The cardiomyocyte "redox rheostat": Redox signalling via the AMPK-mTOR axis and regulation of gene and protein expression balancing survival and death.

Reactive oxygen species (ROS) play a key role in development of heart failure but, at a cellular level, their effects range from cytoprotection to induction of cell death. Understanding how this is regulated is crucial to develop novel strategies to ameliorate only the detrimental effects. Here, we revisited the fundamental hypothesis that the level of ROS per se is a key factor in the cellular response by applying different concentrations of H2O2 to cardiomyocytes. High concentrations rapidly reduced intracellular ATP and inhibited protein synthesis. This was associated with activation of AMPK which phosphorylated and inhibited Raptor, a crucial component of mTOR complex-1 that regulates protein synthesis. Inhibition of protein synthesis by high concentrations of H2O2 prevents synthesis of immediate early gene products required for downstream gene expression, and such mRNAs (many encoding proteins required to deal with oxidant stress) were only induced by lower concentrations. Lower concentrations of H2O2 promoted mTOR phosphorylation, associated with differential recruitment of some mRNAs to the polysomes for translation. Some of the upregulated genes induced by low H2O2 levels are cytoprotective. We identified p21Cip1/WAF1 as one such protein, and preventing its upregulation enhanced the rate of cardiomyocyte apoptosis. The data support the concept of a "redox rheostat" in which different degrees of ROS influence cell energetics and intracellular signalling pathways to regulate mRNA and protein expression. This sliding scale determines cell fate, modulating survival vs death

The Selective Serotonin Reuptake Inhibitor Paroxetine, but not Fluvoxamine, Decreases Methamphetamine Conditioned Place Preference in Mice

Monoamine transporters are the main targets of methamphetamine (METH). Recently, we showed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), decreased METH conditioned place preference (CPP), suggesting that serotonin transporter (SERT) inhibition reduces the rewarding effects of METH. To further test this hypothesis, in the present study we investigated the effects of additional SSRIs, paroxetine and fluvoxamine, on METH CPP in C57BL/6J mice. In the CPP test, pretreatment with 20 mg/kg paroxetine abolished the CPP for METH, whereas pretreatment with 100 mg/kg fluvoxamine prior to administration of METH failed to inhibit METH CPP. These results suggest that paroxetine, a medication widely used to treat depression, may be a useful tool for treating METH dependence. Further, these data suggest that molecules other than the SERT [such as G protein-activated inwardly rectifying K+ (GIRK) channels] whose activities are modulated by paroxetine and fluoxetine, but not by fluvoxamine, are involved in reducing METH CPP by paroxetine and fluoxetine

Sustainability in astroparticle physics

The topic of sustainability is becoming increasingly important in research activities in astroparticle physics, both in existing and also in future instrument. At this year\u27s International cosmic ray conference (ICRC 2021) one session was dedicated to this topic. This publication will summarise the findings of this well-attended online session

Nanoscale noncollinear spin textures in thin Films of a D_2d Heusler compound

Magnetic nano-objects, namely antiskyrmions and Bloch skyrmions, have been found to coexist in single-crystalline lamellae formed from bulk crystals of inverse tetragonal Heusler compounds with D2d symmetry. Here evidence is shown for magnetic nano-objects in epitaxial thin films of Mn2RhSn formed by magnetron sputtering. These nano-objects exhibit a wide range of sizes with stability with respect to magnetic field and temperature that is similar to single-crystalline lamellae. However, the nano-objects do not form well-defined arrays, nor is any evidence found for helical spin textures. This is speculated to likely be a consequence of the poorer homogeneity of chemical ordering in the thin films. However, evidence is found for elliptically distorted nano-objects along perpendicular crystallographic directions within the epitaxial films, which is consistent with elliptical Bloch skyrmions observed in single-crystalline lamellae. Thus, these measurements provide strong evidence for the formation of noncollinear spin textures in thin films of Mn2RhSn. Using these films, it is shown that individual nano-objects can be deleted using a local magnetic field from a magnetic tip and collections of nano-objects can be similarly written. These observations suggest a path toward the use of these objects in thin films with D2d symmetry as magnetic memory elements

Shake table testing of a tuned mass damper inerter (Tmdi)-equipped structure and nonlinear dynamic modeling under harmonic excitations

This paper presents preliminary experimental results from a novel shaking table testing campaign investigating the dynamic response of a two-degree-of-freedom (2DOF) physical specimen with a grounded inerter under harmonic base excitation and contributes a nonlinear dynamic model capturing the behavior of the test specimen. The latter consists of a primary mass connected to the ground through a high damping rubber isolator (HDRI) and a secondary mass connected to the primary mass through a second HDRI. Further, a flywheel-based rack-and-pinion inerter prototype device is used to connect the secondary mass to the ground. The resulting specimen resembles the tuned mass damper inerter (TMDI) configuration with grounded inerter analytically defined and numerically assessed by the authors in a number of previous publications. Physical specimens with three different inerter coefficients are tested on the shake table under sine-sweep excitation with three different amplitudes. Experimental frequency response functions (FRFs) are derived manifesting a softening nonlinear behavior of the specimens and enhanced vibration suppression with increased inerter coefficient. Further, a 2DOF parametric nonlinear model of the specimen is established accounting for non-ideal inerter device behavior and its potential to characterize experimental response time-histories, FRFs, and force-displacement relationships of the HDRIs and of the inerter is verified

Long-Term Effects of Chronic Intermittent Ethanol Exposure in Adolescent and Adult Rats: Radial-Arm Maze Performance and Operant Food Reinforced Responding

Background: Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats. Methodology/Principal Findings: Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward ntegration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory. Conclusions/Significance: These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research

Uncertainties in dynamic response of buildings with non-linear base-isolators

Dynamic response of base-isolated buildings under uni-directional sinusoidal base excitation is numerically investigated considering uncertainties in the isolation and excitation parameters. The buildings are idealized as single degree of freedom (SDOF) system and multi-degrees of freedom (MDOF) system with one lateral degree of freedom at each floor level. The isolation system is modeled using two different mathematical models such as: (i) code-recommended equivalent linear elastic-viscous damping model and (ii) bi-linear hysteretic model. The uncertain parameters of the isolator considered are time period, damping ratio, and yield displacement. Moreover, the amplitude and frequency of the sinusoidal base excitation function are considered uncertain. The uncertainty propagation is investigated using generalized polynomial chaos (gPC) expansion technique. The unknown gPC expansion coefficients are obtained by non-intrusive sparse grid collocation scheme. Efficiency of the technique is compared with the sampling method of Monte Carlo (MC) simulation. The stochastic response quantities of interest considered are bearing displacement and top floor acceleration of the building. Effects of individual uncertain parameters on the building response are quantified using sensitivity analyses. Effect of various uncertainty levels of the input parameters on the dynamic response of the building is also investigated. The peak bearing displacement and top floor acceleration are more influenced by the amplitude and frequency of the sinusoidal base excitation function. The effective time period of the isolation system also produces a considerable influence. However, in the presence of similar uncertainty level in the time period, amplitude and frequency of the sinusoidal forcing function, the effect of uncertainties in the other parameters of the isolator (e.g., damping ratio and yield displacement) is comparatively less. Interestingly, the mean values of the response quantities are found to be higher than the deterministic values in several instances, indicating the need of conducting stochastic analysis. The gPC expansion technique presented here is found to be a computationally efficient yet accurate alternative to the MC simulation for numerically modeling the uncertainty propagation in the dynamic response analyses of the base-isolated buildings

Differential regulation of Krüppel-like factor family transcription factor expression in neonatal rat cardiac myocytes: effects of endothelin-1, oxidative stress and cytokines

Krüppel-like transcription factors (Klfs) modulate fundamental cell processes. Cardiac myocytes are terminally-differentiated, but hypertrophy in response to stimuli such as endothelin-1. H2O2 or cytokines promote myocyte apoptosis. Microarray studies of neonatal rat myocytes identified several Klfs as endothelin-1-responsive genes. We used quantitative PCR for further analysis of Klf expression in neonatal rat myocytes. In response to endothelin-1, Klf2 mRNA expression was rapidly increased ( approximately 9-fold; 15-30 min) with later increases in expression of Klf4 and Klf6 ( approximately 5-fold; 30-60 min). All were regulated as immediate early genes (cycloheximide did not inhibit the increases in expression). Klf5 expression was increased at 1-2 h ( approximately 13-fold) as a second phase response (cycloheximide inhibited the increase). These increases were transient and attenuated by U0126. H2O2 increased expression of Klf2, Klf4 and Klf6, but interleukin-1beta or tumor necrosis factor alpha downregulated Klf2 expression with no effect on Klf4 or Klf6. Of the Klfs which repress transcription, endothelin-1 rapidly downregulated expression of Klf3, Klf11 and Klf15. The dynamic regulation of expression of multiple Klf family members in cardiac myocytes suggests that, as a family, they are actively involved in regulating phenotypic responses (hypertrophy and apoptosis) to extracellular stimuli

Benign thyroid nodules respond to a single administration of 0.3mg recombinant human thyrotropin with highly variable volume increase

IntroductionThe nature of thyroid nodules is heterogenous. Most of them are benign and, in the absence of pressure symptoms of adjunct structures, no treatment is needed. Our objective was to investigate the acute effects of a low dose of recombinant human TSH (rhTSH) on the volume of benign thyroid nodules.Methodswe studied 27 nodules (14 isoechoic and 13 hypoechoic) in 15 (11 women and 4 men; mean age: 51.0 ± 15.9 years) consecutive patients with one to three well-separated asymptomatic benign thyroid nodules. All subjects were euthyroid, with negative thyroid antibodies, and none received levothyroxine. The total thyroid volume and thyroid nodule volume were sonographically determined by two independent examiners (P.B. and M.M.) before, 48 hours and 6 months post intramuscular (IM) administration of 0.3mg rhTSH, and the mean values of the two examiners’ measurements were used; thyroid function tests were obtained at the same time points.ResultsThe mean volume of isoechoic nodules increased by 57.3%, of hypoechoic nodules by 46.6% and of the surrounding thyroid parenchyma by 70.4% 48 hours post-rhTSH; mean volumes had returned to baseline levels 6 months later. A large variance in the volume change responses was observed. The relative change in nodule volume (defined as the percent change in nodule volume divided by the percent change in the surrounding parenchyma) from baseline to 48 hours was significantly higher in isoechoic versus hypoechoic nodules (p<0.05).ConclusionsA single dose of 0.3 mg rhTSH transiently increased the volume of benign thyroid nodules. The increase was more pronounced in isoechoic nodules and had a great variability. Our findings could be useful in the management of benign thyroid nodules, by helping in understanding which nodules would be more responsive to TSH suppression therapy