Inhibition of AP-1 signaling by JDP2 overexpression protects cardiomyocytes against hypertrophy and apoptosis induction

AimsExpression and activity of the transcription factor AP-1 are enhanced during cardiac remodelling and heart failure progression. In order to test if AP-1 inhibition may limit processes contributing to cardiac remodelling, ventricular cardiomyocytes of mice with cardiac overexpression of the AP-1 inhibitor JDP2 were analysed under stimulation of hypertrophy, apoptosis, or contractile function.Methods and resultsThree models of JDP2 overexpressing mice were analysed: JDP2 was overexpressed either life-long, for 7 weeks, or 1 week. Then cardiomyocytes were isolated and stimulated with β-adrenoceptor agonist isoprenaline (ISO, 50 nM). This enhanced cross-sectional area and the rate of protein synthesis in WT but not in JDP2 overexpressing cardiomyocytes. To induce apoptosis, cardiomyocytes were stimulated with 3 ng/mL TGFβ1. Again, JDP2 overexpression prevented apoptosis induction compared with WT cells. Determination of contractile function under electrical stimulation at 2 Hz revealed enhancement of cell shortening, and contraction and relaxation velocities under increasing ISO concentrations (0.3-30 nM) in WT cells. This inotropic effect was abrogated in JDP2 overexpression cells. Responsiveness to increased extracellular calcium concentrations was also impaired in JDP2 overexpressing cardiomyocytes. Simultaneously, a reduction of SERCA expression was found in JDP2 mice.ConclusionA central role of AP-1 in the induction of hypertrophy and apoptosis in cardiomyocytes is demonstrated. Besides these protective effects of AP-1 inhibition on factors of cardiac remodelling, AP-1-inhibition impairs contractile function. Therefore, AP-1 acts as a double-edged sword that mediates mal-adaptive cardiac remodelling, but is required for maintaining a proper contractile function of cardiomyocytes. © 2013 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2013

A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin

Ruthenium complexes are considered as potential replacements for platinum compounds in oncotherapy. Their clinical development is handicapped by a lack of consensus on their mode of action. In this study, we identify three histones (H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium compound (RDC11). Using purified histones, we confirmed an interaction between the ruthenium complex and histones that impacted on histone complex formation. A comparative study of the ruthenium complex versus cisplatin showed differential epigenetic modifications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modifications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures specific for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to specificities distinguishing the ruthenium complex from cisplatin. For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways. To further understand the role of HDACs in these regulations, we used suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin cytotoxicity while antagonizing the ruthenium complex activity. This study provides critical information for the characterization of signaling pathways differentiating both compounds, in particular, by the identification of a non-DNA direct target for an organoruthenium complex

Early structural remodeling and deuterium oxide-derived protein metabolic responses to eccentric and concentric loading in human skeletal muscle

We recently reported that the greatest distinguishing feature between eccentric (ECC) and concentric (CON) muscle loading lays in architectural adaptations: ECC favors increases in fascicle length (Lf), associated with distal vastus lateralis muscle (VL) hypertrophy, and CON increases in pennation angle (PA). Here, we explored the interactions between structural and morphological remodeling, assessed by ultrasound and dual x‐ray absorptiometry (DXA), and long‐term muscle protein synthesis (MPS), evaluated by deuterium oxide (D2O) tracing technique. Ten young males (23 ± 4 years) performed unilateral resistance exercise training (RET) three times/week for 4 weeks; thus, one‐leg trained concentrically while the contralateral performed ECC exercise only at 80% of either CON or ECC one repetition maximum (1RM). Subjects consumed an initial bolus of D2O (150 mL), while a 25‐mL dose was thereafter provided every 8 days. Muscle biopsies from VL midbelly (MID) and distal myotendinous junction (MTJ) were collected at 0 and 4‐weeks. MPS was then quantified via GC–pyrolysis–IRMS over the 4‐week training period. Expectedly, ECC and CON RET resulted in similar increases in VL muscle thickness (MT) (7.5% vs. 8.4%, respectively) and thigh lean mass (DXA) (2.3% vs. 3%, respectively), albeit through distinct remodeling: Lf increasing more after ECC (5%) versus CON (2%) and PA increasing after CON (7% vs. 3%). MPS did not differ between contractile modes or biopsy sites (MID‐ECC: 1.42 vs. MID‐CON: 1.4% day−1; MTJ‐ECC: 1.38 vs. MTJ‐CON: 1.39% day−1). Muscle thickness at MID site increased similarly following ECC and CON RET, reflecting a tendency for a contractile mode‐independent correlation between MPS and MT (P = 0.07; R2 = 0.18). We conclude that, unlike MT, distinct structural remodeling responses to ECC or CON are not reflected in MPS; the molecular mechanisms of distinct protein deposition, and/or the role of protein breakdown in mediating these responses remain to be defined

p90 ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to Gq protein-coupled receptor stimuli, endothelin-1 and α1-adrenergic receptor agonists

Extracellular signal-regulated kinases 1/2 (ERK1/2) and their substrates, p90 ribosomal S6 kinases (RSKs), phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes, ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. Here, we investigated the role of RSKs in the transcriptomic responses to Gq protein-coupled receptor agonists, endothelin-1, phenylephrine (generic α1-adrenergic receptor agonist) and A61603 (α1A-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2-3 min of stimulation (endothelin-1>a61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of 213 RNAs upregulated at 1 h, 51% required RSKs for upregulation whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical to, endothelin-1. As with endothelin-1, PD184352 inhibited upregulation of most phenylephrine-responsive transcripts, but the greater variation in effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α1A-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, upregulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus, RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to Gq protein-coupled receptor stimulation

Is baseline aerobic fitness associated with illness and attrition rate in military training?

Background Respiratory illnesses are a leading cause of morbidity and medical discharge in the military. This study aimed to investigate the effects of baseline aerobic fitness on haematological, salivary and mood variables, and simultaneously, in a novel approach, to identify factors precipitating illness and attrition rate in recruits during military training. Methods Thirty-five healthy male recruits from an Army Training Regiment undertaking 12 weeks of training were prospectively investigated. Their 2.4 km run time (RT) was used as a surrogate of baseline aerobic fitness. Saliva and venous blood samples were analysed for secretory IgA, full blood counts and cell cytokine production (interleukin (IL) 6 and IL-8), respectively. Each recruit completed questionnaires on mood profile, and gastrointestinal and upper respiratory tract symptoms (URTS). Results Significant salivary and haematological perturbations were observed and coincided with increased duration of URTS/week and mood disturbance over this military training period. From Start to End: leucocyte count decreased by 28% ( p<0.001); neutrophil percentage (%) decreased by 13% (p<0.01); lymphocyte % increased by 17% (p<0.05); the neutrophil:lymphocyte ratio decreased by 22% (p<0.01); eosinophil% increased by 71% (p<0.01). From Start to Mid to End: monocyte% increased by 68% at Mid (p<0.01) but only by 30% at End (p<0.01); IL-6 increased by 39% at Mid (p<0.01) and a further 61% by End. The 2.4 km RT was significantly associated with URTS duration (p<0.01). In addition, a 1-min increase in 2.4 km RT increased a recruit’s risk 9.8-fold of developing URTS lasting, on average, 3.36 days/week. In recruits ranked with high-URTS duration their RT was 48 s slower (p<0.01) than those with low-URTS, and their attrition rate reached 45%. Conclusions The least fit recruits may have found training more physically demanding as reflected in the higher URTS duration, which may have led to a high attrition rate from the Army. It is worth considering that baseline aerobic fitness might be an important factor in illness development and attrition rate in recruits during this type of military training

Muscle structural assembly and functional consequences.

The relationship between muscle structure and function has been a matter of investigation since the Renaissance period. Extensive use of anatomical dissections and the introduction of the scientific method enabled early scholars to lay the foundations of muscle physiology and biomechanics. Progression of knowledge in these disciplines led to the current understanding that muscle architecture, together with muscle fibre contractile properties, has a major influence on muscle mechanical properties. Recently, advances in laser diffraction, optical microendoscopy and ultrasonography have enabled in vivo investigations into the behaviour of human muscle fascicles and sarcomeres with varying joint angle and muscle contraction intensity. With these technologies it has become possible to identify the length region over which fascicles and sarcomeres develop maximum isometric force in vivo as well as the operating ranges of fascicles and sarcomeres during real-life activities such as walking. Also, greater insights into the remodelling of muscle architecture in response to overloading and unloading, and in ageing, have been obtained by the use of ultrasonography; these have led to the identification of clinical biomarkers of disuse atrophy and sarcopenia. Recent evidence also shows that the pattern of muscle hypertrophy in response to chronic loading is contraction-mode dependent (eccentric versus concentric), as similar gains in muscle mass, but through differing addition of sarcomeres in series and in parallel (as indirectly inferred from changes in fascicle length and pennation angle), have been found. These innovative observations prompted a new set of investigations into the molecular mechanisms regulating this contraction-specific muscle growth

RANCANG BANGUN DESAIN INTERNET OF THINGS UNTUK PEMANTAUAN KUALITAS UDARA PADA STUDI KASUS POLUSI UDARA

Build, design and develop an Internet of Things design to monitor air quality in thewild with air pollution case studies. By utilizing the ESP-8266 type wifi modulemicrocontroller as the control center for the devices built by adding an IC4051 AnalogMultiplexer as a branching process from 1 analog channel to 7 analog channels. There are5 sensors used, namely CO (MQ-7), CO2 (Analog Infrared CO2), Dust Sensors (PM10),DHT-11 (Temperature &amp; Humidity) and Wind speed &amp; direction. Data recording locationand data monitoring using third party protocol, namely Ubidots.The research was conducted in 2 different locations with the time determined, namelyin the area of the UPR Informatics Engineering Department area and also in the village ofTanjung Taruna, Jabiren Raya District, Pulang Pisau Regency along with the Team of theKopernik Bali Foundation.The results of the study will be analyzed using the AQI (Air Quality Index) standardwhich is also the same as that of the BMKG as an air quality index index. By using realtimeinternet of things technology, it can make it easy to get information about the level of airquality in the wild quickly, efficiently, and the monitoring process can be done anywhereand anytime

The economic trade-offs of large language models: A case study

Contacting customer service via chat is a common practice. Because employing customer service agents is expensive, many companies are turning to NLP that assists human agents by auto-generating responses that can be used directly or with modifications. Large Language Models (LLMs) are a natural fit for this use case; however, their efficacy must be balanced with the cost of training and serving them. This paper assesses the practical cost and impact of LLMs for the enterprise as a function of the usefulness of the responses that they generate. We present a cost framework for evaluating an NLP model's utility for this use case and apply it to a single brand as a case study in the context of an existing agent assistance product. We compare three strategies for specializing an LLM - prompt engineering, fine-tuning, and knowledge distillation - using feedback from the brand's customer service agents. We find that the usability of a model's responses can make up for a large difference in inference cost for our case study brand, and we extrapolate our findings to the broader enterprise space.Comment: Paper to be published at the Association for Computational Linguistics in the Industry Track 202