The search for novel analgesics: re-examining spinal cord circuits with new tools

In this perspective, we propose the absence of detailed information regarding spinal cord circuits that process sensory information remains a major barrier to advancing analgesia. We highlight recent advances showing that functionally discrete populations of neurons in the spinal cord dorsal horn play distinct roles in processing sensory information. We then discuss new molecular, electrophysiological, and optogenetic techniques that can be employed to understand how dorsal horn circuits process tactile and nociceptive information. We believe this information can drive the development of entirely new classes of pharmacotherapies that target key elements in spinal circuits to selectively modify sensory function and blunt pain

Distinct forms of synaptic inhibition and neuromodulation regulate calretinin positive neuron excitability in the spinal cord dorsal horn

The dorsal horn (DH) of the spinal cord contains a heterogenous population of neurons that process incoming sensory signals before information ascends to the brain. We have recently characterized calretinin-expressing (CR+) neurons in the DH and shown that they can be divided into excitatory and inhibitory subpopulations. The excitatory population receives high-frequency excitatory synaptic input and expresses delayed firing action potential discharge, whereas the inhibitory population receives weak excitatory drive and exhibits tonic or initial bursting discharge. Here, we characterize inhibitory synaptic input and neuromodulation in the two CR+ populations, in order to determine how each is regulated. We show that excitatory CR+ neurons receive mixed inhibition from GABAergic and glycinergic sources, whereas inhibitory CR+ neurons receive inhibition, which is dominated by glycine. Noradrenaline and serotonin produced robust outward currents in excitatory CR+ neurons, predicting an inhibitory action on these neurons, but neither neuromodulator produced a response in CR+ inhibitory neurons. In contrast, enkephalin (along with selective mu and delta opioid receptor agonists) produced outward currents in inhibitory CR+ neurons, consistent with an inhibitory action but did not affect the excitatory CR+ population. Our findings show that the pharmacology of inhibitory inputs and neuromodulator actions on CR+ cells, along with their excitatory inputs can define these two subpopulations further, and this could be exploited to modulate discrete aspects of sensory processing selectively in the DH

A Parameter-Free Tour of the Binary Black Hole Population

The continued operation of the Advanced LIGO and Advanced Virgo gravitational-wave detectors is enabling the first detailed measurements of the mass, spin, and redshift distributions of the merging binary black hole population. Our present knowledge of these distributions, however, is based largely on strongly parameteric models; such models typically assume the distributions of binary parameters to be superpositions of power laws, peaks, dips, and breaks, and then measure the parameters governing these "building block" features. Although this approach has yielded great progress in initial characterization of the compact binary population, the strong assumptions entailed leave it often unclear which physical conclusions are driven by observation and which by the specific choice of model. In this paper, we instead model the merger rate of binary black holes as an unknown autoregressive process over the space of binary parameters, allowing us to measure the distributions of binary black hole masses, redshifts, component spins, and effective spins with near-complete agnosticism. We find the primary mass spectrum of binary black holes to be doubly-peaked, with a fairly flat continuum that steepens at high masses. We identify signs of unexpected structure in the redshift distribution of binary black holes: a uniform-in-comoving volume merger rate at low redshift followed by a rise in the merger rate beyond redshift $z\approx 0.5$. Finally, we find that the distribution of black hole spin magnitudes is unimodal and concentrated at small but non-zero values, and that spin orientations span a wide range of spin-orbit misalignment angles but are also unlikely to be truly isotropic.Comment: 24 pages, 14 figures; code can be found at http://github.com/tcallister/autoregressive-bbh-inference and data can be download from https://zenodo.org/record/761609

Contrasting alterations to synaptic and intrinsic properties in upper-cervical superficial dorsal horn neurons following acute neck muscle inflammation

Background: Acute and chronic pain in axial structures, like the back and neck, are difficult to treat, and have incidence as high as 15%. Surprisingly, most preclinical work on pain mechanisms focuses on cutaneous structures in the limbs and animal models of axial pain are not widely available. Accordingly, we developed a mouse model of acute cervical muscle inflammation and assessed the functional properties of superficial dorsal horn (SDH) neurons.<p></p> Results: Male C57/Bl6 mice (P24-P40) were deeply anaesthetised (urethane 2.2?g/kg i.p) and the rectus capitis major muscle (RCM) injected with 40??l of 2% carrageenan. Sham animals received vehicle injection and controls remained anaesthetised for 2?hrs. Mice in each group were sacrificed at 2?hrs for analysis. c-Fos staining was used to determine the location of activated neurons. c-Fos labelling in carrageenan-injected mice was concentrated within ipsilateral (87% and 63% of labelled neurons in C1 and C2 segments, respectively) and contralateral laminae I - II with some expression in lateral lamina V. c-Fos expression remained below detectable levels in control and sham animals. In additional experiments, whole cell recordings were obtained from visualised SDH neurons in transverse slices in the ipsilateral C1 and C2 spinal segments. Resting membrane potential and input resistance were not altered. Mean spontaneous EPSC amplitude was reduced by ~20% in neurons from carrageenan-injected mice versus control and sham animals (20.63???1.05 vs. 24.64???0.91 and 25.87???1.32 pA, respectively). The amplitude (238???33 vs. 494???96 and 593???167 pA) and inactivation time constant (12.9???1.5 vs. 22.1???3.6 and 15.3???1.4?ms) of the rapid A type potassium current (IAr), the dominant subthreshold current in SDH neurons, were reduced in carrageenan-injected mice.<p></p> Conclusions: Excitatory synaptic drive onto, and important intrinsic properties (i.e., IAr) within SDH neurons are reduced two hours after acute muscle inflammation. We propose this time point represents an important transition period between peripheral and central sensitisation with reduced excitatory drive providing an initial neuroprotective mechanism during the early stages of the progression towards central sensitisation

Ceramic Substrates for High-temperature Electronic Integration

One of the most attractive ways to increase power handling capacity in power modules is to increase the operating temperature using wide-band-gap semiconductors. Ceramics are ideal candidates for use as substrates in high-power high-temperature electronic devices. The present article aims to determine the most suitable ceramic material for this application

Structural, elastic and thermal properties of cementite (Fe3_3C) calculated using Modified Embedded Atom Method

Structural, elastic and thermal properties of cementite (Fe$_3$C) were studied using a Modified Embedded Atom Method (MEAM) potential for iron-carbon (Fe-C) alloys. Previously developed Fe and C single element potentials were used to develop an Fe-C alloy MEAM potential, using a statistically-based optimization scheme to reproduce structural and elastic properties of cementite, the interstitial energies of C in bcc Fe as well as heat of formation of Fe-C alloys in L$_{12}$ and B$_1$ structures. The stability of cementite was investigated by molecular dynamics simulations at high temperatures. The nine single crystal elastic constants for cementite were obtained by computing total energies for strained cells. Polycrystalline elastic moduli for cementite were calculated from the single crystal elastic constants of cementite. The formation energies of (001), (010), and (100) surfaces of cementite were also calculated. The melting temperature and the variation of specific heat and volume with respect to temperature were investigated by performing a two-phase (solid/liquid) molecular dynamics simulation of cementite. The predictions of the potential are in good agreement with first-principles calculations and experiments.Comment: 12 pages, 9 figure

Plastic Deformation of 2D Crumpled Wires

When a single long piece of elastic wire is injected trough channels into a confining two-dimensional cavity, a complex structure of hierarchical loops is formed. In the limit of maximum packing density, these structures are described by several scaling laws. In this paper it is investigated this packing process but using plastic wires which give origin to completely irreversible structures of different morphology. In particular, it is studied experimentally the plastic deformation from circular to oblate configurations of crumpled wires, obtained by the application of an axial strain. Among other things, it is shown that in spite of plasticity, irreversibility, and very large deformations, scaling is still observed.Comment: 5 pages, 6 figure

Deforming glassy polystyrene: Influence of pressure, thermal history, and deformation mode on yielding and hardening

The toughness of a polymer glass is determined by the interplay of yielding, strain softening, and strain hardening. Molecular-dynamics simulations of a typical polymer glass, atactic polystyrene, under the influence of active deformation have been carried out to enlighten these processes. It is observed that the dominant interaction for the yield peak is of interchain nature and for the strain hardening of intrachain nature. A connection is made with the microscopic cage-to-cage motion. It is found that the deformation does not lead to complete erasure of the thermal history but that differences persist at large length scales. Also we find that the strain-hardening modulus increases with increasing external pressure. This new observation cannot be explained by current theories such as the one based on the entanglement picture and the inclusion of this effect will lead to an improvement in constitutive modeling

The evolution of TEP1, an exceptionally polymorphic immunity gene in Anopheles gambiae

<p>Abstract</p> <p>Background</p> <p>Host-parasite coevolution can result in balancing selection, which maintains genetic variation in the susceptibility of hosts to parasites. It has been suggested that variation in a thioester-containing protein called <it>TEP1 </it>(AGAP010815) may alter the ability of <it>Anopheles </it>mosquitoes to transmit <it>Plasmodium </it>parasites, and high divergence between alleles of this gene suggests the possible action of long-term balancing selection. We studied whether <it>TEP1 </it>is a case of an ancient balanced polymorphism in an animal immune system.</p> <p>Results</p> <p>We found evidence that the high divergence between <it>TEP1 </it>alleles is the product of genetic exchange between <it>TEP1 </it>and other TEP loci, i.e. gene conversion. Additionally, some <it>TEP1 </it>alleles showed unexpectedly low variability.</p> <p>Conclusion</p> <p>The <it>TEP1 </it>gene appears to be a chimera produced from at least two other <it>TEP </it>loci, and the divergence between <it>TEP1 </it>alleles is probably not caused by long-term balancing selection, but is instead due to two independent gene conversion events from one of these other genes. Nevertheless, <it>TEP1 </it>still shows evidence of natural selection, in particular there appears to have been recent changes in the frequency of alleles that has diminished polymorphism within each allelic class. Although the selective force driving this dynamic was not identified, given that susceptibility to <it>Plasmodium </it>parasites is known to be associated with allelic variation in <it>TEP1</it>, these changes in allele frequencies could alter the vectoring capacity of populations.</p