Catecholaminergic polymorphic ventricular tachycardia is a form of exercise-induced sudden cardiac death that has been linked to mutations in the cardiac Ca 2؉ release channel͞ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR). We have shown that catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutations significantly decrease the binding affinity for calstabin-2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. We have proposed that RyR2-mediated diastolic SR Ca 2؉ leak triggers ventricular tachycardia (VT) and sudden cardiac death. In calstabin-2-deficient mice, we have now documented diastolic SR Ca 2؉ leak, monophasic action potential alternans, and bidirectional VT. Calstabin-deficient cardiomyocytes exhibited SR Ca 2؉ leak-induced aberrant transient inward currents in diastole consistent with delayed after-depolarizations. The 1,4-benzothiazepine JTV519, which increases the binding affinity of calstabin-2 for RyR2, inhibited the diastolic SR Ca 2؉ leak, monophasic action potential alternans and triggered arrhythmias. Our data suggest that calstabin-2 deficiency is as a critical mediator of triggers that initiate cardiac arrhythmias.calcium release channel ͉ calstabin ͉ heart failure ͉ JTV519 ͉ sudden cardiac death

on-alcoholic fatty liver disease (NAFLD) is associated with obesity, metabolic syndrome, dyslipidemia and type 2 diabetes (T2D). NASH is the progressive form of NAFLD, defined as ≥5% hepatic steatosis with inflammation and hepatocyte injury (that is, ballooning), with or without fibrosis 1 . Despite a predicted global prevalence of 2-12% in adults 2,3 , currently there is no approved treatment. Most clinically evaluated therapeutic mechanisms target the metabolic dysfunction of hepatocytes or suppress inflammation and fibrosis 4 . However, an ideal therapeutic would treat advanced fibrosis and resolve the profibrotic milieu driven by hepatocyte death (apoptosis) associated with chronic steatosis, lipotoxicity and oxidative and endoplasmic reticulum stress.FGF21 is a key regulator of whole-body and individual organ metabolism 5 . It activates a cell membrane co-receptor complex of β-klotho and one of its cognate FGF receptors (FGFRs), FGFR1c, FGFR2c or FGFR3c. FGF21 and its analogs improve metabolic status in preclinical models of obesity, diabetes and NASH 6 , suggesting promise as a therapeutic for NASH. However, many FGF21 analogs have not fulfilled the preclinical promise of FGF21 therapeutics, with disappointing translation into the clinic. Although substantial reductions in serum triglycerides have been seen in patients with T2D and obesity, effects on high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol have been variable, with inconsistent effects on glycemic control and body weight [7][8][9] . Furthermore, in patients with NASH, liver fat reductions have been moderate 10 . Two antibody-based therapeutics that act on the FGF21 co-receptor complex are also in development. Unlike analogs of the FGF21 polypeptide, BFKB8488A (Genentech) and MK3655 (Merck Sharp & Dohme; formerly NGM313 (NGM Biopharmaceuticals)) activate only the FGFR1c/β-klotho co-receptor complex. In patients with NAFLD, the highest adequately tolerated dose of BFKB8488A reduced HFF by 38% after 12 weeks 11 but did not improve markers of glycemic control in patients with T2D 12 . After a single dose, MK3655 improved glycemic control in obese non-diabetic participants with 37% relative reduction in liver fat 36 d after administration; however, significant weight gain was seen 13 .Efruxifermin is a fusion protein of human IgG 1 Fc domain linked to a modified human FGF21 (Fc-FGF21) with balanced in vitro agonist potency at FGFR1c, FGFR2c and FGFR3c 14 . Efruxifermin is longer acting than most FGF21 analogs, with a 3-3.5-d half-life 15 . A study in patients with T2D showed improvements in lipoprotein profiles and glycemic control 15 , which supported investigation of efruxifermin in patients with NASH. This study aimed to test the safety and efficacy of weekly subcutaneous administration for 16 weeks in patients with NASH.

Precise nucleosome-positioning patterns at promoters are thought to be crucial for faithful transcriptional regulation. However, the mechanisms by which these patterns are established, are dynamically maintained, and subsequently contribute to transcriptional control are poorly understood. The switch/sucrose non-fermentable chromatin remodeling complex, also known as the Brg1 associated factors complex, is a master developmental regulator and tumor suppressor capable of mobilizing nucleosomes in biochemical assays. However, its role in establishing the nucleosome landscape in vivo is unclear. Here we have inactivated Snf5 and Brg1, core subunits of the mammalian Swi/Snf complex, to evaluate their effects on chromatin structure and transcription levels genomewide. We find that inactivation of either subunit leads to disruptions of specific nucleosome patterning combined with a loss of overall nucleosome occupancy at a large number of promoters, regardless of their association with CpG islands. These rearrangements are accompanied by gene expression changes that promote cell proliferation. Collectively, these findings define a direct relationship between chromatin-remodeling complexes, chromatin structure, and transcriptional regulation.