical deviatoric rate independent plasticity theory may dramatically overpredict the permanent strains in UHMWPE. A secondary goal of this study was to determine the ultimate true stress and strain for UHMWPE and to characterize the fracture surfaces after failure. Using a fracture mechanics approach, the critical flaw sizes were used in combination with the true ultimate stresses to predict the fracture toughness of the two resins. A custom video-based strain measurement system was developed and validated to characterize the true stress-strain behavior up to failure and to verify the accuracy of the incompressibility assumption in calculating the true stress-strains up to failure. In a detailed uncertainty analysis, theoretical expressions were derived for the relative uncertainty in digital video-based estimates of nominal strain, true strain, homogeneous stress, and true stress. Although the yielding behavior of the two UHMWPE resins was similar, the hardening and plastic flow behavior clearly discriminated between the GUR 1120 and 4150 HP. A statistically significant difference between the fracture toughness of the two resins was also evident. The long-term goal of this research is to provide detailed true stress strain data for UHMWPE under uniaxial tension and compression for future numerical simulations and comparison with more complex multiaxial loading conditions.

Biocompatible Materials↗

The role of neural cell adhesion molecules in plasticity and repair.

Repair and functional recovery after brain injury critically depends on structural and functional plasticity of preserved neuronal networks. A striking feature of brain structures where tissue reorganization and plasticity occur is a strong expression of the polysialylated neural cell adhesion molecule (PSA-NCAM). An important role of this molecule in various aspects of neuronal and synaptic plasticity has been revealed by many studies. Recently, a new mechanism has been elucidated whereby PSA-NCAM may contribute to signalling mediated by the neurotrophic factor BDNF, thereby sensitizing neurons to this growth factor. This mechanism was shown to be important for activity-induced synaptic plasticity and for the survival and differentiation of cortical neurons. A cross-talk between these molecules may, thus, reveal a key factor for properties of structural plasticity and in particular could mediate the activity-dependent aspects of synaptic network remodeling. Animal models have been developed to assess the role of these molecules in functional recovery after lesions.

Animals↗

The role of synaptic morphology in neural plasticity: structural interactions underlying synaptic power.

The study of synaptic plasticity has revealed a common cascade of ultrastructural events across several paradigms. Most notable of these paradigms are development, long-term potentiation (LTP), and adult reactive synaptogenesis (RS). These plastic neural events are discussed in terms of major categories of synaptic morphological change--synaptic density, curvature, and perforations, as well as the size of synaptic elements. The potential functional implications of these morphological changes are reviewed, along with considerations based on recently developed mathematical models of synaptic function. These considerations are then incorporated into the common structural alterations observed during multiple forms of synaptic activation, producing a sequential model supporting increased efficacy associated with neural plasticity. The data suggest that during a plastic challenge, synapses move through a continuum of morphological change, dependent upon the interaction of structural parameters and their effect on various aspects critical to synaptic efficacy. This complex interplay of morphological alterations and synaptic types over time and location may form a critical aspect of neural plasticity.

Animals↗

Neuronal plasticity: adaptation and readaptation to the environment of space.

While there have been few documented permanent neurological changes resulting from space travel, there is a growing literature which suggests that neural plasticity sometimes occurs within peripheral and central vestibular pathways during and following spaceflight. This plasticity probably has adaptive value within the context of the space environment, but it can be maladaptive upon return to the terrestrial environment. Fortunately, the maladaptive responses resulting from neuronal plasticity diminish following return to earth. However, the literature suggests that the longer the space travel, the more difficult the readaptation. With the possibility of extended space voyages and extended stays on board the international space station, it seems worthwhile to review examples of plastic vestibular responses and changes in the underlying neural substrates. Studies and facilities needed for space station investigation of plastic changes in the neural substrates are suggested.

Adaptation, Physiological↗

Comparison of usefulness of three types of artificial substrata (glass, wood and plastic) when studying settlement patterns of periphyton in lakes of different trophic status.

Usefulness of three types of artificial substrata (glass, wood and plastic) was tested when studying settlement patterns of periphyton in lakes of different trophic status. Strictly eu-, meso- and oligotrophic lakes in central Sweden were chosen as objects of the study. Glass slides, glass tubes, pieces of plastic (PVC) and pieces of wood of similar dimensions were placed for 9 weeks in July-August vertically 3 cm above bottom at a total depth of ca. 30 cm. Substrata were located at well-illuminated places without any other submerged objects (like macrophytes and stones), which could potentially affect colonisation patterns by algae. Periphyton communities, which colonised both the glass tubes and the pieces of wood tested, were specific enough to enable a clear classification of the lakes studied in eu-, meso- and oligotrophic. Glass tubes turned out to be the most favourable substratum when investigating settlement patterns of periphyton in this study. Although also colonised by periphytic species, wood did not support the same diversity and abundance of species as glass did. No algae were detected on the plastics studied. The plastics were covered entirely by a slime layer of bacteria. It is discussed if the nature of plastics could have some inhibitory effects on algal growth or the slime layer itself may have prevented settlement of algal spores.

Bacteria↗

Effects of normal aging on visuo-motor plasticity.

Normal aging is associated with declines in neurologic function. Uncompensated visual and vestibular problems may have dire consequences including dangerous falls. Visuo-motor plasticity is a form of behavioral neural plasticity, which is important in the process of adapting to visual or vestibular alteration, including those changes due to pathology, pharmacotherapy, surgery or even entry into microgravity or an underwater environment. To determine the effects of aging on visuo-motor plasticity, we chose the simple and easily measured paradigm of visual-motor rearrangement created by using visual displacement prisms while throwing small balls at a target. Subjects threw balls before, during and after wearing a set of prisms which displace the visual scene by twenty degrees to the right. Data obtained during adaptation were modeled using multilevel modeling techniques for 73 subjects, aged 20 to 80 years. We found no statistically significant difference in measures of visuo-motor plasticity with advancing age. Further studies are underway examining variable practice training as a potential mechanism for enhancing this form of behavioral neural plasticity.

Adult↗

Cellular and molecular connections between sleep and synaptic plasticity.

The hypothesis that sleep promotes learning and memory has long been a subject of active investigation. This hypothesis implies that sleep must facilitate synaptic plasticity in some way, and recent studies have provided evidence for such a function. Our knowledge of both the cellular neurophysiology of sleep states and of the cellular and molecular mechanisms underlying synaptic plasticity has expanded considerably in recent years. In this article, we review findings in these areas and discuss possible mechanisms whereby the neurophysiological processes characteristic of sleep states may serve to facilitate synaptic plasticity. We address this issue first on the cellular level, considering how activation of T-type Ca(2+) channels in nonREM sleep may promote either long-term depression or long-term potentiation, as well as how cellular events of REM sleep may influence these processes. We then consider how synchronization of neuronal activity in thalamocortical and hippocampal-neocortical networks in nonREM sleep and REM sleep could promote differential strengthening of synapses according to the degree to which activity in one neuron is synchronized with activity in other neurons in the network. Rather than advocating one specific cellular hypothesis, we have intentionally taken a broad approach, describing a range of possible mechanisms whereby sleep may facilitate synaptic plasticity on the cellular and/or network levels. We have also provided a general review of evidence for and against the hypothesis that sleep does indeed facilitate learning, memory, and synaptic plasticity.

Animals↗