Bale Band V 2.2

Sarcomeric structure-function relations. A Schematic of sarcomere (above) and sarcomere ultrastructure observed by electron microscopy (below). The sarcomere is an elastic scaffold that consists of structural proteins lined out from Z-disk to M-band, including actin (black), myosin (green), and titin (grey) that extends through the half-sarcomere. Scale is 100 nm. BLength-tension relation, a contributor to the Frank-Starling Law of the heart. Adapted from (Gordon et al. 1966). C Sarcomere length changes during systole and diastole. D Myofilament compressions during diastolic filling, Myosin in green and actin in red

Bale Band v 2.2

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At its core, the mature cardiac sarcomere is a regular hexagonal lattice of thin, actin-containing filaments attached to the Z-disk and thick, myosin-containing filaments interconnected in the middle of the sarcomere via the M-band (Figure 1A). In addition, the filamentous protein titin spans the half-sarcomere from the Z-disk to M-band and stabilizes contraction, among other functions discussed below. The structural properties of sarcomeric proteins and their arrangement are central to cardiac contraction. Sarcomeres are connected in series at the Z-disk and arranged in parallel to form bundles of myofibrils about 1 μm in diameter. Sliding of thick and thin filaments relative to each other results in muscle contraction.

The thick filament mainly consists of myosin molecules. The myosin superfamily encodes 18 classes of myosin motors, which are ubiquitous in eukaryotes and participate in several cellular motile processes (Hartman and Spudich 2012). A subset of class II myosins power muscle contraction in striated muscles, MYH6 (α-MyHC) and MYH7 (β-MyHC), are known as the cardiac myosin heavy chain isoforms and, albeit 93% identical in humans, display significantly different functional properties. α-MyHC has a higher ATPase activity but generates less force than β-MyHC (Pope et al. 1980; Aksel et al. 2015). In the adult human ventricle, the cardiac myosin composition is 95% β-MyHC and 5% α-MyHC (Reiser et al. 2001), a ratio that further changes in favor of β-MyHC in cardiac diseases (Bouvagnet et al. 1989; Nadal-Ginard and Mahdavi 1989). There are two functional units in class II myosins, a globular motor domain (myosin head) that contains the catalytic ATPase site and binds actin and an α-helical coiled-coil rod domain that dimerizes and assembles into bipolar thick filaments. In the center of the thick filament, the bare zone is free of myosin heads as a consequence of the bipolar arrangement of the myosin molecules. Three-dimensional studies on tarantula thick filaments showed that two myosin heads pack together to form an interacting-heads motif (IHM) (Woodhead et al. 2005). The IHM forms only in relaxed muscle and is an evolutionarily conserved motif among species and muscle types (Alamo et al. 2016). Relaxed myosin exists in two conformations: disordered relaxation (DRX), with one of the two paired myosin heads folded (blocked head) and super relaxation (SRX), with both heads folded back along the thick-filament backbone. As compared to the DRX conformation, myosins in SRX do not participate in contraction and conserve energy, while providing reserve heads that can be activated in response to increased mechanical need (McNamara et al. 2015). The thick filaments contain cardiac myosin-binding protein-C (cMyBP-C) (Carrier et al. 2015), which resides in the A band and interacts with myosin (Starr and Offer 1978; Alyonycheva et al. 1997) and titin (Labeit et al. 1992; Soteriou et al. 1993) and helps maintain sarcomeric structure and regulates cardiac contraction and relaxation.

As DCM is characterized by the reduced mechanical force generation, pathogenic gene mutations (Kamisago et al. 2000; McNally et al. 2013) result generally in opposite molecular mechanisms as compared to HCM. In fact, DCM mutations in MYH7 reduce myosin ATPase activity and motor function (Schmitt et al. 2006), while DCM mutations in thin-filament proteins decrease myofibril calcium sensitivity, resulting in reduced tension and faster relaxation (Robinson et al. 2007; Gangadharan et al. 2017). Approximately 90% of titin mutations are associated with DCM phenotype, and the remaining to HCM (Greaser 2009). Specifically, mutations that lead to titin truncated variants are highly associated with DCM (Herman et al. 2012; Merlo et al. 2013; Tharp et al. 2019). Integrated analysis of sequencing and transcriptional data from large human cohorts has demonstrated that the effect of titin-truncated variants is dependent on the position of the truncation within the protein (Roberts et al. 2015). The majority of DCM patients carry titin-truncated variants located in the A-band (Herman et al. 2012; Roberts et al. 2015; Akinrinade et al. 2016; Schafer et al. 2017), but in general, truncations occurring in constitutive (highly expressed) exons of titin lead to DCM (Roberts et al. 2015). Mechanisms by which titin-truncating variants cause DCM are probably related to haploinsufficiency rather than dominant negative effects. In fact, truncated titin peptides are not found in DCM hearts (Roberts et al. 2015) likely due to nonsense-mediated decay and rapid turnover of the mutant peptides (Schafer et al. 2017). Accessory proteins of the sarcomere contribute to cardiac contraction and are linked mechanically to thin, thick, and titin filaments as well as additional non-sarcomeric compartments. Mutations of these proteins can also lead to HCM and DCM (Selcen and Carpen 2008; Lange et al. 2020; Wadmore et al. 2021) and have shown to exhibit altered contractility via different mechanisms (Adams et al. 2007; Friedrich et al. 2012; Crocini et al. 2013).

