Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

Background

Persistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.

Methods

Primary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.

Results

ApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).

Conclusion

ApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.

     

Tyrosine 842 in the activation loop is required for full transformation by the oncogenic mutant FLT3-ITD

The type III receptor tyrosine kinase FLT3 is frequently mutated in acute myeloid leukemia. Oncogenic FLT3 mutants display constitutive activity leading to aberrant cell proliferation and survival. Phosphorylation on several critical tyrosine residues is known to be essential for FLT3 signaling. Among these tyrosine residues, Y842 is located in the so-called activation loop. The position of this tyrosine residue is well conserved in all receptor tyrosine kinases. It has been reported that phosphorylation of the activation loop tyrosine is critical for catalytic activity for some but not all receptor tyrosine kinases. The role of Y842 residue in FLT3 signaling has not yet been studied. In this report, we show that Y842 is not important for FLT3 activation or ubiquitination but plays a critical role in regulating signaling downstream of the receptor as well as controlling receptor stability. We found that mutation of Y842 in the FLT3-ITD oncogenic mutant background reduced cell viability and increased apoptosis. Furthermore, the introduction of the Y842 mutation in the FLT3-ITD background led to a dramatic reduction in in vitro colony forming capacity. Additionally, mice injected with cells expressing FLT3-ITD/Y842F displayed a significant delay in tumor formation, compared to FLT3-ITD expressing cells. Microarray analysis comparing gene expression regulated by FLT3-ITD versus FLT3-ITD/Y842F demonstrated that mutation of Y842 causes suppression of anti-apoptotic genes. Furthermore, we showed that cells expressing FLT3-ITD/Y842F display impaired activity of the RAS/ERK pathway due to reduced interaction between FLT3 and SHP2 leading to reduced SHP2 activation. Thus, we suggest that Y842 is critical for FLT3-mediated RAS/ERK signaling and cellular transformation.     

Dynamic Dominating Set and Turbo-Charging Greedy Heuristics

The main purpose of this paper is to exposit two very different, but very general, motivational schemes in the art of parameterization and a concrete example connecting them. We introduce a dynamic version of the DOMINATING SET problem and prove that it is fixed-parameter tractable（FPT）. The problem is motivated by settings where problem instances evolve. It also arises in the quest to improve a natural greedy heuristic for the DOMINATING SET problem.     

Polycaprolactone Grafting of Cellulose Nanocrystals in Ionic Liquid[BMIM]CI

A polycaprolactone-grafted cellulose nanocrystal(PCL-g-CN) was prepared in ionic liquid and characterized by Fourier transform infrared spectrum(FT-IR),X-ray diffraction(XRD),and transmission electron microscopy(TEM).A peak assigned to the carbonyl group appears at 1 730 cm~(-1) in the FT-IR of PCL-g-CN,which confirms that the grafting reaction is successfully completed.The morphologies of PCL-g-CNs still maintain rod-like structure according to the TEM images.XRD results show that the crystal type of the PCL-g-CNs changed from cellulose Ⅰ to cellulose Ⅱ.The reasons for crystal transition of CNs turn out to be combined effects of anion and cation in ionic liquid with CNs.     

Spawning behaviour of Engystomops pustulatus (Anura: Leptodactylidae)

Foam nests have evolved independently in several amphibian groups as an adaptive response to prevent predation and desiccation in dry environments. Nests are normally laid on ponds, or in underground galleries, humid forest leaf litter or terrestrial bromeliads. They are built when males or females beat a foam precursor associated with the egg masses extruded by the female. The spawning process requires the synchronic actions of the mating pair to obtain a hemispheric nest that protects the offspring. Herein, we describe the spawning behaviour of Engystomops pustulatus based on videos from 13 nesting couples from the lowlands of western Ecuador. Three variables were measured as indicators of male effort: duration of mixing events, duration of resting periods, and number of kicks per mixing event. We consider that not only male physical effort but also female behaviour influences nest structure. We suggest that nest building requires prolonged and intense physical activity by the male as well as the female’s steady position during spawning and female’s oviposition site selection. Nest building has two phases. In the first phase, the duration of resting periods, the duration of mixing events, and the number of kicks increase and are highly variable. During the second phase the three variables stabilise until the end. The volume of the nest increased mainly during the second phase. In four nesting events we observed kicking movements by the female. To our knowledge, this is the first time that female kicking has been observed in leptodactylid frogs. The function of this behaviour is unknown but our observations suggest that it may be triggered by insufficient male effort. Traditionally, female mate choice in Engystomops has been explained under models of indirect benefits exclusively. We argue that the prolonged male activity during nesting could influence female fitness directly. This will allow the operation of sexual selection via direct benefits.     

On a relation between modular functions and Dirichlet series: found in the estate of Adolf Hurwitz

Archive for History of Exact Sciences - Adolf Hurwitz’s estate contains a note from the early 1880s on the converse to Riemann’s proof of the functional equation for the zeta-function;...     

Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins

Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.