Transgenic rabbit models for cardiac disease research.

To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and whole heart levels need to be considered. As in vitro cell-based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research, however, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical, and structural cardiac characteristics of rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of transgenic rabbits for cardiac disease research - such as pronuclear microinjection, the sleeping beauty transposon system and novel genome editing methods (ZFN and CRISPR/Cas9) - will be discussed. In the second section, we will introduce the different currently available transgenic rabbit models for monogenic cardiac diseases (such as long-QT syndrome, short-QT syndrome, and hypertrophic cardiomyopathy) in detail, especially in regards to their utility to increase the understanding of pathophysiological disease-mechanisms and novel treatment options

Active deformation evidence in the offshore of western Calabria (southern Tyrrhenian Sea) from ultra-resolution multichannel seismic reflection data: results from the Gulf of Sant'Eufemia

An ultra-resolution, multichannel seismic reflection data set was collected during an oceanographic cruise organised in the frame of the “Earthquake Potential of Active Faults using offshore Geological and Morphological Indicators” (EPAF) project, which was founded by the Scientific and Technological Cooperation (Scientific Track 2017) between the Italian Ministry of Foreign Affairs and International Cooperation and the Ministry of Science, Technology and Space of the State of Israel. The data acquisition approach was based on innovative technologies for the offshore imaging of stratigraphy and structures along continental margins with a horizontal and vertical resolution at decimetric scale. In this work, we present the methodology used for the 2D HR-seismic reflection data acquisition and the preliminary interpretation of the data set. The 2D seismic data were acquired onboard the R/V Atlante by using an innovative data acquisition equipment composed by a dual-sources Sparker system and one HR 48-channel, slant streamers, with group spacing variable from 1 to 2 meters, at 10 kHz sampling rate. An innovative navigation system was used to perform all necessary computations to determining real-time positions of sources and receivers. The resolution of the seismic profiles obtained from this experiment is remarkable high respect to previously acquired seismic data for both scientific and industrial purposes. In addition to the seismic imaging, gravity core data were also collected for sedimentological analysis and to give a chronological constraint using radiocarbon datings to the shallower reflectors. The investigated area is located in the western offshore sector of the Calabrian Arc (southern Tyrrhenian Sea) where previous research works, based on multichannel seismic profiles coupled with Chirp profiles, have documented the presence of an active fault system. One of the identified faults was tentatively considered as the source of the Mw 7, 8 September 1905 seismic event that hit with highest macroseismic intensities the western part of central Calabria, and was followed by a tsunami that inundated the coastline between Capo Vaticano and the Angitola plain. On this basis, the earthquake was considered to have a source at sea, but so far, the location, geometry and kinematics of the causative fault are still poorly understood. In this study we provide preliminary results of the most technologically advanced ultra-high-resolution geophysical method used to reveal the 3D faulting pattern, the late Quaternary slip rate and the earthquake potential of the marine fault system located close to the densely populated west coast of Calabria

Transgenic LQT2, LQT5, and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias

Background and Purpose Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S , loss of IKr; LQT2), KCNE1 (KCNE1‐G52R , decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart. Experimental Approach Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts. Key Results LQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT. Conclusion and Implications LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements