Interaction between Angiotensin II and BDNF in Modulating Sympathetic Nerve Activity

Over activation of the sympathetic nervous system is prevalent in many forms of cardiovascular disease such as chronic heart failure (CHF) and hypertension. Although increased neuronal renin-angiotensin system activity in presympathetic neurons has been well implicated in mediating this sympatho-excitation, many of the neuronal effects of angiotensin II (Ang II) signaling remain poorly understood. One particular mechanism of Ang II-mediated increases in presympathetic neuronal activity is through reductions in voltage-gated K+ currents. Another pathway that has profound effects on neuronal K+ currents and that has been previously implicated in Ang II-signaling is brain-derived neurotrophic factor (BDNF) activity through its receptor tyrosine kinase B (TrkB). Therefore, we hypothesized that BDNF/TrkB signaling is an important mediator of the neuronal effects of Ang II in modulating voltage-gated K+ currents and autonomic dysfunction in cardiovascular disease states such as CHF and hypertension. We employed cell culture and whole-animal models to explore this hypothesis and utilized electrophysiological, molecular, and in vivo physiological techniques. Patch-clamp studies demonstrated that BDNF is involved in Ang II-induced reductions to K+ currents. Further in-vivo experiments found that overexpression of Kv4.3 into the rostral ventrolateral medulla attenuates the increase in sympathetic nerve activity of rats post-myocardial infarction. Baroreflex dysfunction is common in CHF, and desensitization of central neuronal areas such as the nucleus tractus solitarius (NTS) can mediate this dysfunction. We therefore hypothesized that changes in BDNF/TrkB signaling in the NTS mediated baroreflex dysfunction in CHF. Blocking TrkB with ANA-12 in the NTS blunted baroreflex sensitivity in sham rats but had little effect on the already blunted baroreflex sensitivity of CHF rats. TrkB expression was reduced in CHF rats, implicating reduced BDNF/TrkB signaling in the NTS as a mechanism for reduced baroreflex sensitivity during CHF. In a final set of experiments we explored the connection between Ang II and BDNF in vivo. Central administration of Ang II increased mean arterial pressure and induced sympatho-excitation, both of which were attenuated by coinfusion of ANA-12. Overall, these data implicate BDNF as an important factor in mediating the neuronal effects of Ang II on K+ currents, hemodynamics, baroreflex sensitivity, and sympathetic nerve activity

BDNF contributes to angiotensin II-mediated reductions in peak voltage-gated K+ current in cultured CATH.a cells.

Increased central angiotensin II (Ang II) levels contribute to sympathoexcitation in cardiovascular disease states such as chronic heart failure and hypertension. One mechanism by which Ang II increases neuronal excitability is through a decrease in voltage-gated, rapidly inactivating K(+) current (IA); however, little is known about how Ang II signaling results in reduced IA. Brain-derived neurotrophic factor (BDNF) has also been demonstrated to decrease IA and has signaling components common to Ang II. Therefore, we hypothesized that Ang II-mediated suppression of voltage-gated K(+) currents is due, in part, to BDNF signaling. Differentiated CATH.a, catecholaminergic cell line treated with BDNF for 2 h exhibited a reduced IA in a manner similar to that of Ang II treatment as demonstrated by whole-cell patch-clamp analysis. Inhibiting BDNF signaling by pretreating neurons with an antibody against BDNF significantly attenuated the Ang II-induced reduction of IA. Inhibition of a common component of both BDNF and Ang II signaling, p38 MAPK, with SB-203580 attenuated the BDNF-mediated reductions in IA. These results implicate the involvement of BDNF signaling in Ang II-induced reductions of IA, which may cause increases in neuronal sensitivity and excitability. We therefore propose that BDNF may be a necessary component of the mechanism by which Ang II reduces IA in CATH.a cells

Creatinine-Based Estimations of Kidney Function Are Unreliable in Obese Kidney Donors

Accurate assessment of kidney function by measurement of glomerular filtration rate (GFR) is essential to the risk assessment of prospective living kidney donors. We evaluated the performance of various estimating equations for creatinine clearance (Cockcroft-Gault), GFR (Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration), and 24-hour urine collections for creatinine clearance in obese potential kidney donors. We evaluated 164 potential kidney donors including 49 with a BMI of 30–35 and 32 with a BMI >35 that have completed a routine living donor evaluation with a measured GFR. All the estimating equations performed poorly in obese donors. While 24-hour urine collections performed better, only 15% had an adequate 24-hour urine collection. Since obese kidney donors may be at higher than average risk for kidney failure, accurate assessment of kidney function in these donors is crucial to ensure their long-term health postdonation

Chandra Observations of the Crab-like Supernova Remnant G21.5-0.9

Chandra observations of the Crab-like supernova remnant G21.5-0.9 reveal a compact central core and spectral variations indicative of synchrotron burn-off of higher energy electrons in the inner nebula. The central core is slightly extended, perhaps indicating the presence of an inner wind-shock nebula surrounding the pulsar. No pulsations are observed from the central region, yielding an upper limit of ~40% for the pulsed fraction. A faint outer shell may be the first evidence of the expanding ejecta and blast wave formed in the initial explosion, indicating a composite nature for G21.5-0.9.Comment: 4 pages, 2 figures, formatted with emulateapj, submitted to ApJ

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Background Acute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor. Methods and Results Adult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction. Conclusions These findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress

Ecological study of the tidal segment of the James River encompassing Hog Point : 1975 final technical report

Volume 1: Technical Reports Section 1: River Biota and Phytoplankton Entrainment Studies at the VEPCO Surry Nuclear Power Station Section 2: Zooplankton Entrainment at the Surry Nuclear Power Plant, James River, Virginia by G. C. Grant and B. B. Bryan Section 3: a. Plant Entrainment of Ichthyoplankton at the VEPCO Nuclear Power Station by J. V. Merriner and A. D. Estes b: Thermal Plume Entrainment of Ichthyoplankton at the· VEPCO Nuclear Power Station by J. V. Merriner and A. D. Este

Discovery of X-ray Pulsations from the Compact Central Source in the Supernova Remnant 3C 58

We report on high time resolution observations of the SNR 3C 58 using the High Resolution Camera on the Chandra X-ray Observatory. These data show a point-like central source, from which we detect 65.68 ms pulsations at 6.7 sigma significance. We interpret these pulsations as corresponding to a young rotation-powered pulsar (PSR J-205+6449) which is associated with, and powers, 3C 58. Analysis of archival RXTE data from three years earlier confirms these pulsations, and allows us to determine a spin-down rate of P-dot=1.93x10^-13 s/s. Assuming a magnetic dipole model for PSR J0205+6449, we infer a surface magnetic field of 3.6x10^12 G. The characteristic age for this pulsar is 5400 yr, indicating either that 3C 58 was not the supernova of 1181 CE, or that the pulsar's initial spin period was ~60 ms.Comment: 11 pages, 4 figures, 1 tabl

Leptin is a four-helix bundle: secondary structure by NMR

AbstractLeptin is a signaling protein that in its mutant forms has been associated with obesity and Type II diabetes. The lack of sequence similarity has precluded analogies based on structural resemblance to known systems. Backbone NMR signals for mouse leptin (13C/15N -labeled) have been assigned and its secondary structure reveals it to be a four-helix bundle cytokine. Helix lengths and disulfide pattern are in agreement with leptin as a member of the short-helix cytokine family. A three-dimensional model was built verifying the mechanical consistency of the identified elements with a short-helix cytokine core

Helium reionization and the thermal proximity effect

We examine the temperature structure of the intergalactic medium IGM) surounding a hard radiation source, such as a Quasi-Stellar Object (QSO), as it responds to the onset of helium reionization by the source. We model the reionization using a radiative transfer (RT) code coupled to a particle-mesh (PM) N-body code. Neutral hydrogen and helium are initially ionized by a starburst spectrum, which is allowed to gradually evolve into a power law spectrum (fnu ~ nu^(-0.5)). Multiple simulations were performed with different times for the onset and dominance of the hard spectrum, with onset redshifts ranging from z = 3.5 to 5.5. The source is placed in a high-density region to mimic the expected local environment of a QSO. Simulations with the source placed in a low-density environment were also performed as control cases to explore the role of the environment on the properties of the surrounding IGM. We find in both cases that the IGM temperature within the HeIII region produced exceeds the IGM temperature before full helium reionization, resulting in a "thermal proximity effect", but that the temperature in the HeIII region increases systematically with distance from the source. With time the temperature relaxes with a reduced spread as a function of impact parameter along neighbouring lines of sight, although the trend continues to persist until z = 2. Such a trend could be detected using the widths of intervening metal absorption systems using high resolution, high signal-to-noise ratio spectra.Comment: 17 pages, 12 figures, for publication in MNRA

The Gaseous Environment of High-z Galaxies: Precision Measurements of Neutral Hydrogen in the Circumgalactic Medium of z ~ 2-3 Galaxies in the Keck Baryonic Structure Survey

We present results from the Keck Baryonic Structure Survey (KBSS), a unique spectroscopic survey designed to explore the connection between galaxies and intergalactic baryons. The KBSS is optimized for the redshift range z ~ 2-3, combining S/N ~ 100 Keck/HIRES spectra of 15 hyperluminous QSOs with densely sampled galaxy redshift surveys surrounding each QSO sightline. We perform Voigt profile decomposition of all 6000 HI absorbers within the full Lya forest in the QSO spectra. Here we present the distribution, column density, kinematics, and absorber line widths of HI surrounding 886 star-forming galaxies with 2.0 < z < 2.8 and within 3 Mpc of a QSO sightline. We find that N_HI and the multiplicity of HI components increase rapidly near galaxies. The strongest HI absorbers within ~ 100 physical kpc of galaxies have N_HI ~ 3 dex higher than those near random locations in the IGM. The circumgalactic zone of most enhanced HI absorption (CGM) is found within 300 kpc and 300 km/s of galaxies. Nearly half of absorbers with log(N_HI) > 15.5 are found within the CGM of galaxies meeting our photometric selection, while their CGM occupy only 1.5% of the cosmic volume. The spatial covering fraction, multiplicity of absorption components, and characteristic N_HI remain elevated to transverse distances of 2 physical Mpc. Absorbers with log(N_HI) > 14.5 are tightly correlated with the positions of galaxies, while absorbers with lower N_HI are correlated only on Mpc scales. Redshift anisotropies on Mpc scales indicate coherent infall toward galaxies, while on scales of ~100 physical kpc peculiar velocities of 260 km/s are indicated. The median Doppler widths of absorbers within 1-3 virial radii of galaxies are ~50% larger than randomly chosen absorbers of the same N_HI, suggesting higher gas temperatures and/or increased turbulence likely caused by accretion shocks and/or galactic winds.Comment: Accepted to Ap