M-type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain

Funding: Royal Society: NIF/R1/180091; Wellcome Trust: 204821/Z/16/Z; Canadian Institute for Health Research: 202012MFE – 459188 – 297534.The size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage-sensitive ion channels that create non-linearities in their input-output functions. Here we describe a role for the M-type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole-cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M-currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the presence of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed-firing motoneurons afforded a greater proportion of the total M-current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M-currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M-type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage-sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force.Publisher PDFPeer reviewe

Peptidergic modulation of motor neuron output via CART signaling at C bouton synapses

Funding: This work was supported by the General Secretariat for Research and Technology (ARISTEIA II 4257, L.Z.), Fondation SANTE (L.Z.), a Marie Curie Re-Integration Grant (268323, L.Z.), the Hellenic Foundation for Research and Innovation (spinMNALS, 4013, L.Z.) and by a St. Andrews Restarting Research Fund (S.A.S. and G.B.M.). S.A.S. was funded by a Royal Society Newton International Fellowship (NIF/R1/180091) and a Natural Sciences and Engineering Research Council of Canada (NSERC) Postdoctoral Fellowship (NSERC-PDF-517295-2018) and M.M. by the National Scholarship Foundation (IKY).The intensity of muscle contraction, and therefore movement vigour, needs to be adaptable to enable complex motor behaviors. This can be achieved by adjusting the properties of motor neurons, which form the final common pathway for all motor output from the central nervous system. Here we identify novel roles for a neuropeptide, Cocaine and Amphetamine Regulated Transcript (CART), in the control of movement vigour. We reveal distinct, but parallel mechanisms by which CART and acetylcholine, both released at C bouton synapses on motor neurons, selectively amplify the output of subtypes of motor neurons that are recruited during intense movement. We find that mice with broad genetic deletion of CART or selective elimination of acetylcholine from C boutons exhibit deficits in behavioral tasks that require higher levels of motor output. Overall, these data uncover novel spinal modulatory mechanisms that control movement vigour to support movements that require a high degree of muscle force.Publisher PDFPeer reviewe

Contributions of h- and Na+ /K+ pump currents to the generation of episodic and continuous rhythmic activities

Authors acknowledge studentships from the Natural Sciences and Engineering Research Council of Canada (NSERC-PGS-D: SS); Alberta Innovates (AIHS: SS and AL); Hotchkiss Brain Institute (SS and AL); and the Faculty of Veterinary Medicine (LY). This research was supported by grants from the Canadian Institute of Health Research (PW); an NSERC Discovery grant (PW); and National Institutes of Health, National Institute of Neurological Disorders and Stroke 1 R21 NS111355 (GC and Ronald L. Calabrese).Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-center oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (IPump) and hyperpolarization-activated currents (Ih) playing key roles. Modulation of either IPump or Ih produced transitions between episodic and continuous rhythms and silence. As maximal activity of IPump decreased, the interepisode interval and period increased along with a reduction in episode duration. Decreasing maximal conductance of Ih decreased episode duration and increased interepisode interval. Pharmacological manipulations of Ih with ivabradine, and IPump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modeling and experimental results highlight key roles of Ih and IPump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.Publisher PDFPeer reviewe

ISOGAL Survey of Baade's Windows in the Mid-infrared

The ISOGAL mid-infrared survey of areas close to the Galactic Plane aims to determine their stellar content and its possible bearing on the history of the Galaxy. The NGC6522 and Sgr I Baade's Windows of low obscuration towards the inner parts of the Bulge represent ideal places in which to calibrate and understand the ISOGAL colour-magnitude diagrams. The survey observations were made with the ISOCAM instrument of the ISO satellite. The filter bands chosen were LW2(~7 microns) and LW3(~15 microns). The results presented here show that most of the detected objects are late M-type giants on the AGB, with a cut-off for those earlier than M3-M4. The most luminous members of these two Bulge fields at 7 microns are the Mira variables. However, it is evident that they represent the end of a sequence of increasing 15 micron dust emission which commences with M giants of earlier sub-type. In observations of late-type giants the ISOCAM 15 micron band is mainly sensitive to the cool silicate or aluminate dust shells which overwhelm the photospheric emission. However, in ordinary M-giant stars, the 7 micron band is not strongly affected by dust emission and may be influenced instead by absorption. The nu2 band of water at 6.25 microns and the SiO fundamental at 7.9 microns are likely contribitors to this effect. A group of late M stars has been found which vary little or not at all but have infrared colours typical of well-developed dust shells. Their luminosities are similar to those of 200-300 day Miras but they have slightly redder [7]-[15] colours which form an extension of the ordinary M giant sequence. The Mira dust shells show a mid-infrared [7]-[15] colour-period relation. ca 700 days.Comment: 13 pages 15 figure

Lifespan theorem for constrained surface diffusion flows

We consider closed immersed hypersurfaces in $\R^{3}$ and $\R^4$ evolving by a class of constrained surface diffusion flows. Our result, similar to earlier results for the Willmore flow, gives both a positive lower bound on the time for which a smooth solution exists, and a small upper bound on a power of the total curvature during this time. By phrasing the theorem in terms of the concentration of curvature in the initial surface, our result holds for very general initial data and has applications to further development in asymptotic analysis for these flows.Comment: 29 pages. arXiv admin note: substantial text overlap with arXiv:1201.657

Rationale and design of the LIBERATES trial: Protocol for a randomised controlled trial of flash glucose monitoring for optimisation of glycaemia in individuals with type 2 diabetes and recent myocardial infarction.

Hyperglycaemia in individuals with type 2 diabetes (T2D) and myocardial infarction (MI) is associated with guarded clinical prognosis. Studies improving glucose levels in T2D following MI relied on HbA1c as the main glycaemic marker, failing to address potential adverse effects of hypoglycaemia and glucose variability. We describe the design of the LIBERATES trial that investigates the role of flash glucose monitoring in optimising glycaemic markers in high vascular risk individuals with T2D. This multicentre trial is designed to recruit up to 150 insulin and/or sulphonylurea-treated T2D patients, within 5 days of a proven MI. Individuals will be randomised 1:1 into intervention and control groups using flash glucose monitoring sensors and traditional self-monitoring of blood glucose, respectively. The control group will also wear a blinded continuous glucose monitoring sensor. The primary outcome is the difference in time spent in euglycaemia (defined as glucose levels between 3.9-10.0 mmol/l), comparing study groups 3 months following recruitment, assessed daily for 14 days and as an average. Secondary and exploratory end points include time spent in hypoglycaemia and hyperglycaemia, HbA1c, quality of life measures, major adverse cardiac events and cost-effectiveness of the intervention. This study will establish the role of flash glucose monitoring in glycaemic management of individuals with T2D sustaining a cardiac event.(Trial Registration: ISRCTN14974233, registered 12th June 2017)

ISOGAL: A deep survey of the obscured inner Milky Way with ISO at 7 and 15 micron and with DENIS in the near-infrared

The ISOGAL project is an infrared survey of specific regions sampling the Galactic Plane selected to provide information on Galactic structure,stellar populations,stellar mass-loss and the recent star formation history of the inner disk and Bulge of the Galaxy. ISOGAL combines 7 and 15 micron ISOCAM observations - with a resolution of 6'' at worst - with DENIS IJKs data to determine the nature of the sources and theinterstellar extinction. We have observed about 16 square degrees with a sensitivity approaching 10-20mJy, detecting ~10^5 sources,mostly AGB stars,red giants and young stars. The main features of the ISOGAL survey and the observations are summarized in this paper,together with a brief discussion of data processing and quality. The primary ISOGAL products are described briefly (a full description is given in Schuller et al. 2003, astro-ph/0304309): viz. the images and theISOGAL-DENIS five-wavelength point source catalogue. The main scientific results already derived or in progress are summarized. These include astrometrically calibrated 7 and 15um images,determining structures of resolved sources; identification and properties of interstellar dark clouds; quantification of the infrared extinction law and source dereddening; analysis of red giant and (especially) AGB stellar populations in the central Bulge,determining luminosity,presence of circumstellar dust and mass--loss rate,and source classification,supplemented in some cases by ISO/CVF spectroscopy; detection of young stellar objects of diverse types,especially in the inner Bulge with information about the present and recent star formation rate; identification of foreground sources with mid-IR excess. These results are the subject of about 25 refereed papers published or in preparation.Comment: A&A in press. 19 pages,10 Ps figures; problems with figures fixe

Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy

Objectives To compare the effects of rituximab versus placebo on salivary gland ultrasound (SGUS) in primary Sjögren’s syndrome (PSS) in a multicentre, multiobserver phase III trial substudy. Methods Subjects consenting to SGUS were randomised to rituximab or placebo given at weeks 0, 2, 24 and 26, and scanned at baseline and weeks 16 and 48. Sonographers completed a 0–11 total ultrasound score (TUS) comprising domains of echogenicity, homogeneity, glandular definition, glands involved and hypoechoic foci size. Baseline-adjusted TUS values were analysed over time, modelling change from baseline at each time point. For each TUS domain, we fitted a repeated-measures logistic regression model to model the odds of a response in the rituximab arm (≥1-point improvement) as a function of the baseline score, age category, disease duration and time point. Results 52 patients (n=26 rituximab and n=26 placebo) from nine centres completed baseline and one or more follow-up visits. Estimated between-group differences (rituximab-placebo) in baseline-adjusted TUS were −1.2 (95% CI −2.1 to −0.3; P=0.0099) and −1.2 (95% CI −2.0 to −0.5; P=0.0023) at weeks 16 and 48. Glandular definition improved in the rituximab arm with an OR of 6.8 (95% CI 1.1 to 43.0; P=0.043) at week 16 and 10.3 (95% CI 1.0 to 105.9; P=0.050) at week 48. Conclusions We demonstrated statistically significant improvement in TUS after rituximab compared with placebo. This encourages further research into both B cell depletion therapies in PSS and SGUS as an imaging biomarker

Spatial Variation in Foraging Behaviour of a Marine Top Predator (Phoca vitulina) Determined by a Large-Scale Satellite Tagging Program

The harbour seal (Phoca vitulina) is a widespread marine predator in Northern Hemisphere waters. British populations have been subject to rapid declines in recent years. Food supply or inter-specific competition may be implicated but basic ecological data are lacking and there are few studies of harbour seal foraging distribution and habits. In this study, satellite tagging conducted at the major seal haul outs around the British Isles showed both that seal movements were highly variable among individuals and that foraging strategy appears to be specialized within particular regions. We investigated whether these apparent differences could be explained by individual level factors: by modelling measures of trip duration and distance travelled as a function of size, sex and body condition. However, these were not found to be good predictors of foraging trip duration or distance, which instead was best predicted by tagging region, time of year and inter-trip duration. Therefore, we propose that local habitat conditions and the constraints they impose are the major determinants of foraging movements. Specifically the distance to profitable feeding grounds from suitable haul-out locations may dictate foraging strategy and behaviour. Accounting for proximity to productive foraging resources is likely to be an important component of understanding population processes. Despite more extensive offshore movements than expected, there was also marked fidelity to the local haul-out region with limited connectivity between study regions. These empirical observations of regional exchange at short time scales demonstrates the value of large scale electronic tagging programs for robust characterization of at-sea foraging behaviour at a wide spatial scale