It is well-recognized that, despite similar pain characteristics, some people with chronic pain recover, whereas others do not. In this review, we discuss possible contributions and interactions of biological, social, and psychological perturbations that underlie the evolution of treatment-resistant chronic pain. Behavior and brain are intimately implicated in the production and maintenance of perception. Our understandings of potential mechanisms that produce or exacerbate persistent pain remain relatively unclear. We provide an overview of these interactions and how differences in relative contribution of dimensions such as stress, age, genetics, environment, and immune responsivity may produce different risk profiles for disease development, pain severity, and chronicity. We propose the concept of "stickiness" as a soubriquet for capturing the multiple influences on the persistence of pain and pain behavior, and their stubborn resistance to therapeutic intervention. We then focus on the neurobiology of reward and aversion to address how alterations in synaptic complexity, neural networks, and systems (eg, opioidergic and dopaminergic) may contribute to pain stickiness. Finally, we propose an integration of the neurobiological with what is known about environmental and social demands on pain behavior and explore treatment approaches based on the nature of the individual's vulnerability to or protection from allostatic load.

/pdf/when-pain-gets-stuck-the-evolution-of-pain-chronification-2qv81jlog8.pdf

When pain gets stuck: the evolution of pain chronification and treatment resistance.

Background and purposeEarly stroke rehabilitation has shown benefits over spontaneous recovery. Insufficient evidence exists to determine the benefits of early aphasia intervention. We hypothesized...

Very early poststroke aphasia therapy: a pilot randomized controlled efficacy trial.

Gold nanoclusters (Au NCs) are promising luminescent nanomaterials due to their outstanding optical properties. However, their relatively low quantum yields and environment-dependent photoluminescence properties have limited their biological applications. To address these problems, we developed a novel strategy to prepare chitosan oligosaccharide lactate (Chi)-functionalized Au NCs (Au NCs@Chi), which exhibited emission with enhanced quantum yield and elongated emission lifetime as compared to the Au NCs, as well as exhibited environment-independent photoluminescence properties. In addition, utilizing the free amino groups of Chi onto Au NCs@Chi, we designed a FRET-based sensing platform for the detection of hydrogen sulfide (H2S). The Au NCs and the specific H2S-sensitive merocyanine compound were respectively employed as an energy donor and acceptor in the platform. The addition of H2S induced changes in the emission profile and luminescence lifetime of the platform with high sensitivity and selectivity. Utilization of the platform was demonstrated to detect exogenous and endogenous H2S in vitro and in vivo through wavelength-ratiometric and time-resolved luminescence imaging (TLI). Compared to previously reported luminescent molecules, the platform was less affected by experimental conditions and showed minimized autofluorescence interference and improved accuracy of detection.

Luminescent gold nanocluster-based sensing platform for accurate H2S detection in vitro and in vivo with improved anti-interference.

Strengthening by fiber-reinforced polymers (FRPs) is one of the most common solutions to the ageing infrastructures. However, long-term durability of such systems under different environmental conditions needs to be understood properly before widely adopting these methods in the field. This paper presents research outcomes from an experimental program carried out to determine the influence of moisture on the durability of the bond between FRP and concrete along with its constituent materials. Performance was evaluated through single lap shear bond tests and various kinds of tests on the resin samples, including water absorption, mechanical characterization, and glass transition temperature (Tg) analysis. The specimens were exposed to continuous water immersion and wet-dry cycles for a maximum period of up to 24 and 18 months, respectively. The results show some deterioration on the material and the bond properties in both exposure conditions. The bond strength decreased up to 32 and 12% for high-s...

/pdf/durability-of-frp-concrete-bonds-and-its-constituent-4ogyl3o96m.pdf

Durability of FRP Concrete Bonds and Its Constituent Properties under the Influence of Moisture Conditions

A single exposure to social isolation in domestic piglets activates behavioural arousal, neuroendocrine stress hormones, and stress-related gene expression in the brain

/pdf/learning-and-memory-accelerated-ageing-2zonhbh5dt.pdf

Learning and memory: Accelerated ageing

action potentials propagate along myelinated nerves — depends on the fact that voltagegated Na+ channels form clusters at the nodes of Ranvier, between sections of the myelin sheath. New findings from Eshed et al. show that Schwann cells produce a protein called gliomedin, and that this is responsible for the clustering of these channels. The formation of the nodes of Ranvier is specified by the myelinating cells, not the axons, and an important component of this process in the peripheral nervous system is the extension of microvilli by Schwann cells. These microvilli contact the axons at the nodes, and it is here that the Schwann cells express the newly discovered protein gliomedin. Eshed et al. showed that gliomedin is a ligand for two axonal cell adhesion molecules — neurofascin and NrCAM — that are found at the nodes of Ranvier, where they interact with Na+ channels. When the authors either disrupted the localization of gliomedin by using a soluble fusion protein that contained the extracellular domain of neurofascin, or used RNA interference to suppress the expression of gliomedin, the characteristic clustering of Na+ channels at the nodes of Ranvier did not occur. Aggregation of the domain of gliomedin that binds neurofascin and NrCAM on the surface of purified neurons also caused the clustering of neurofascin, Na+ channels and other nodal proteins. These findings support a model in which gliomedin on Schwann cell microvilli binds to neurofascin and NrCAM on axons, causing them to cluster at the nodes of Ranvier, and leading to the formation of complexes that contain Na+ channels. Rachel Jones References and links ORIGINAL RESEARCH PAPER Eshed, Y. et al. Gliomedin mediates Schwann cell–axon interaction and the molecular assembly of the nodes of Ranvier. Neuron 47, 215–229 (2005) FURTHER READING Sherman, D. L. & Brophy, P. J. Mechanisms of axon ensheathment and myelin growth. Nature Rev. Neurosci. 6, 683–690 (2005) G L I A

