Facioscapulohumeral muscular dystrophy (FSHD) is characterized by misexpression of the double homeobox 4 (DUX4) developmental transcription factor in mature skeletal muscle, where it is responsible for muscle degeneration. Preventing expression of DUX4 mRNA is a disease-modifying therapeutic strategy with the potential to halt or reverse the course of disease. We previously reported that agonists of the -2 adrenergic receptor suppress expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 mitogen-activated protein kinase as a major regulator of expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress expression in FSHD type 1 and 2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual small interfering RNA-mediated knockdown of either p38 or p38 suppresses expression, demonstrating that each kinase isoform plays a distinct requisite role in activating Finally, p38 inhibitors effectively suppress expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38 and p38 isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD. SIGNIFICANCE STATEMENT: Facioscapulohumeral muscular dystrophy (FSHD) currently has no treatment options. This work provides evidence that repurposing a clinically advanced p38 inhibitor may provide the first disease-modifying drug for FSHD by suppressing toxic DUX4 expression, the root cause of muscle degeneration in this disease.

In the last decade, we have seen increasing evidence of the importance of structural nuclear proteins such as lamins in nuclear architecture and compartmentalization of genome function and in the maintenance of mechanical stability and genome integrity. With over 400 mutations identified in the LMNA gene (encoding for A-type lamins) associated with more than ten distinct degenerative disorders, the role of lamins as genome caretakers and the contribution of lamins dysfunction to disease are unarguable. However, the molecular mechanisms whereby lamins mutations cause pathologies remain less understood. Here, we review pathways and mechanisms recently identified as playing a role in the pathophysiology of laminopathies, with special emphasis in Hutchinson Gilford Progeria Syndrome (HGPS). This devastating incurable accelerated aging disease is caused by a silent mutation in the LMNA gene that generates a truncated lamin A protein "progerin" that exerts profound cellular toxicity and organismal decline. Patients usually die in their teens due to cardiovascular complications such as myocardial infarction or stroke. To date, there are no efficient therapies that ameliorate disease progression, stressing the need to understand molecularly disease mechanisms that can be targeted therapeutically. We will summarize data supporting that replication stress is a major cause of genomic instability in laminopathies, which contributes to the activation of innate immune responses to self-DNA that in turn accelerate the aging process.

The peptide hormone adropin regulates energy metabolism in skeletal muscle and plays important roles in the regulation of metabolic homeostasis. Besides muscle, the liver has an essential role in regulating glucose homeostasis. Previous studies have reported that treatment of diet-induced obese (DIO) male mice with adropin(the putative secreted domain) reduces fasting blood glucose independently of body weight changes, suggesting that adropin suppresses glucose production in the liver. Here, we explored the molecular mechanisms underlying adropin's effects on hepatic glucose metabolism in DIO mice. Male DIO B6 mice maintained on a high-fat diet received five intraperitoneal injections of adropin (450 nmole/kg per injection) over a 48-h period. We found that adropin34-76enhances major intracellular signaling activities in the liver that are involved in insulin-mediated regulation of glucose homeostasis. Moreover, treatment with adropin alleviated endoplasmic reticulum (ER) stress responses and reduced activity of c-Jun N-terminal kinase (JNK) in the liver, explaining the enhanced activities of hepatic insulin signaling pathways observed with adropin34-76 treatment. Furthermore, adropin improved hepatic insulin receptor substrate (IRS) signaling and suppressed cAMP-activated protein kinase A (PKA) activities, resulting in reduced phosphorylation of inositol trisphosphate receptor (IP3R), which mediates ER calcium efflux, and of cAMP-responsive element-binding protein (CREB), a key transcription factor in hepatic regulation of glucose metabolism. Adropin directly affected liver metabolism, decreasing glucose production and reducing PKA-mediated phosphorylation in primary mouse hepatocytes in vitro. Our findings indicate that major hepatic signaling pathways contribute to the improved glycemic control achieved with adropin treatment in situations of obesity.

