Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling

In platelets, the nitric oxide (NO)–induced cGMP response is indicative of a highly regulated interplay of cGMP formation and cGMP degradation. Recently, we showed that within the NO-induced cGMP response in human platelets, activation and phosphorylation of phosphodiesterase type 5 (PDE5) occurred. Here, we identify cyclic GMP-dependent protein kinase I as the kinase responsible for the NO-induced PDE5 phosphorylation. However, we demonstrate that cGMP can directly activate PDE5 without phosphorylation in platelet cytosol, most likely via binding to the regulatory GAF domains. The reversal of activation was slow, and was not completed after 60 min. Phosphorylation enhanced the cGMP-induced activation, allowing it to occur at lower cGMP concentrations. Also, in intact platelets, a sustained NO-induced activation of PDE5 for as long as 60 min was detected. Finally, the long-term desensitization of the cGMP response induced by a low NO concentration reveals the physiological relevance of the PDE5 activation within NO/cGMP signaling. In sum, we suggest NO-induced activation and phosphorylation of PDE5 as the mechanism for a long-lasting negative feedback loop shaping the cGMP response in human platelets in order to adapt to the amount of NO available

Rapid nitric oxide–induced desensitization of the cGMP response is caused by increased activity of phosphodiesterase type 5 paralleled by phosphorylation of the enzyme

Most of the effects of the signaling molecule nitric oxide (NO) are mediated by cGMP, which is synthesized by soluble guanylyl cyclase and degraded by phosphodiesterases. Here we show that in platelets and aortic tissue, NO led to a biphasic response characterized by a tremendous increase in cGMP (up to 100-fold) in less than 30 s and a rapid decline, reflecting the tightly controlled balance of guanylyl cyclase and phosphodiesterase activities. Inverse to the reported increase in sensitivity caused by NO shortage, concentrating NO attenuated the cGMP response in a concentration-dependent manner. We found that guanylyl cyclase remained fully activated during the entire course of the cGMP response; thus, desensitization was not due to a switched off guanylyl cyclase. However, when intact platelets were incubated with NO and then lysed, enhanced activity of phosphodiesterase type 5 was detected in the cytosol. Furthermore, this increase in cGMP degradation is paralleled by the phosphorylation of phosphodiesterase type 5 at Ser-92. Thus, our data suggest that NO-induced desensitization of the cGMP response is caused by the phosphorylation and subsequent activity increase of phosphodiesterase type 5

Absolute frequency measurement of the magnesium intercombination transition 1S0→3P1^1S_0 \to ^3P_1

We report on a frequency measurement of the $(3s^2)^1S_0\to(3s3p)^3P_1$ clock transition of $^{24}$Mg on a thermal atomic beam. The intercombination transition has been referenced to a portable primary Cs frequency standard with the help of a femtosecond fiber laser frequency comb. The achieved uncertainty is $2.5\times10^{-12}$ which corresponds to an increase in accuracy of six orders of magnitude compared to previous results. The measured frequency value permits the calculation of several other optical transitions from $^1S_0$ to the $^3P_J$-level system for $^{24}$Mg, $^{25}$Mg and $^{26}$Mg. We describe in detail the components of our optical frequency standard like the stabilized spectroscopy laser, the atomic beam apparatus used for Ramsey-Bord\'e interferometry and the frequency comb generator and discuss the uncertainty contributions to our measurement including the first and second order Doppler effect. An upper limit of $3\times10^{-13}$ in one second for the short term instability of our optical frequency standard was determined by comparison with a GPS disciplined quartz oscillator.Comment: 8 pages, 8 figure

Interactions of Bacillus Mojavensis and Fusarium Verticillioides With a Benzoxazolinone (Boa) and Its Transformation Product, Apo

En:Journal of Chemical Ecology (2007, vol. 33, n. 10, p. 1885-1897)The benzoxazolinones, specifically benzoxazolin-2(3H)-one (BOA), are important transformation products of the benzoxazinones that can serve as allelochemicals providing resistance to maize from pathogenic bacteria, fungi, and insects. However, maize pathogens such as Fusarium verticillioides are capable of detoxifying the benzoxazolinones to 2-aminophenol (AP), which is converted to the less toxic N-(2-hydroxyphenyl) malonamic acid (HPMA) and 2-acetamidophenol (HPAA). As biocontrol strategies that utilize a species of endophytic bacterium, Bacillus mojavensis, are considered efficacious as a control of this Fusarium species, the in vitro transformation and effects of BOA on growth of this bacterium was examined relative to its interaction with strains of F. verticillioides. The results showed that a red pigment was produced and accumulated only on BOA-amended media when wild type and the progeny of genetic crosses of F. verticillioides are cultured in the presence of the bacterium. The pigment was identified as 2-amino-3H-phenoxazin-3-one (APO), which is a stable product. The results indicate that the bacterium interacts with the fungus preventing the usual transformation of AP to the nontoxic HPMA, resulting in the accumulation of higher amounts of APO than when the fungus is cultured alone. APO is highly toxic to F. verticillioides and other organisms. Thus, an enhanced biocontrol is suggested by this in vitro study. =580 $aEn:Journal of Chemical Ecolog

