Epicardial adipose tissue as a mediator of cardiac arrhythmias

Obesity is associated with higher risks of cardiac arrhythmias. Although this may be partly explained by concurrent cardiometabolic ill-health, growing evidence suggests that increasing adiposity independently confers risk for arrhythmias. Amongst fat depots, epicardial adipose tissue (EAT) exhibits a proinflammatory secretome, and given the lack of fascial separation, has been implicated as a transducer of inflammation to the underlying myocardium. The present review explores the mechanisms underpinning adverse electrophysiological remodelling as a consequence of EAT accumulation and the consequent inflammation. We first describe the physiological and pathophysiological function of EAT and its unique secretome, and subsequently discuss the evidence for ionic channel and connexin expression modulation as well as fibrotic remodelling induced by cytokines and free fatty acids that are secreted by EAT. Finally, we highlight how weight reduction and regression of EAT volume may cause reverse remodelling to ameliorate arrhythmic risk.

Embryonic Development of the Avian Sternum and Its Morphological Adaptations for Optimizing Locomotion

The sternum is part of the forelimb appendicular skeleton found in most terrestrial vertebrates and has become adapted across tetrapods for distinctive modes of locomotion. We review the regulatory mechanisms underlying sternum and forelimb development and discuss the possible gene expression modulation that could be responsible for the sternal adaptations and associated reduction in the forelimb programme found in flightless birds. In three phylogenetically divergent vertebrate lineages that all undertake powered flight, a ventral extension of the sternum, named the keel, has evolved independently, most strikingly in volant birds. In flightless birds, however, the sternal keel is absent, and the sternum is flattened. We review studies in a variety of species that have analysed adaptations in sterna morphology that are related to the animal’s mode of locomotion on land, in the sky and in water.

CRY1 Gene Polymorphism and Racing Performance of Homing Pigeons

Cryptochromes (CRY) are the family of proteins proposed as the putative magnetoreceptor molecules. In birds, among others in pigeons, CRY1 is widely expressed in a retina. Homing pigeons are known for their navigational abilities, and pigeon racing is a popular sport. So, the purpose of this study was to analyze the variability of the nucleotide sequence of the homing pigeon CRY1 gene, spanning the region coding the two amino acids W320 and W374 of Trp-triad, and estimate the relationship between genotypes and the racing performance. Investigations were carried out on 129 pigeons. Analysis of sequencing results indicated the AG to TT change within the seventh intron of CRY1 gene. Genotypes were determined by the forced PCR-RFLP method. The influence of detected polymorphism on the results of racing pigeons in 100–400 km flights was shown. The AG/TT individuals achieved significantly higher (p ≤ 0.05) mean values of ace points (AP) than the AG/AG ones. Regarding the detected nucleotide change localization, the polymorphism may be involved in CRY1 gene expression modulation. The AG to TT change in CRY1 gene may be considered as a potential genetic marker of racing performance in homing pigeons.

Chemically modified guide RNAs enhance CRISPR-Cas13 knockdown in human cells

RNA-targeting CRISPR-Cas13 proteins have recently emerged as a powerful platform to transiently modulate gene expression outcomes. However, protein and CRISPR RNA (crRNA) delivery in human cells can be challenging and knockdown can be transient due to rapid crRNA degradation. Here we compare several chemical RNA modifications at different positions to identify synthetic crRNAs that improve RNA targeting efficiency and half-life in human cells. We show that co-delivery of modified crRNAs and recombinant Cas13 enzyme in ribonucleoprotein (RNP) complexes enables transient gene expression modulation in primary CD4+ and CD8+ T-cells. This system represents a robust and efficient method to transiently modulate transcripts without genetic manipulation.

The effect of long-term doxycycline treatment in a mouse model of cigarette smoke-induced emphysema and pulmonary hypertension

Chronic obstructive pulmonary disease (COPD) is a major cause of death and a still incurable disease, comprising emphysema and chronic bronchitis. In addition to airflow limitation, COPD patients can suffer from pulmonary hypertension (PH). Doxycycline, an antibiotic from the tetracycline family, in addition to its pronounced antimicrobial activity, acts as a matrix metalloproteinase (MMP) inhibitor and has anti-inflammatory properties. Furthermore, doxycycline treatment exhibited a beneficial effect in several preclinical cardiovascular disease models. In preclinical research, doxycycline is frequently employed for gene expression modulation in Tet-On/Tet-Off transgenic animal models. Therefore, it is crucial to know whether doxycycline treatment in Tet-On/Tet-Off systems has effects independent of gene expression modulation by such systems. Against this background, we assessed the possible curative effects of long-term doxycycline administration in a mouse model of chronic CS exposure. Animals were exposed to CS for 8 months and then subsequently treated with doxycycline for additional 3 months in room-air conditions. Doxycycline decreased the expression of MMPs and general pro-inflammatory markers in the lungs from CS-exposed mice. This downregulation was, however, insufficient to ameliorate CS-induced emphysema or PH. Tet-On/Tet-Off induction by doxycycline in such models is a feasible genetic approach to study curative effects at least in established CS-induced emphysema and PH. However, we report several parameters that are influenced by doxycycline, and use of a Tet-On/Tet-Off system when evaluating those parameters should be interpreted with caution.