/pdf/long-distance-communication-4l2g3ur8il.pdf

Long-distance communication

Ischaemic injury involves a pronounced reduction in oxygen and glucose around the affected area, which leads to rapid cell death that is associated with Ca2+, Na+, K+ and Cl– dysregulation. But which channels mediate these changes? Writing in Science, Thompson and colleagues report the surprising finding that the ionic dysregulation seen in ischaemia results from the opening of hemichannels — sets of proteins that form one half of large conductance channels, known as gap junctions, that allow molecules and ions to flow directly between most cell types. Thompson and co-workers created ischaemic-like conditions in which there was oxygen and glucose deprivation (OGD) in isolated rat hippocampal pyramidal neurons. Voltage-clamp recordings revealed that OGD activated a current with a large amplitude, a linear current–voltage relationship and a reversal potential close to 0 mV — key features of hemichannel activation when Na+, Ca2+ and K+ currents were blocked. Selective blockage of hemichannels using carbenoxolone (Cbx) or lanthanum chloride confirmed their involvement in OGD-activated current. Prolonged (>20 min) OGD led to irreversible current activation, neuronal swelling and breakdown of cell membranes. Further investigations showed that blocking the ion channel ASIC1a or the purinergic P2X7 receptor (previously implicated in ischaemiarelated ionic dysregulation) failed to affect the large current triggered by OGD activation, although there was a minor effect of blocking the transient receptor potential channels TRPC4 and TRPC5 on the small residual current that remained after blockage of hemichannels. Nevertheless, the large amplitude current attributable to hemichannels indicated that they are the major contributors to the OGD-activated current, so these researchers explored their role in ionic dysregulation in more detail. Thompson and colleagues separately assessed the movement of two types of small fluorescent molecule that can permeate gap junctions: calcein AM and sulphorhodamine (SR101). Under normal conditions calcein AM remains inside neurons, whereas SR101 is absent from neurons. But during OGD there was a steady reduction in calcein and an increase in SR101 in neurons. The ability of these molecules to cross the membrane was prevented by Cbx, indicating that hemichannel opening was responsible for their movement. Gap junctions are formed from two hemichannels that comprise connexin or pannexin (PX) proteins. Pannexins, but not connexins, are expressed in pyramidal neurons and were therefore likely to form the hemichannels under scrutiny here. The single-channel biophysical properties — including amplitude, conductance, opening probability, current–voltage relationship and reversal potential — were consistent with those of PX1 hemichannels. This comprehensive set of studies provides compelling evidence that the opening of PX1 gap junction hemichannels is crucial for the ionic dysregulation and consequent neuronal death that follows ischaemia. Hemichannels therefore represent a promising therapeutic target in the treatment of ischaemic injury. Alison Rowan

/pdf/neurological-disorders-changing-channels-y8rkfgmfii.pdf

Neurological disorders: Changing channels

odours in this perceptual space correlated with physiological distances — a measure of the similarity of odours based on neural activation patterns — obtained in optical imaging experiments of antennal lobe activity. This study confirms that olfactory neural activity corresponds to olfactory perception, and shows how invertebrate models such as the honeybee can be used to answer fundamental questions about the neurobiology of perception. As this line of enquiry is pursued with more odours, comprising a range of molecular features, we will gain a more complete description of the honeybee’s olfactory perceptual space, and a better understanding of how perceptual measures relate to patterns of neural activity. Rebecca Craven

/pdf/micrornas-and-brain-morphogenesis-tu2mzrl8qi.pdf

MicroRNAs and brain morphogenesis

inherited neurodegenerative disorder that results from expanded polyglutamine (polyQ) repeats in the huntingtin protein (HTT). This leads to progressive striatal and cortical neurodegeneration and associated motor, cognitive and behavioural disturbances. Reducing the expression of the mutant HTT gene using RNA interference (RNAi) has emerged as a promising treatment for this fatal neurodegenerative disorder, according to a new report in the Proceedings of the National Academy of Sciences USA. Previous attempts to develop therapeutic interventions for Huntington’s disease have focused on targeting the downstream effectors of HTT expression. However, until now, there have been no efforts to directly target the underlying mutant gene. Davidson and colleagues injected vectors that encode short hairpin RNA sequences into a transgenic mouse model of Huntington’s disease. This resulted in reduced expression of mutant human HTT in the striatum and marked improvements in motor and neuropathological abnormalities. The authors suggest that the hairpin sequence could be further optimized according to more recently issued guidelines, which might lead to greater therapeutic benefit. In this study, RNAi affected the expression of mutant human HTT but not normal mouse Htt owing to differences in the mouse and human genes. However, if this method were used in human patients, the expression of both the normal and the mutated copies of the gene would be reduced, which raises the interesting question of whether reduced expression of both normal and mutated HTT could be tolerated in humans. This question needs to be tackled before RNAi can be tested therapeutically in humans with Huntington’s disease. Nevertheless, these results provide encouraging evidence that gene silencing techniques could be developed to directly target the underlying genetic abnormality in Huntington’s disease, and, potentially, other neurodegenerative disorders. Alison Rowan

/pdf/gene-silencing-in-huntington-s-disease-4nszzf64j2.pdf

Gene silencing in Huntington's disease

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