Anti-phosphatidylserine/prothrombin (aPS/PT) antibodies are often detected in patients with antiphospholipid syndrome (APS), but how aPS/PT engage prothrombin at the molecular level remains unknown. Here, the antigenic determinants of immunoglobulin G aPS/PT were investigated in 24 triple-positive APS patients at high risk of thrombosis by using prothrombin mutants biochemically trapped in closed and open conformations, and relevant fragments spanning the entire length of prothrombin. Two novel unexpected findings emerged from these studies. First, we discovered that some aPS/PT are unique among other anti-prothrombin antibodies insofar as they efficiently recognize prothrombin in solution after a conformational change requiring exposure of fragment-1 to the solvent. Second, we identified and characterized 2 previously unknown subpopulations of aPS/PT, namely type I and type II, which engage fragment-1 of prothrombin at different epitopes and with different mechanisms. Type I target a discontinuous density-dependent epitope, whereas type II engage the C-terminal portion of the Gla-domain, which remains available for binding even when prothrombin is bound to the phospholipids. Based on these findings, APS patients positive for aPS/PT were classified into 2 groups, group A and group B, according to their autoantibody profile. Group A contains mostly type I antibodies whereas group B contains both type I and type II antibodies. In conclusion, this study offers a first encouraging step toward unveiling the heterogeneity of anti-prothrombin antibodies in correlation with thrombosis, shedding new light on the mechanisms of antigen-autoantibody recognition in APS.

Hydrops Fetalis (HF) is a serious pregnancy complication defined by edema in two or more fetal compartments, typically in the first or second trimesters. Nearly 90% of cases are attributed to non-immune causes (NIHF) and include a wide number of pathologies: cardiac abnormalities, chromosomal anomalies, or inborn errors of metabolism (lysosomal storage diseases - LSDs). This article is protected by copyright. All rights reserved.

The development of new treatments for heart failure lack animal models that encompass the increasingly heterogeneous disease profile of this patient population. This report provides evidence supporting the hypothesis that Western Diet-fed, aortic-banded Ossabaw swine display an integrated physiological, morphological, and genetic phenotype evocative of cardio-metabolic heart failure. This new preclinical animal model displays a distinctive constellation of findings that are conceivably useful to extending the understanding of how pre-existing cardio-metabolic syndrome can contribute to developing HF.

Progress towards a more circular phosphorus economy necessitates development of innovative water treatment systems which can reversibly remove inorganic phosphate (P) to ultra-low levels (<100 μg L), and subsequently recover the P for reuse. In this study, a novel approach using the high-affinity phosphate binding protein (PBP) as a reusable P bio-adsorbent was investigated. PBP was expressed, extracted, purified and immobilized on NHS-activated Sepharose beads. The resultant PBP beads were saturated with P and exposed to varying pH (pH 4.7 to 12.5) and temperatures (25-45 °C) to induce P release. Increase in temperature from 25 to 45 °C and pH conditions between 4.7 and 8.5 released less than 20% of adsorbed P. However, 62% and 86% of the adsorbed P was released at pH 11.4 and 12.5, respectively. Kinetic experiments showed that P desorption occurred nearly instantaneously (<5 min), regardless of pH conditions, which is advantageous for P recovery. Additionally, no loss in P adsorption or desorption capacity was observed when the PBP beads were exposed to 10 repeated cycles of adsorption/desorption using neutral and high pH (≥12.5) washes, respectively. The highest average P adsorption using the PBP beads was 83 ± 5%, with 89 ± 4.1% average desorption using pH 12.5 washes over 10 wash cycles at room temperature. Thermal shift assay of the PBP showed that the protein was structurally stable after 10 cycles, with statistically similar melting temperatures between pH 4 and 12.5. These results indicate that immobilized high-affinity PBP has the potential to be an effective and reversible bio-adsorbent suitable for P recovery from water/wastewater.