Determinants of TRPV4 Activity following Selective Activation by Small Molecule Agonist GSK1016790A

TRPV4 (Transient Receptor Potential Vanilloid 4) channels are activated by a wide range of stimuli, including hypotonic stress, non-noxious heat and mechanical stress and some small molecule agonists (e.g. phorbol ester 4α-PDD). GSK1016790A (GSK101) is a recently discovered specific small molecule agonist of TRPV4. Its effects on physical determinants of TRPV4 activity were evaluated in HeLa cells transiently transfected with TRPV4 (HeLa-TRPV4). GSK101 (10 nM) causes a TRPV4 specific Ca2+ influx in HeLa-TRPV4 cells, but not in control transfected cells, which can be inhibited by ruthenium red and Ca2+-free medium more significantly at the early stage of the activation rather than the late stage, reflecting apparent partial desensitization. Western blot analysis showed that GSK101 activation did not induce an increase in TRPV4 expression at the plasma membrane, but caused an immediate and sustained downregulation of TRPV4 on the plasma membrane in HeLa-TRPV4 cells. Patch clamp analysis also revealed an early partial desensitization of the channel which was Ca2+-independent. FRET analysis of TRPV4 subunit assembly demonstrated that the GSK101-induced TRPV4 channel activation/desensitization was not due to alterations in homotetrameric channel formation on the plasma membrane. It is concluded that GSK101 specifically activates TRPV4 channels, leading to a rapid partial desensitization and downregulation of the channel expression on the plasma membrane. TRPV4 subunit assembly appears to occur during trafficking from the ER/Golgi to the plasma membrane and is not altered by agonist stimulation

Hubble Space Telescope Planetary Camera Images of NGC 1316

We present HST Planetary Camera V and I~band images of the central region of the peculiar giant elliptical galaxy NGC 1316. The inner profile is well fit by a nonisothermal core model with a core radius of 0.41" +/- 0.02" (34 pc). At an assumed distance of 16.9 Mpc, the deprojected luminosity density reaches \sim 2.0 \times 10^3 L_{\sun} pc$^{-3}$. Outside the inner two or three arcseconds, a constant mass-to-light ratio of $\sim 2.2 \pm 0.2$ is found to fit the observed line width measurements. The line width measurements of the center indicate the existence of either a central dark object of mass 2 \times 10^9 M_{\sun}, an increase in the stellar mass-to-light ratio by at least a factor of two for the inner few arcseconds, or perhaps increasing radial orbit anisotropy towards the center. The mass-to-light ratio run in the center of NGC 1316 resembles that of many other giant ellipticals, some of which are known from other evidence to harbor central massive dark objects (MDO's). We also examine twenty globular clusters associated with NGC 1316 and report their brightnesses, colors, and limits on tidal radii. The brightest cluster has a luminosity of 9.9 \times 10^6 L_{\sun} ($M_V = -12.7$), and the faintest detectable cluster has a luminosity of 2.4 \times 10^5 L_{\sun} ($M_V = -8.6$). The globular clusters are just barely resolved, but their core radii are too small to be measured. The tidal radii in this region appear to be $\le$ 35 pc. Although this galaxy seems to have undergone a substantial merger in the recent past, young globular clusters are not detected.Comment: 21 pages, latex, postscript figures available at ftp://delphi.umd.edu/pub/outgoing/eshaya/fornax

VII Zw 403: H I structure in a blue compact dwarf galaxy

‘In these times, during the rise in the popularity of institutional repositories, the Society does not forbid authors from depositing their work in such repositories. However, the AAS regards the deposit of scholarly work in such repositories to be a decision of the individual scholar, as long as the individual's actions respect the diligence of the journals and their reviewers.’ Original article can be found at : http://iopscience.iop.org/ Copyright American Astronomical SocietyWe present optical (UBVJ), ultraviolet (FUV, NUV), and high-resolution atomic hydrogen (H I) observations of the nearby blue compact dwarf (BCD), VII Zw 403. We find that VII Zw 403 has a relatively high H I mass-to-light ratio for a BCD. The rotation velocity is nominally 10-15 km s(-1), but rises to similar to 20 km s(-1) after correction for the similar to 8-10 km s(-1) random motions present in the gas. The velocity field is complex, including a variation in the position angle of the major axis going from the northeast to the southwest parts of the galaxy. Our high-resolution Hi maps reveal structure in the central gas, including a large, low-density Hi depression or hole between the southern and northern halves of the galaxy, coincident with an unresolved X-ray source. Although interactions have been proposed as the triggering mechanism for the vigorous star formation occurring in BCDs, VII Zw 403 does not seem to have been tidally triggered by an external interaction, as we have found no nearby possible perturbers. It also does not appear to fall in the set of galaxies that exhibit a strong central mass density concentration, as its optical scale length is large in comparison to similar systems. However, there are some features that are compatible with an accretion event: optical/Hi axis misalignment, a change in position angle of the kinematic axis, and a complex velocity field.Peer reviewe

Emerging role of the calcium-activated, small conductance, SK3 K ⁺ channel in distal tubule function: Regulation by TRPV4

The Ca2+-activated, maxi-K (BK) K+ channel, with low Ca2+-binding affinity, is expressed in the distal tubule of the nephron and contributes to flow-dependent K+ secretion. In the present study we demonstrate that the Ca2+-activated, SK3 (KCa2.3) K + channel, with high Ca2+-binding affinity, is also expressed in the mouse kidney (RT-PCR, immunoblots). Immunohistochemical evaluations using tubule specific markers demonstrate significant expression of SK3 in the distal tubule and the entire collecting duct system, including the connecting tubule (CNT) and cortical collecting duct (CCD). In CNT and CCD, main sites for K+ secretion, the highest levels of expression were along the apical (luminal) cell membranes, including for both principal cells (PCs) and intercalated cells (ICs), posturing the channel for Ca2+- dependent K+ secretion. Fluorescent assessment of cell membrane potential in native, split-opened CCD, demonstrated that selective activation of the Ca2+-permeable TRPV4 channel, thereby inducing Ca2+ influx and elevating intracellular Ca2+ levels, activated both the SK3 channel and the BK channel leading to hyperpolarization of the cell membrane. The hyperpolarization response was decreased to a similar extent by either inhibition of SK3 channel with the selective SK antagonist, apamin, or by inhibition of the BK channel with the selective antagonist, iberiotoxin (IbTX). Addition of both inhibitors produced a further depolarization, indicating cooperative effects of the two channels on Vm. It is concluded that SK3 is functionally expressed in the distal nephron and collecting ducts where induction of TRPV4-mediated Ca2+ influx, leading to elevated intracellular Ca2+ levels, activates this high Ca2+- affinity K+ channel. Further, with sites of expression localized to the apical cell membrane, especially in the CNT and CCD, SK3 is poised to be a key pathway for Ca2+-dependent regulation of membrane potential and K+ secretion. © 2014 Berrout et al

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo