Cardiac hypertrophy is inhibited by a local pool of cAMP regulated by phosphodiesterase 2

Rationale: Chronic elevation of 3'-5'-cyclic adenosine monophosphate (cAMP) levels has been associated with cardiac remodelling and cardiac hypertrophy. However, enhancement of particular aspects of cAMP/protein kinase A (PKA) signalling appears to be beneficial for the failing heart. cAMP is a pleiotropic second messenger with the ability to generate multiple functional outcomes in response to different extracellular stimuli with strict fidelity, a feature that relies on the spatial segregation of the cAMP pathway components in signalling microdomains. Objective: How individual cAMP microdomains impact on cardiac pathophysiology remains largely to be established. The cAMP-degrading enzymes phosphodiesterases (PDEs) play a key role in shaping local changes in cAMP. Here we investigated the effect of specific inhibition of selected PDEs on cardiac myocyte hypertrophic growth. Methods and Results: Using pharmacological and genetic manipulation of PDE activity we found that the rise in cAMP resulting from inhibition of PDE3 and PDE4 induces hypertrophy whereas increasing cAMP levels via PDE2 inhibition is anti-hypertrophic. By real-time imaging of cAMP levels in intact myocytes and selective displacement of PKA isoforms we demonstrate that the anti-hypertrophic effect of PDE2 inhibition involves the generation of a local pool of cAMP and activation of a PKA type II subset leading to phosphorylation of the nuclear factor of activated T cells (NFAT). Conclusions: Different cAMP pools have opposing effects on cardiac myocyte cell size. PDE2 emerges as a novel key regulator of cardiac hypertrophy in vitro and in vivo and its inhibition may have therapeutic applications

MSK-Mediated Phosphorylation of Histone H3 Ser28 Couples MAPK Signalling with Early Gene Induction and Cardiac Hypertrophy

Heart failure is a leading cause of death that develops subsequent to deleterious hypertrophic cardiac remodelling. MAPK pathways play a key role in coordinating the induction of gene expression during hypertrophy. Induction of the immediate early gene (IEG) response including activator protein 1 (AP-1) complex factors is a necessary and early event in this process. How MAPK and IEG expression are coupled during cardiac hypertrophy is not resolved. Here, in vitro, in rodent models and in human samples, we demonstrate that MAPK-stimulated IEG induction depends on the mitogen and stress-activated protein kinase (MSK) and its phosphorylation of histone H3 at serine 28 (pH3S28). pH3S28 in IEG promoters in turn recruits Brg1, a BAF60 ATP-dependent chromatin remodelling complex component, initiating gene expression. Without MSK activity and IEG induction, the hypertrophic response is suppressed. These studies provide new mechanistic insights into the role of MAPK pathways in signalling to the epigenome and regulation of gene expression during cardiac hypertrophy

A computational pipeline for quantification of mouse myocardial stiffness parameters

The mouse is an important model for theoretical-experimental cardiac research, and biophysically based whole organ models of the mouse heart are now within reach. However, the passive material properties of mouse myocardium have not been much studied. We present an experimental setup and associated computational pipeline to quantify these stiffness properties. A mouse heart was excised and the left ventricle experimentally inflated from 0 to 1.44kPa in eleven steps, and the resulting deformation was estimated by echocardiography and speckle tracking. An in silico counterpart to this experiment was built using finite element methods and data on ventricular tissue microstructure from diffusion tensor MRI. This model assumed a hyperelastic, transversely isotropic material law to describe the force-deformation relationship, and was simulated for many parameter scenarios, covering the relevant range of parameter space. To identify well-fitting parameter scenarios, we compared experimental and simulated outcomes across the whole range of pressures, based partly on gross phenotypes (volume, elastic energy, and short- and long-axis diameter), and partly on node positions in the geometrical mesh. This identified a narrow region of experimentally compatible values of the material parameters. Estimation turned out to be more precise when based on changes in gross phenotypes, compared to the prevailing practice of using displacements of the material points. We conclude that the presented experimental setup and computational pipeline is a viable method that deserves wider application

Rømt oppdrettslaks i vassdrag i 2021 : Rapport fra det nasjonale overvåkningsprogrammet

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Reading religion in Norwegian textbooks: are individual religions ideas or people?

Different religions are treated in different ways in Norwegian sixth form textbooks. We carried out an exhaustive content analysis of the chapters devoted to individual religions in textbooks for the Religion and Ethics course currently available in Norway, using rigorous indicators to code each word, image and question according to whether they were treated the religion as a set of ideas or a group of people. After adjusting for trends in the different kinds of data (word, image, question), we found that Buddhism and Christianity receive significantly more attention for their ideas than Hinduism, Islam and Judaism, which are treated more as people. This difference cannot be explained by the national syllabus or the particularities of the individual religions. The asymmetry also has implications for the pupils’ academic, moral and pedagogical agency for which teachers play a critical role in compensating.acceptedVersio

Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle

Activation of 5-HT4 receptors in failing ventricles elicits a cAMP-dependent positive inotropic response which is mainly limited by the cGMP-inhibitable phosphodiesterase (PDE) 3. However, PDE4 plays an additional role which is demasked by PDE3 inhibition. The objective of this study was to evaluate the effect of cGMP generated by particulate and soluble guanylyl cyclase (GC) on the 5-HT4-mediated inotropic response. Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats, exhibiting heart failure 6 weeks after surgery. Contractility was measured in left ventricular preparations. Cyclic GMP was measured by EIA. In ventricular preparations, ANP or BNP displayed no impact on 5-HT4-mediated inotropic response. However, CNP increased the 5-HT4-mediated inotropic response as well as the β1-adrenoceptor (β1-AR)-mediated response to a similar extent as PDE3 inhibition by cilostamide. Pretreatment with cilostamide eliminated the effect of CNP. Inhibition of nitric oxide (NO) synthase and soluble GC by l-NAME and ODQ, respectively, attenuated the 5-HT4-mediated inotropic response, whereas the NO donor Sin-1 increased this response. The effects were absent during PDE3 inhibition, suggesting cGMP-dependent inhibition of PDE3. However, in contrast to the effects on the 5-HT4 response, Sin-1 inhibited whereas l-NAME and ODQ enhanced the β1-AR-mediated inotropic response. cGMP generated both by particulate (NPR-B) and soluble GC increases the 5-HT4-mediated inotropic response in failing hearts, probably through inhibition of PDE3. β1-AR and 5-HT4 receptor signalling are subject to opposite regulatory control by cGMP generated by soluble GC in failing hearts. Thus, cGMP from different sources is functionally compartmented, giving differential regulation of different Gs-coupled receptors

Considerations and consequences of allowing DNA sequence data as types of fungal taxa

Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.publishedVersionLicensed under a Creative Commons License BY-NC-ND-4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Attenuated Fatigue in Slow Twitch Skeletal Muscle during Isotonic Exercise in Rats with Chronic Heart Failure

During isometric contractions, slow twitch soleus muscles (SOL) from rats with chronic heart failure (chf) are more fatigable than those of sham animals. However, a muscle normally shortens during activity and fatigue development is highly task dependent. Therefore, we examined the development of skeletal muscle fatigue during shortening (isotonic) contractions in chf and sham-operated rats. Six weeks following coronary artery ligation, infarcted animals were classified as failing (chf) if left ventricle end diastolic pressure was >15mmHg. During isoflurane anaesthesia, SOL with intact blood supply was stimulated (1s on 1s off) at 30Hz for 15 min and allowed to shorten isotonically against a constant afterload. Muscle temperature was maintained at 37°C. In resting muscle, maximum isometric force (Fmax) and the concentrations of ATP and CrP were not different in the two groups. During stimulation, Fmax and the concentrations declined in parallel sham and chf. Fatigue, which was evident as reduced shortening during stimulation, was also not different in the two groups. The isometric force decline was fitted to a bi-exponential decay equation. Both time constants increased transiently and returned to initial values after approximately 200 s of the fatigue protocol. This resulted in a transient rise in baseline tension between stimulations, although this effect which was less prominent in chf than sham. Myosin light chain 2s phosphorylation declined in both groups after 100 s of isotonic contractions, and remained at this level throughout 15 min of stimulation. In spite of higher energy demand during isotonic than isometric contractions, both shortening capacity and rate of isometric force decline were as well or better preserved in fatigued SOL from chf rats than in sham. This observation is in striking contrast to previous reports which have employed isometric contractions to induce fatigue

Rømt oppdrettslaks i vassdrag i 2022 — Rapport fra det Nasjonale Overvåkningsprogrammet for Rømt Oppdrettslaks

Det nasjonale programmet for overvåking av rømt oppdrettslakshar vurdert innslaget av rømt oppdrettslaks i 195 vassdrag i 2022. Vassdragene som er overvåket, er valgt ut fra en rekke kriterier. Blant disse er god geografisk spredning, inkludering av de nasjonale laksevassdragene, og representasjon av vassdrag av ulik størrelse. Det har også blitt lagt vekt på å bygge videre på vassdrag med tidsserier og med gode lokale nettverk. Data ble samlet inn fra sportsfiske om sommeren, høstfiske, stamfiske og drivtellinger om høsten (også kalt gytefisktelling). De tre førstnevnte metodene er i hovedsak basert på stangfiske og skiller mellom rømt oppdrettslaks og villaks ved å undersøke fiskens skjell, noe som også gir et bilde av fiskens vekstbetingelser tidligere i livet. Drivtellinger innebærer at snorklere foretar en visuell inspeksjon av fisken i elven og teller opp og karakteriserer vill og rømt oppdrettet laks på basis av utseende i hele, eller deler av lakseførende strekning. I et flertall av elvene ble det benyttet mer enn én metode. Alle innsamlete data har vært gjennom en kvalitetssikringsprosess og har blitt gitt en score i henhold til en rekke kriterier for å få en vurdering av dataenes representativitet. Innslaget av rømt oppdrettslaks for hver elv presenteres som prosentandeler registrert ved de ulike metodene, samt som en 'årsprosent' som beregnes fra andel oppdrettslaks i sportsfisket og/eller høstfiske/stamfiske. Denne tar hensyn til at sportsfiske ofte gir et lavt, og høstfiske sannsynligvis et for høyt estimat av innslaget av rømt oppdrettslaks gjennom en sesong. Det ble beregnet årsprosent for 122 elver, og det presenteres data fra drivtellinger fra 131 elver.Rømt oppdrettslaks i vassdrag i 2022 — Rapport fra det Nasjonale Overvåkningsprogrammet for Rømt OppdrettslakspublishedVersio

Rømt oppdrettslaks i vassdrag i 2020 - Rapport fra det nasjonale overvåkningsprogrammet

I 2014 ble et nytt nasjonalt overvåkningsprogram for rømt oppdrettslaks i vassdrag utformet og etablert på oppdrag fra Fiskeridirektoratet etter føringer fra Nærings- og Fiskeridepartementet. Dette overvåkingsprogrammet bygger på tidligere overvåking som ble etablert i 1989. Det overordnete målet for programmet er å øke både kvantitet og kvalitet på overvåkningsdata som gir grunnlag for å estimere prosentandel rømt oppdrettslaks i vassdrag. Denne rapporten oppsummerer resultatene fra undersøkelser utført i 2020.publishedVersio