As mentioned, titin-based stiffness can be adjusted both in the long term by titin isoform switching (Granzier and Irving 1995; Opitz et al. 2004) or more rapidly by post-translational modifications (Koser et al. 2019). Abnormal isoform ratios or post-translational modifications can dramatically affect passive tension of cardiomyocytes and have been described in many human cardiac diseases (LeWinter and Granzier 2014). In the heart, there are 3 main types of titin isoforms: fetal cardiac titin, adult N2BA, and adult N2B. They differ in their I-band extensible regions. Fetal cardiac titin isoforms are longer and more compliant than either N2B or N2BA (Lahmers et al. 2004; Opitz et al. 2004) (Figure 2A). These isoforms could be beneficial in fetal-neonatal development because of the low filling pressure of the fetal heart and the structural constraints provided by other tissues that limit cardiac reserve in the fetus (Walker and de Tombe 2004). Fetal isoforms gradually disappear during postnatal development in favor of the mature N2BA and N2B. Titin N2BA isoforms have a longer PEVK sequence and a variable number of additional Ig domains resulting in more compliant isoforms than N2B titin. Both isoforms are co-expressed in the cardiac sarcomere, and their ratio is a determinant of passive stiffness. In adult human left ventricle, the N2BA/N2B ratio is 0.6 and can change in disease (Neagoe et al. 2002; Makarenko et al. 2004; Nagueh et al. 2004) (Figure 2B). The N2BA:N2B ratio is increased in DCM patients (Nagueh et al. 2004) and would result in reduced passive tension leading to reduced diastolic forces and dilation of the heart, both hallmarks of DCM. Switching to the longer N2BA isoform could represent an initial compensatory mechanism that improves diastolic function; however, long-term reduction of passive tension and diastolic pressure could worsen contractile performance in systole (Makarenko et al. 2004).

Barge Ballad is the opening track of Written in Salt. This song is a Longest Johns original , written by Josh Bowker, who originally also sang lead on it. Since his departure from the band, JD usually leads the song.The chorus is cumulative, with the list of instructions in the last line growing with each iteration.

Ring carriers (typically known as six-pack rings). Ring carriers are deformable bands that are placed on beverage containers (e.g., cans, bottles) to package them for transport. They can be cut to hold different multiples of containers (e.g., two-packs, eight-packs). They are typically made from low-density polyethylene. Ring carriers are not typically recycled in Canada and are not accepted by provincial or municipal recycling systems. Ring carriers are a common form of plastic litter (e.g. 1 627 units collected from Canadian shorelines in 2019 through the Great Canadian Shoreline Cleanup) and are recognized as posing a threat of entanglement for wildlife such as seabirds;

SUP ring carriers, which are plastic manufactured items made entirely or in part from plastic and formed in the shape of a series of deformable rings or bands that are designed to surround beverage containers in order to carry them together;

Much later, when the Kobolds summon Titan, Merlwyb meets the adventurer and Y'shtola at Maelstrom Command. She admits the crisis was her fault for violating Limsa Lominsa's treaty with the kobolds in the wake of the Calamity. She later gathers with the other leaders when they receive Gaius van Baelsar's ultimatum to surrender. They discuss whether to capitulate or resist in the face of Gaius's ultimate weapon, until Minfilia convinces them to band against the Garlean threat. In the aftermath of the Praetorium's fall, Merlwyb and the other leaders celebrate in Lake Silvertear while renewing the Eorzean Alliance.

In 1.0, a quest sparked a rumor that Merlwyb and the pirate Rycharde Mistbeard were lovers. Merlwyb's father, Bloefhis, led the League of Lost Bastards in a war against Mistbeard (a battle that gave Bloodshore its name), which may be the reason she declined leadership of the Lost Bastards. Quests added in patches 2.2 & 2.3 strongly imply that her second-in-command, Eynzahr Slafyrsyn, is none other than Mistbeard himself. This was confirmed with the release of Patch 3.3. However, there has been no indication since then regarding them being lovers, and it seems the rumour has been long since abandoned. 041b061a72