Pathophysiology of atrial fibrillation: From initiation to maintenance

Atrial fibrillation (AF) is the most common arrhythmia in adults; it affects approximately 0.8 million patients in Japan alone. Yet despite many years of basic and clinical research, the exact mechanisms underlying the initiation and maintenance of AF remain poorly understood. In this review article, we summarize recent high‐resolution optical mapping studies in isolated sheep hearts, which have provided new insights into the dynamics and mechanisms of AF. We focus on 3 models of AF. First, we discuss results from experiments on AF induced by atrial stretch that revealed the presence of spatio‐temporally organized waves emerging from the posterior wall of the left atrium. In the presence of adreno‐cholinergic stimulation and stretch, AF was governed by evolving interactions between reentry and spontaneous focal discharges. Next, we outline the results obtained from a persistent AF model (average AF duration: 21.3 day) induced by intermittent rapid atrial pacing. By using simultaneous optical mapping of epicardial and endocardial activation patterns, we demonstrated that AF in this model was maintained by 3‐dimensional scroll waves with I‐shaped filaments anchored to junctions between thin and thick myocardium. Numerical simulation results predicted that wall thickness‐dependent activation of stretch‐activated channels and the filament tension dynamics were sufficient to explain the specific localization of the I‐shaped filament. In a final set of studies discussed herein, we investigated AF in sheep with tachypacing‐induced heart failure and found that micro‐reentry in the left atria was a major mechanism of AF maintenance, although focal discharges at the pulmonary vein area also played a role. Large fibrotic patches in failing hearts may serve as potential anchoring sites for micro‐reentry in this model. Thus, the 3 different experimental results in isolated sheep hearts presented here clearly suggest that self‐sustained rotors do exist in the atria and that such rotors are in fact the high frequency sources that determine the complex patterns of activation that characterize AF.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142071/1/joa3129.pd

Miocene Offshore Tractive Current-Worked Conglomerates -Tsubutegaura, Chita Peninsula, Central Japan- (Chapter 4: SLOPE TO DEEP-WATER FACIES)

Edited by Asahiko Taira and Fujio Masuda.The Tsubutegaura Conglomerates occur in the middle part of the Miocene Morozaki Group, developed in southwestern Chita Peninsula, central Japan. Most of the group is characterized by storm-induced deposits from the uppermost bathyal environment (200~400 m deep). The Tsubutegaura Conglomerates, consisting of several hemilenticular or bunch-shaped bodies 10 to 40 meters across and a few meters high, were strictly distributed at one horizon in the storm sequence. Some of the hemilenticular bodies consist of a few layers. The framework gravels of the layers are angular to subangular and form clast-supported fabrics; a mud matrix is absent. The gravel size is variable, from pebbles to giant boulders. The finer gravels are characteristically imbricated in many places; the larger ones, i.e. boulders, often form gravel clusters as seen in alluvial channels. Most of the gravels in the Tsubutegaura Conglomerates are of Ryoke gneissose rocks, which are assumed to underlie the Morozaki Group. Very undurable soft siltstone and carbonized woods are minor constituents. No simple mass transportation model can synthetically explain all these sedimentary features; only submarine tractive current-worked deposits after some mass movements seem to be possible. Synsedimentary fault movements, previously clarified by other authors, are consistent with the idea of a submarine avalanche and a subsequent wash by offshore tractive currents induced by a tsunami

Purification of rabbit tumor necrosis factor

AbstractRabbit tumor necrosis factor (TNF) was purified and shown by SDS-PAGE to be a single protein of 18 kDa. TNF in 355 ml rabbit serum was precipitated with ammonium sulfate, and purified by repeated DEAE-Sephadex and Sephacryl S-200 chromatographies, and the final fractionation on Blue-Sepharose 6B. By this procedure its yield was 22% and its specific activity was 2.4 × 107 U/mg protein. The sequence of the N-terminal 20 amino acids was determined

Cell cycle-specific phase separation regulated by protein charge blockiness

Dynamic morphological changes of intracellular organelles are often regulated by protein phosphorylation or dephosphorylation1-6. Phosphorylation modulates stereospecific interactions among structured proteins, but how it controls molecular interactions among unstructured proteins and regulates their macroscopic behaviours remains unknown. Here we determined the cell cycle-specific behaviour of Ki-67, which localizes to the nucleoli during interphase and relocates to the chromosome periphery during mitosis. Mitotic hyperphosphorylation of disordered repeat domains of Ki-67 generates alternating charge blocks in these domains and increases their propensity for liquid–liquid phase separation (LLPS). A phosphomimetic sequence and the sequences with enhanced charge blockiness underwent strong LLPS in vitro and induced chromosome periphery formation in vivo. Conversely, mitotic hyperphosphorylation of NPM1 diminished a charge block and suppressed LLPS, resulting in nucleolar dissolution. Cell cycle-specific phase separation can be modulated via phosphorylation by enhancing or reducing the charge blockiness of disordered regions, rather than by attaching phosphate groups to specific sites