A novel BAG5 variant impairs the ER stress response pathway, causing dilated cardiomyopathy and arrhythmia.

Pathogenic BAG5 variants recently linked to dilated cardiomyopathy (DCM) prompt further investigation into phenotypic, mutational, and pathomechanistic aspects. We explored the clinical and molecular characteristics of DCM associated with BAG5 variants, uncovering the consistently severe manifestations of the disease and its impact on the endoplasmic reticulum (ER) stress response. The analysis involved three siblings affected by DCM and arrhythmia, along with their four unaffected siblings, their unaffected father, and their mother who exhibited arrhythmia. The parents were consanguineous. Exome and Sanger sequencing identified a novel BAG5 variant, c.444_445delGA (p.Lys149AsnfsTer6), homozygous in affected siblings and heterozygous in parents and unaffected siblings. We generated heterozygous and homozygous Bag5 point mutant knock-in (KI) mice and evaluated cardiac pathophysiology under stress conditions, including tunicamycin (TN) administration. Bag5-/- mice displayed no abnormalities up to 12 months old and showed no anomalies during an exercise stress test. However, following TN injection, Bag5-/- mice exhibited significantly reduced left ventricular fractional shortening (LVFS) and ejection fraction (LVEF). Their cardiac tissues exhibited a notable increase in apoptotic cells, despite non-distinctive changes in CHOP and GRP78 levels. Interestingly, only Bag5 KI male mice demonstrated arrhythmia, which was more pronounced in Bag5-/- than in Bag5+/-males. Here, our study reveals a novel BAG5 mutation causing DCM by impairing the ER stress response, with observed sex-specific arrhythmia differences.

Long-read Nanopore sequencing identified D4Z4 contractions in patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic muscle disorder caused by abnormal expression of the DUX4 protein, commonly resulting from a contraction of D4Z4 repeat units with the presence of a polyadenylation (polyA) signal. More than 10 units of the D4Z4 repeat, with a length of 3.3 kb per unit, are typically required to silence DUX4 expression. Consequently, molecular diagnosis of FSHD is challenging. We used Oxford Nanopore technology to perform whole-genome sequencing of seven unrelated patients with FSHD, their six unaffected parents, and 10 unaffected controls. All seven patients were successfully identified to harbor one to five D4Z4 repeat units and the polyA signal, whereas none of the 16 unaffected individuals met the molecular diagnostic criteria. Our newly developed method provides a straightforward and powerful molecular diagnostic tool for FSHD.

Anti-obesity effect of Carica papaya in high-fat diet fed rats.

The present study evaluated the anti-obesity properties of papaya in high-fat (HF) diet fed rats. In the in vitro portion of the present study, the effects of papaya juice on pancreatic lipase enzyme activity was assessed, and it was shown that papaya exhibited an inhibitory effect on these enzymes. In the in vivo portion of the study, papaya was found to reduce the expression levels of markers of obesity, inflammation and oxidative stress in rats. Obesity was induced in 28 male Sprague Dawley rats by feeding them a HF diet for 12 weeks. The anti-obesity effects of papaya was evaluated by feeding papaya juice orally in with two experimental doses: 0.5 ml (HFL) and 1.0 ml (HFH) per 100 g of body weight. The HF diet resulted in significant increases in the body weight, serum triglyceride, serum total cholesterol and serum low-density lipoprotein cholesterol levels, as well as a decrease in serum high-density lipoprotein cholesterol levels. The HF diet also induced adipocyte hypertrophy, lipid accumulation and increased malondialdehyde levels. Papaya reversed all of these changes and significantly increased serum superoxide dismutase and decreased serum cytokine (interleukin-6) levels. The protein expression of levels PPARγ in the HF group was significantly increased compared with the other groups, but was decreased significantly in the HFH group. Histological observations of epididymal adipose tissue provided evidence for the lipid-lowering effects of papaya. The results of the present study demonstrate that papaya has the potential to reduce the risk of obesity associated with adiposity, anti-inflammation and anti-oxidation.