β\beta-BaB2_2O4_4 deep UV monolithic walk-off compensating tandem

The generation of watt-level cw narrow-linewidth sources at specific deep UV wavelengths corresponding to atomic cooling transitions usually employs external cavity-enhanced second-harmonic generation (SHG) of moderate-power visible lasers in birefringent materials. In this work, we investigate a novel approach to cw deep-UV generation by employing the low-loss BBO in a monolithic walkoff-compensating structure [Zondy {\it{et al}}, J. Opt. Soc. Am. B {\bf{20}} (2003) 1675] to simultaneously enhance the effective nonlinear coefficient while minimizing the UV beam ellipticity under tight focusing. As a preliminary step to cavity-enhanced operation, and in order to apprehend the design difficulties stemming from the extremely low acceptance angle of BBO, we investigate and analyze the single-pass performance of a $L_c=8$mm monolithic walk-off compensating structure made of 2 optically-contacted BBO plates cut for type-I critically phase-matched SHG of a cw $\lambda=570.4$nm dye laser. As compared with a bulk crystal of identical length, a sharp UV efficiency enhancement factor of 1.65 has been evidenced with the tandem structure, but at $\sim-1$nm from the targeted fundamental wavelength, highlighting the sensitivity of this technique when applied to a highly birefringent material such as BBO. Solutions to angle cut residual errors are identified so as to match accurately more complex periodic-tandem structure performance to any target UV wavelength, opening the prospect for high-power, good beam quality deep UV cw laser sources for atom cooling and trapping.Comment: 21 pages, 8 figures, to appear in Opt. Commu

Resistance to Wheat streak mosaic virus identified in synthetic wheat lines

Citation: Shoup Rupp, J. L., Simon, Z. G., Gillett-Walker, B., & Fellers, J. P. (2014). Resistance to Wheat streak mosaic virus identified in synthetic wheat lines. Retrieved from http://krex.ksu.eduWheat streak mosaic virus (WSMV) is an important pathogen in wheat that causes significant yield losses each year. WSMV is typically controlled using cultural practices such as the removal of volunteer wheat. Genetic resistance is limited. Until recently, no varieties have been available with major resistance genes to WSMV. Two resistance genes have been derived from Thinopyrum intermedium through chromosome engineering, while a third gene was transferred from bread wheat through classical breeding. New sources of resistance are needed and synthetic wheat lines provide a means of accessing genetic variability in wheat progenitors. A collection of wheat synthetic lines was screened for WSMV resistance. Four lines, 07-SYN-27, -106, -164, and -383 had significant levels of resistance. Resistance was effective at 18 °C and virus accumulation was similar to the resistant control, WGGRC50 containing Wsm1. At 25 °C, resistance was no longer effective and virus accumulation was similar to the susceptible control, Tomahawk

Remote frequency measurement of the 1S0-3P1 transition in laser cooled Mg-24

We perform Ramsey-Bord\'e spectroscopy on laser-cooled magnesium atoms in free fall to measure the 1S0 \rightarrow 3P1 intercombination transition frequency. The measured value of 655 659 923 839 730 (48) Hz is consistent with our former atomic beam measurement (Friebe et al 2008 Phys. Rev. A 78 033830). We improve upon the fractional accuracy of the previous measurement by more than an order of magnitude to 7e-14. The magnesium frequency standard was referenced to a fountain clock of the Physikalisch-Technische Bundesanstalt (PTB) via a phase-stabilized telecom fiber link and its stability was characterized for interrogation times up to 8000 s. The high temperature of the atomic ensemble leads to a systematic shift due to the motion of atoms across the spectroscopy beams. In our regime, this leads to a counterintuitive reduction of residual Doppler shift with increasing resolution. Our theoretical model of the atom-light interaction is in agreement with the observed effect and allows us to quantify its contribution in the uncertainty budget.Comment: 16 pages, 8 figures. Accepted in New Journal of Physic

The Concise Guide to PHARMACOLOGY 2023/24:Catalytic receptors

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and nearly 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16180. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.</p