Building Advocacy Capacity: Where Grantees Started

Describes the baseline levels of core advocacy capacities of groups participating in Consumer Voices for Coverage, a twelve-state initiative to build consumer organizations' network and advocacy capacity. Discusses lessons learned and recommendations

Consumer Voices for Coverage: Advocacy Evaluation Toolkit

Offers step-by-step guidance on evaluating advocacy projects, including developing a logic model, collecting evaluation data, and using focus groups and interviews to evaluate or inform program performance. Includes surveys on RWJF's advocacy initiative

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast, FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents, suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate that FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies

CHANG-ES VI: Probing Supernova Energy Deposition in Spiral Galaxies Through Multi-Wavelength Relationships

How a galaxy regulates its SNe energy into different interstellar/circumgalactic medium components strongly affects galaxy evolution. Based on the JVLA D-configuration C- (6 GHz) and L-band (1.6 GHz) continuum observations, we perform statistical analysis comparing multi-wavelength properties of the CHANG-ES galaxies. The high-quality JVLA data and edge-on orientation enable us for the first time to include the halo into the energy budget for a complete radio-flux-limited sample. We find tight correlations of $L_{\rm radio}$ with the mid-IR-based SFR. The normalization of our $I_{\rm 1.6GHz}/{\rm W~Hz^{-1}}-{\rm SFR}$ relation is $\sim$2-3 times of those obtained for face-on galaxies, probably a result of enhanced IR extinction at high inclination. We also find tight correlations between $L_{\rm radio}$ and the SNe energy injection rate $\dot{E}_{\rm SN(Ia+CC)}$, indicating the energy loss via synchrotron radio continuum accounts for $\sim0.1\%$ of $\dot{E}_{\rm SN}$, comparable to the energy contained in CR electrons. The integrated C-to-L-band spectral index is $\alpha\sim0.5-1.1$ for non-AGN galaxies, indicating a dominance by the diffuse synchrotron component. The low-scatter $L_{\rm radio}-{\rm SFR}$/$L_{\rm radio}-\dot{E}_{\rm SN (Ia+CC)}$ relationships have super-linear logarithmic slopes at $\sim2~\sigma$ in L-band ($1.132\pm0.067$/$1.175\pm0.102$) while consistent with linear in C-band ($1.057\pm0.075$/$1.100\pm0.123$). The super-linearity could be naturally reproduced with non-calorimeter models for galaxy disks. Using Chandra halo X-ray measurements, we find sub-linear $L_{\rm X}-L_{\rm radio}$ relations. These results indicate that the observed radio halo of a starburst galaxy is close to electron calorimeter, and a galaxy with higher SFR tends to distribute an increased fraction of SNe energy into radio emission (than X-ray).Comment: 16 pages, 6 figures, 1 table, MNRAS in pres

Continuum Halos in Nearby Galaxies -- an EVLA Survey (CHANG-ES) -- I: Introduction to the Survey

We introduce a new survey to map the radio continuum halos of a sample of 35 edge-on spiral galaxies at 1.5 GHz and 6 GHz in all polarization products. The survey is exploiting the new wide bandwidth capabilities of the Karl G. Jansky Very Large Array (i.e. the Expanded Very Large Array, or EVLA) in a variety of array configurations (B, C, and D) in order to compile the most comprehensive data set yet obtained for the study of radio halo properties. This is the first survey of radio halos to include all polarization products. In this first paper, we outline the scientific motivation of the survey, the specific science goals, and the expected improvements in noise levels and spatial coverage from the survey. Our goals include investigating the physical conditions and origin of halos, characterizing cosmic ray transport and wind speed, measuring Faraday rotation and mapping the magnetic field, probing the in-disk and extraplanar far-infrared - radio continuum relation, and reconciling non-thermal radio emission with high-energy gamma-ray models. The sample size allows us to search for correlations between radio halos and other properties, including environment, star formation rate, and the presence of AGNs. In a companion paper (Paper II) we outline the data reduction steps and present the first results of the survey for the galaxy, NGC 4631.Comment: 17 pages, 1 figure, accepted to the Astronomical Journal, Version 2 changes: added acknowledgement to NRA

CHANG-ES IV: Radio continuum emission of 35 edge-on galaxies observed with the Karl G. Jansky Very Large Array in D-configuration, Data Release 1

We present the first part of the observations made for the Continuum Halos in Nearby Galaxies, an EVLA Survey (CHANG-ES) project. The aim of the CHANG-ES project is to study and characterize the nature of radio halos, their prevalence as well as their magnetic fields, and the cosmic rays illuminating these fields. This paper reports observations with the compact D configuration of the Karl G. Jansky Very Large Array (VLA) for the sample of 35 nearby edge-on galaxies of CHANG-ES. With the new wide bandwidth capabilities of the VLA, an unprecedented sensitivity was achieved for all polarization products. The beam resolution is an average of 9.6" and 36" with noise levels reaching approximately 6 and 30 microJy per beam for C- and L-bands, respectively (robust weighting). We present intensity maps in these two frequency bands (C and L), with different weightings, as well as spectral index maps, polarization maps, and new measurements of star formation rates (SFRs). The data products described herein are available to the public in the CHANG-ES data release available at www.queensu.ca/changes. We also present evidence of a trend among galaxies with larger halos having higher SFR surface density, and we show, for the first time, a radio continuum image of the median galaxy, taking advantage of the collective signal-to-noise ratio of 30 of our galaxies. This image shows clearly that a typical spiral galaxy is surrounded by a halo of magnetic fields and cosmic rays.Comment: 70 pages, of which 35 pages present the data of each galax

Navβ4 regulates fast resurgent sodium currents and excitability in sensory neurons

BACKGROUND: Increased electrical activity in peripheral sensory neurons including dorsal root ganglia (DRG) and trigeminal ganglia neurons is an important mechanism underlying pain. Voltage gated sodium channels (VGSC) contribute to the excitability of sensory neurons and are essential for the upstroke of action potentials. A unique type of VGSC current, resurgent current (INaR), generates an inward current at repolarizing voltages through an alternate mechanism of inactivation referred to as open-channel block. INaRs are proposed to enable high frequency firing and increased INaRs in sensory neurons are associated with pain pathologies. While Nav1.6 has been identified as the main carrier of fast INaR, our understanding of the mechanisms that contribute to INaR generation is limited. Specifically, the open-channel blocker in sensory neurons has not been identified. Previous studies suggest Navβ4 subunit mediates INaR in central nervous system neurons. The goal of this study was to determine whether Navβ4 regulates INaR in DRG sensory neurons. RESULTS: Our immunocytochemistry studies show that Navβ4 expression is highly correlated with Nav1.6 expression predominantly in medium-large diameter rat DRG neurons. Navβ4 knockdown decreased endogenous fast INaR in medium-large diameter neurons as measured with whole-cell voltage clamp. Using a reduced expression system in DRG neurons, we isolated recombinant human Nav1.6 sodium currents in rat DRG neurons and found that overexpression of Navβ4 enhanced Nav1.6 INaR generation. By contrast neither overexpression of Navβ2 nor overexpression of a Navβ4-mutant, predicted to be an inactive form of Navβ4, enhanced Nav1.6 INaR generation. DRG neurons transfected with wild-type Navβ4 exhibited increased excitability with increases in both spontaneous activity and evoked activity. Thus, Navβ4 overexpression enhanced INaR and excitability, whereas knockdown or expression of mutant Navβ4 decreased INaR generation. CONCLUSION: INaRs are associated with inherited and acquired pain disorders. However, our ability to selectively target and study this current has been hindered due to limited understanding of how it is generated in sensory neurons. This study identified Navβ4 as an important regulator of INaR and excitability in sensory neurons. As such, Navβ4 is a potential target for the manipulation of pain sensations

Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis

The finding of TDP-43 as a major component of ubiquitinated protein inclusions in amyotrophic lateral sclerosis (ALS) has led to the identification of 30 mutations in the transactive response-DNA binding protein (TARDBP) gene, encoding TDP-43. All but one are in exon 6, which encodes the glycine-rich domain. The aim of this study was to determine the frequency of TARDBP mutations in a large cohort of motor neurone disease patients from Northern England (42 non-superoxide dismutase 1 (SOD1) familial ALS (FALS), nine ALS-frontotemporal dementia, 474 sporadic ALS (SALS), 45 progressive muscular atrophy cases). We identified four mutations, two of which were novel, in two familial (FALS) and two sporadic (SALS) cases, giving a frequency of TARDBP mutations in non-SOD1 FALS of 5% and SALS of 0.4%. Analysis of clinical data identified that patients had typical ALS, with limb or bulbar onset, and showed considerable variation in age of onset and rapidity of disease course. However, all cases had an absence of clinically overt cognitive dysfunction

Continuum Halos in Nearby Galaxies -- an EVLA Survey (CHANG-ES) -- II: First Results on NGC 4631

We present the first results from the CHANG-ES survey, a new survey of 35 edge-on galaxies to search for both in-disk as well as extra-planar radio continuum emission. The motivation and science case for the survey are presented in a companion paper (Paper I). In this paper (Paper II), we outline the observations and data reduction steps required for wide-band calibration and mapping of EVLA data, including polarization, based on C-array test observations of NGC 4631. With modest on-source observing times (30 minutes at 1.5 GHz and 75 minutes at 6 GHz for the test data) we have achieved best rms noise levels of 22 and 3.5 $\mu$Jy beam$^{-1}$ at 1.5 GHz and 6 GHz, respectively. New disk-halo features have been detected, among them two at 1.5 GHz that appear as loops in projection. We present the first 1.5 GHz spectral index map of NGC 4631 to be formed from a single wide-band observation in a single array configuration. This map represents tangent slopes to the intensities within the band centered at 1.5 GHz, rather than fits across widely separated frequencies as has been done in the past and is also the highest spatial resolution spectral index map yet presented for this galaxy. The average spectral index in the disk is $\bar\alpha_{1.5 GHz}\,=\,-0.84\,\pm\,0.05$ indicating that the emission is largely non-thermal, but a small global thermal contribution is sufficient to explain a positive curvature term in the spectral index over the band. Two specific star forming regions have spectral indices that are consistent with thermal emission. Polarization results (uncorrected for internal Faraday rotation) are consistent with previous observations and also reveal some new features. On broad scales, we find strong support for the notion that magnetic fields constrain the X-ray emitting hot gas.Comment: Accepted to the Astronomical Journal, Version 2 changes: Added acknowledgement to NRA

Synapse loss in the prefrontal cortex is associated with cognitive decline in amyotrophic lateral sclerosis

In addition to motor neurone degeneration, up to 50% of amyotrophic lateral sclerosis (ALS) patients present with cognitive decline. Understanding the neurobiological changes underlying these cognitive deficits is critical, as cognitively impaired patients exhibit a shorter survival time from symptom onset. Given the pathogenic role of synapse loss in other neurodegenerative diseases in which cognitive decline is apparent, such as Alzheimer's disease, we aimed to assess synaptic integrity in the ALS brain. Here, we have applied a unique combination of high-resolution imaging of post-mortem tissue with neuropathology, genetic screening and cognitive profiling of ALS cases. Analyses of more than 1 million synapses using two complimentary high-resolution techniques (electron microscopy and array tomography) revealed a loss of synapses from the prefrontal cortex of ALS patients. Importantly, synapse loss was significantly greater in cognitively impaired cases and was not due to cortical atrophy, nor associated with dementia-associated neuropathology. Interestingly, we found a trend between pTDP-43 pathology and synapse loss in the frontal cortex and discovered pTDP-43 puncta at a subset of synapses in the ALS brains. From these data, we postulate that synapse loss in the prefrontal cortex represents an underlying neurobiological substrate of cognitive decline in ALS