No abstract

regulates skeletal muscle regeneration in vivo through kinase-dependent and kinase-independent mechanisms.

The primary cause of heart failure is the loss of cardiomyocytes in the diseased adult heart. Previously, we reported that the miR-17-92 cluster plays a key role in cardiomyocyte proliferation. Here, we report that expression of miR-19a/19b, members of the miR-17-92 cluster, is induced in heart failure patients. We show that intra-cardiac injection of miR-19a/19b mimics enhances cardiomyocyte proliferation and stimulates cardiac regeneration in response to myocardial infarction (MI) injury. miR-19a/19b protected the adult heart in two distinctive phases: an early phase immediately after MI and long-term protection. Genome-wide transcriptome analysis demonstrates that genes related to the immune response are repressed by miR-19a/19b. Using an adeno-associated virus approach, we validate that miR-19a/19b reduces MI-induced cardiac damage and protects cardiac function. Finally, we confirm the therapeutic potential of miR-19a/19b in protecting cardiac function by systemically delivering miR-19a/19b into mice post-MI. Our study establishes miR-19a/19b as potential therapeutic targets to treat heart failure.

The Hippo pathway senses cellular conditions and regulates YAP/TAZ to control cellular and tissue homeostasis, while TBK1 is central for cytosolic nucleic acid sensing and antiviral defense. The correlation between cellular nutrient/physical status and host antiviral defense is interesting but not well understood. Here we find that YAP/TAZ act as natural inhibitors of TBK1 and are vital for antiviral physiology. Independent of transcriptional regulation and through transactivation domain, YAP/TAZ associate directly with TBK1 and abolish virus-induced TBK1 activation, by preventing TBK1 K63-linked ubiquitination and adaptors/substrates binding. Accordingly, YAP/TAZ deletion/depletion or cellular conditions inactivating YAP/TAZ through Lats1/2 kinases relieve TBK1 suppression and boost antiviral responses, whereas expression of the transcriptionally inactive YAP dampens cytosolic RNA/DNA sensing and weakens the antiviral defense in cells and zebrafish. Thus, we describe a function of YAP/TAZ and the Hippo pathway in innate immunity, by linking cellular nutrient/physical status to antiviral host defense.

TGF-β family signaling through Smads is conceptually a simple and linear signaling pathway, driven by sequential phosphorylation, with type II receptors activating type I receptors, which in turn activate R-Smads. Nevertheless, TGF-β family proteins induce highly complex programs of gene expression responses that are extensively regulated, and depend on the physiological context of the cells. Regulation of TGF-β signaling occurs at multiple levels, including TGF-β activation, formation, activation and destruction of functional TGF-β receptor complexes, activation and degradation of Smads, and formation of Smad transcription complexes at regulatory gene sequences that cooperate with a diverse set of DNA binding transcription factors and coregulators. Here we discuss recent insights into the roles of post-translational modifications and molecular interaction networks in the functions of receptors and Smads in TGF-β signal responses. These layers of regulation demonstrate how a simple signaling system can be coopted to exert exquisitely regulated, complex responses.

Ectodomain shedding mediated by tumor necrosis factor–α (TNF-α)–converting enzyme [TACE; also known as ADAM17 (a disintegrin and metalloproteinase 17)] provides an important switch in regulating cell proliferation, inflammation, and cancer progression. TACE-mediated ectodomain cleavage is activated by signaling of the mitogen-activated protein kinases (MAPKs) p38 and ERK (extracellular signal– regulated kinase). Here, we found that under basal conditions, TACE was predominantly present as dimers at the cell surface, which required its cytoplasmic domain and enabled efficient association with tissue inhibitor of metalloproteinase-3 (TIMP3) and silencing of TACE activity. Upon activation of the ERK or p38 MAPK pathway, the balance shifted from TACE dimers to monomers, and this shift was associated with increased cell surface presentation of TACE and decreased TIMP3 association, which relieved the inhibition of TACE by TIMP3 and increased TACE-mediated proteolysis of transforming growth factor–α. Thus, cell signaling altered the dimer-monomer equilibrium and inhibitor association to promote activation of TACE-mediated ectodomain shedding, a regulatory mechanism that may extend to other ADAM proteases.

A magnetically separable palladium catalyst was simply synthesized through a wet impregnation incorporating palladium nanoparticles and superparamagnetic Fe3O4 nanoparticles in KBH4 solution, which is a highly efficient catalyst for the carbonylative Sonogashira coupling reaction of aryl iodides with terminal alkynes under phosphine-free conditions. This catalyst is completely magnetically recoverable due to the super paramagnetic behavior of Fe3O4 and can be reused with sustained selectivity and activity.

To assess adherence to antiepileptic drugs (AEDs) and factors associated with non-adherence in a sample of Chinese patients with epilepsy. Methods. A cross-sectional descriptive study was carried out on patients who had no change in treatment regimen over the last six months. Data on adherence to medication and related factors for each patient were gathered using a questionnaire. Results. Of a total of 368 patients studied, 48.1% of patients were non-adherent with regards to AEDs. There were no demographic differences (based on gender, age, seizure type, and rural or urban location) between adherent and non-adherent patients. Adherence was positively and significantly correlated with duration of illness (p=0.007). The primary reason for non-adherence was forgetfulness or not having medication on hand (69.6%), followed by a negative attitude (12.8%), a bad patient-prescriber relationship (9.5%), side effects (5.4%), inability to buy drugs (1.9%), and other reasons (0.8%). Conclusion. The non-adherence of epilepsy patients is common in China. Targeted management programs and communication strategies are necessary to improve adherence to AED treatments in patients with epilepsy and avoid the clinical consequences of poor adherence.