The role of dihydropydine-sensitive Ca2 + channels in stimulus-evoked catecholamine release from chemoreceptor cells of the carotid body

Producción CientíficaAhatraet-The present study utilized an in vitro preparation of the rabbit carotid body, with tissue catecholamine stores labeled by incubation with ‘H-tyrosine. The goal was to characterize pharmacologically the vol~g~~n&nt Ca*+ channels present in the type I (glomus) cells of this arterial chemoreceptor organ, and to elucidate their role as pathways for Ca2+ entry. We found that release of ‘H-dopamine induced by high external potassium was over 95% dependent on external cakium concentration and that this release was 9&100% inhibited by the dihydropy~~ne antagonists, nisoldipine and nitrendipine, and was potentiated by the dihydropyridine agonist, BayK 8444. Therefore, any stimulus-induced, cakiumdependent release of 3H-dopamine that was inhibited by nisoldipine and potentiated by BayK 8644, was considered to be supported by Ca2+ entry into the cells via voltage-dependent Ca2+ channels. Significant differences were observed in the release of ‘H-dopamine induced by 75 vs 25mM K+. On prolonged stimulation, release induced by 75 mM K+ was large and transient, whilst that induced by 25 mM K+, although more moderate, was sustained. The release elicited by 75 mM K+ was inhibited approximately 90% by 1.5 mM Co2+ or 625 nM nisoldipine, while release by 25 mM K+ was completely blocked by 0.6 mM Co*+ or 125 nM nisoldipine. Low PO,-induced release of 3H-dopamine was 95% dependent on Ca*+, and was inhibited by nisoldipine (625 nM) in a manner inversely proportional to the intensity of hypoxic stimulation, i.e. 79% inhibition at a PO, of 49 Torr, and 20% inhibition at PO2 of 0 Torr. BayK 8644 potentiatcd the release induced by moderate hypoxic stimuli. Release elicited by high PCOJlow pH, or by Na+-propionate or dinitrophenol~n~ining solutions, was approximately 80% Ca’+-dependent, and the ~hyd~y~din~ failed to modify this release. It is concluded that type I mlls possess vol~~de~nd~t Ca ‘+ channels sensitive to the dihydropy~dines, which in agreement with previous el~trophysiolo~~l data should be defined as L-type Ca*+ channels. Calcium entry which supports the release of 3H-dopamine elicited by moderate hypoxia should occur mainly through these channels while the release induced by strong hypoxic stimuli will be SetNed by Ca2+ entry which occurs in part via voltage-dependent Ca2+ channels, and in part through an additional pathway, probably a Na+/Ca2+ exchanger. The insensitivity to dihydropyridines of the release of )H-dopamine induced by high 1DC02/low pH, Na+-propionate and dinitrophenol may indicate a complete loss of efficacy of the drugs to modulate Ca 2+ channels under these conditions or more likely, that other mechanisms are activated, probably the Na+-Ca’+ exchanger. Carotid body (CB) chemoreceptors are thought to be composite receptors in which the type I (glomus) cells detect changes in blood PO,, PCO, and pH and respond with the release of neurotransmitt~ to activate the closely apposed chemosensory nerve terminals.~** One such neurotransmitter that has received considerable attention in recent years and is known to be released by the type I cells is dopamine (DA). This biogenic amine has been shown to be released in proportion to both the intensity of stimulation and the resultant sensory discharge recorded from the carotid sinus nerve $To whom correspondence should be addressed. Abbr~~~~~~ CB, carotid body; CSN, carotid sinus nerve; DA, dopamine; DHMA, dihydrox~~delic acid, DOPAC, dihydroxyphenyl acetic acid; NE, norepinephrine. (CSN). This relationship between stimulu

A Cryogenic Silicon Interferometer for Gravitational-wave Detection

The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument that will have 5 times the range of Advanced LIGO, or greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby universe, as well as observing the universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

First searches for optical counterparts to gravitational-wave candidate events

During the Laser Interferometer Gravitational-wave Observatory and Virgo joint science runs in 2009-2010, gravitational wave (GW) data from three interferometer detectors were analyzed within minutes to select GW candidate events and infer their apparent sky positions. Target coordinates were transmitted to several telescopes for follow-up observations aimed at the detection of an associated optical transient. Images were obtained for eight such GW candidates. We present the methods used to analyze the image data as well as the transient search results. No optical transient was identified with a convincing association with any of these candidates, and none of the GW triggers showed strong evidence for being astrophysical in nature. We compare the sensitivities of these observations to several model light curves from possible sources of interest, and discuss prospects for future joint GW-optical observations of this type. © 2014. The American Astronomical Society. All rights reserved

A cryogenic silicon interferometer for gravitational-wave detection

The detection of gravitational waves from compact binary mergers by LIGO has opened the era of gravitational wave astronomy, revealing a previously hidden side of the cosmos. To maximize the reach of the existing LIGO observatory facilities, we have designed a new instrument able to detect gravitational waves at distances 5 times further away than possible with Advanced LIGO, or at greater than 100 times the event rate. Observations with this new instrument will make possible dramatic steps toward understanding the physics of the nearby Universe, as well as observing the Universe out to cosmological distances by the detection of binary black hole coalescences. This article presents the instrument design and a quantitative analysis of the anticipated noise floor

First searches for optical counterparts to gravitational-wave candidate events

During the Laser Interferometer Gravitational-wave Observatory and Virgo joint science runs in 2009-2010, gravitational wave (GW) data from three interferometer detectors were analyzed within minutes to select GW candidate events and infer their apparent sky positions. Target coordinates were transmitted to several telescopes for follow-up observations aimed at the detection of an associated optical transient. Images were obtained for eight such GW candidates. We present the methods used to analyze the image data as well as the transient search results. No optical transient was identified with a convincing association with any of these candidates, and none of the GW triggers showed strong evidence for being astrophysical in nature. We compare the sensitivities of these observations to several model light curves from possible sources of interest, and discuss prospects for future joint GW-optical observations of this type. © 2014. The American Astronomical Society. All rights reserved

Trajectories in Argentine children’s literature: Constancio C. Vigil and Horacio Quiroga

Children's author and publishing entrepreneur Constancio C. Vigil was a Uruguayan who spent most of his working life in Argentina. He was best known for his children's magazine Billiken (1919 to present). Vigil's contemporary and compatriot Horacio Quiroga also made the move across the River Plate and went on to have a transformative impact on Argentine literary culture, in part through his Jungle Tales for Children (1924). Both Quiroga and Vigil aspired to have their works for children accepted as school reading books, recognising the role of school authorities in the formation of the national canon. Vigil and Quiroga's trajectories of inclusion and exclusion, and their extraordinary contribution to the Argentine and Latin American cultural landscape in the first half of the twentieth century, provide a window onto the curation of an Argentine national children's literature at the same time as challenging the very nature of such a category

Prediction and Testing of Biological Networks Underlying Intestinal Cancer

Colorectal cancer progresses through an accumulation of somatic mutations, some of which reside in so-called “driver” genes that provide a growth advantage to the tumor. To identify points of intersection between driver gene pathways, we implemented a network analysis framework using protein interactions to predict likely connections – both precedented and novel – between key driver genes in cancer. We applied the framework to find significant connections between two genes, Apc and Cdkn1a (p21), known to be synergistic in tumorigenesis in mouse models. We then assessed the functional coherence of the resulting Apc-Cdkn1a network by engineering in vivo single node perturbations of the network: mouse models mutated individually at Apc (Apc1638N+/−) or Cdkn1a (Cdkn1a−/−), followed by measurements of protein and gene expression changes in intestinal epithelial tissue. We hypothesized that if the predicted network is biologically coherent (functional), then the predicted nodes should associate more specifically with dysregulated genes and proteins than stochastically selected genes and proteins. The predicted Apc-Cdkn1a network was significantly perturbed at the mRNA-level by both single gene knockouts, and the predictions were also strongly supported based on physical proximity and mRNA coexpression of proteomic targets. These results support the functional coherence of the proposed Apc-Cdkn1a network and also demonstrate how network-based predictions can be statistically tested using high-throughput biological data