Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated sodium channels, Na(v)1.1-Na(v)1.9, are essential for ...generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several channels as pivotal for signal transmission along the pain axis, including Na(v)1.3, Na(v)1.7, Na(v)1.8, and Na(v)1.9, with the latter three preferentially expressed in peripheral sensory neurons and Na(v)1.3 being upregulated along pain-signaling pathways after nervous system injuries. Na(v)1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these sodium channel isoforms to pain.
Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition which affects 2-10% of school age children worldwide. Although the underlying molecular mechanism for the ...disorder is poorly understood, familial, twin and adoption studies suggest a strong genetic component. Here we provide a state-of-the-art review of the molecular genetics of ADHD incorporating evidence from candidate gene and linkage designs, as well as genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs) and rare copy number variations (CNVs). Bioinformatic methods such as functional enrichment analysis and protein-protein network analysis are used to highlight biological processes of likely relevance to the aetiology of ADHD. Candidate gene associations of minor effect size have been replicated across a number of genes including SLC6A3, DRD5, DRD4, SLC6A4, LPHN3, SNAP-25, HTR1B, NOS1 and GIT1. Although case-control SNP-GWAS have had limited success in identifying common genetic variants for ADHD that surpass critical significance thresholds, quantitative trait designs suggest promising associations with Cadherin13 and glucose-fructose oxidoreductase domain 1 genes. Further, CNVs mapped to glutamate receptor genes (GRM1, GRM5, GRM7 and GRM8) have been implicated in the aetiology of the disorder and overlap with bioinformatic predictions based on ADHD GWAS SNP data regarding enriched pathways. Although increases in sample size across multi-center cohorts will likely yield important new results, we advocate that this must occur in parallel with a shift away from categorical case-control approaches that view ADHD as a unitary construct, towards dimensional approaches that incorporate endophenotypes and statistical classification methods.
Background The Special Interest Quality of Life Group has updated its set of statements defining the quality of life (QOL) construct to reflect emerging areas of agreement and the framework for ...understanding better the QOL construct.
Method This article examines the major areas currently under discussion involving the objective–subjective dichotomy, needs, and core domains.
Results It is concluded that while the new statements constitute a significant advance, further progress requires testable theory. In order to facilitate such future research, a conceptual model is proposed that distinguishes causal and indicator variables within the framework of a homeostatic management system.
Conclusion Several lines of empirical investigation are suggested to test this and similar theoretical models with a view to taking our conceptualization of QOL to the next level.
Many epilepsy patients are refractory to conventional antiepileptic drugs. Resurgent and persistent currents can be enhanced by epilepsy mutations in the Nav1.2 channel, but conventional ...antiepileptic drugs inhibit normal transient currents through these channels, along with aberrant resurgent and persistent currents that are enhanced by Nav1.2 epilepsy mutations. Pharmacotherapies that specifically target aberrant resurgent and/or persistent currents would likely have fewer unwanted side effects and be effective in many patients with refractory epilepsy. This study investigated the effects of cannbidiol (CBD) and GS967 (each at 1 μM) on transient, resurgent, and persistent currents in human embryonic kidney (HEK) cells stably expressing wild-type hNav1.2 channels. We found that CBD preferentially inhibits resurgent currents over transient currents in this paradigm; and that GS967 preferentially inhibits persistent currents over transient currents. Therefore, CBD and GS967 may represent a new class of more targeted and effective antiepileptic drugs.
Understanding the role of voltage-gated sodium channels in nociception may provide important insights into pain mechanisms. Voltage-gated sodium channels are critically important for electrogenesis ...and nerve impulse conduction, and a target for important clinically relevant analgesics such as lidocaine. Furthermore, within the last decade studies have shown that certain sodium channel isoforms are predominantly expressed in peripheral sensory neurons associated with pain sensation, and that the expression and functional properties of voltage-gated sodium channels in peripheral sensory neurons can be dynamically regulated following axonal injury or peripheral inflammation. These data suggest that specific voltage-gated sodium channels may play crucial roles in nociception. Experiments with transgenic mice lines have clearly implicated Na
v1.7, Na
v1.8 and Na
v1.9 in inflammatory, and possibly neuropathic, pain. However the most convincing and perhaps most exciting results regarding the role of voltage-gated sodium channels have come out recently from studies on human inherited disorders of nociception. Point mutations in Na
v1.7 have been identified in patients with two distinct autosomal dominant severe chronic pain syndromes. Electrophysiological experiments indicate that these pain-associated mutations cause small yet significant changes in the gating properties of voltage-gated sodium channels that are likely to contribute substantially to the development of chronic pain. Equally exciting, recent studies indicate that recessive mutations in Na
v1.7 that eliminate functional current can result in an apparent complete, and possibly specific, indifference to pain in humans, suggesting that isoform specific blockers could be very effective in treating pain. In this review we will examine what is known about the roles of voltage-gated sodium channels in nociception.
Dorsal root ganglion neurons express an array of sodium channel isoforms allowing precise control of excitability. An increasing
body of literature indicates that regulation of firing behaviour in ...these cells is linked to their patterns of expression
of specific sodium channel isoforms, which have been discovered to possess distinct biophysical characteristics. The pattern
of expression of sodium channels differs in different subclasses of DRG neurons and is not fixed but, on the contrary, changes
in response to a variety of disease insults. Moreover, modulation of channels by their environment has been found to play
an important role in the response of these neurons to stimuli. In this review we illustrate how excitability can be finely
tuned to provide contrasting firing templates in different subclasses of DRG neurons by selective deployment of various sodium
channel isoforms, by plasticity of expression of these proteins, and by interactions of these sodium channel isoforms with
each other and with other modulatory molecules.
We autocorrelate the continuously recorded seismic wavefield across a dense network of seismometers to map the P wave reflectivity response of the Jakarta Basin, Indonesia. The proximity of this mega ...city to known active faults and the subduction of the Australian plate, especially when the predominance of masonry construction and thick sedimentary basin fill are considered, suggests that it is a hot spot for seismic risk. In order to understand the type of ground motion that earthquakes might cause in the basin, it is essential to obtain reliable information on its seismic velocity structure. The body wave reflections are sensitive to the sharp velocity contrasts, which makes them useful in seismic imaging. Results show autocorrelograms at different seismic stations with reflected‐wave travel time variations, which reflect the variation in basement depth across the thick sedimentary basin. We also confirm the validity of the observed autocorrelation waveforms by conducting a 2‐D full waveform modeling.
Key Points
Seismic risk is high in Jakarta, and the subsurface basin structure is still poorly understood
The basin response of Jakarta is mapped from stacked autocorrelations of the continuous seismic noise recorded across a seismic array
The relative change of arrival times of autocorrelograms suggests a thinning of the basin from the north to the south
The great Sumatra-Andaman earthquake and Indian Ocean tsunami of 2004 came as a surprise to most of the earth science community. Although it is now widely recognized that the risk of another giant ...earthquake is high off central Sumatra, just east of the 2004 earthquake, there seems to be relatively little concern about the subduction zone to the north, in the northern Bay of Bengal along the coast of Myanmar. Here I show that similar indicators suggest a high potential for giant earthquakes along the coast of Myanmar. These indicators include the tectonic environment, which is similar to other subduction zones that experience giant megathrust earthquakes, stress and crustal strain observations, which indicate that the seismogenic zone is locked, and historical earthquake activity, which indicates that giant tsunamigenic earthquakes have occurred there in the past. These are all consistent with active subduction in the Myanmar subduction zone and I suggest that the seismogenic zone extends beneath the Bengal Fan. I conclude therefore that giant earthquakes probably occur off the coast of Myanmar, and that a large and vulnerable population is thereby exposed to a significant earthquake and tsunami hazard.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hydrogen evolution reaction is catalysed efficiently with precious metals, such as platinum; however, transition metal dichalcogenides have recently emerged as a promising class of materials for ...electrocatalysis, but these materials still have low activity and durability when compared with precious metals. Here we report a simple one-step scalable approach, where MoOx/MoS2 core-shell nanowires and molybdenum disulfide sheets are exposed to dilute aqueous hydrazine at room temperature, which results in marked improvement in electrocatalytic performance. The nanowires exhibit ∼100 mV improvement in overpotential following exposure to dilute hydrazine, while also showing a 10-fold increase in current density and a significant change in Tafel slope. In situ electrical, gate-dependent measurements and spectroscopic investigations reveal that hydrazine acts as an electron dopant in molybdenum disulfide, increasing its conductivity, while also reducing the MoOx core in the core-shell nanowires, which leads to improved electrocatalytic performance.
Cardiac voltage-gated sodium channels (Nav1.5) play an essential role in regulating cardiac electric activity by initiating and propagating action potentials in the heart. Altered Nav1.5 function is ...associated with multiple cardiac diseases including long-QT3 and Brugada syndrome. Here, we show that Nav1.5 is subject to palmitoylation, a reversible post-translational lipid modification. Palmitoylation increases channel availability and late sodium current activity, leading to enhanced cardiac excitability and prolonged action potential duration. In contrast, blocking palmitoylation increases closed-state channel inactivation and reduces myocyte excitability. We identify four cysteines as possible Nav1.5 palmitoylation substrates. A mutation of one of these is associated with cardiac arrhythmia (C981F), induces a significant enhancement of channel closed-state inactivation and ablates sensitivity to depalmitoylation. Our data indicate that alterations in palmitoylation can substantially control Nav1.5 function and cardiac excitability and this form of post-translational modification is likely an important contributor to acquired and congenital arrhythmias.
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