RNS60 exerts therapeutic effects in the SOD1 ALS mouse model through protective glia and peripheral nerve rescue

Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects the motor neuromuscular system leading to complete paralysis and premature death. The multifactorial nature of ALS that involves both cell-autonomous and non-cell-autonomous processes contributes to the lack of effective therapies, usually targeted to a single pathogenic mechanism. RNS60, an experimental drug containing oxygenated nanobubbles generated by modified Taylor-Couette-Poiseuille flow with elevated oxygen pressure, has shown anti-inflammatory and neuroprotective properties in different experimental paradigms. Since RNS60 interferes with multiple cellular mechanisms known to be involved in ALS pathology, we evaluated its effect in in vitro and in vivo models of ALS. Methods: Co-cultures of primary microglia/spinal neurons exposed to LPS and astrocytes/spinal neurons from SOD1 G93A mice were used to examine the effect of RNS60 or normal saline (NS) on the selective motor neuron degeneration. Transgenic SOD1 G93A mice were treated with RNS60 or NS (300\u3bcl/mouse intraperitoneally every other day) starting at the disease onset and examined for disease progression as well as pathological and biochemical alterations. Results: RNS60 protected motor neurons in in vitro paradigms and slowed the disease progression of C57BL/6-SOD1 G93A mice through a significant protection of spinal motor neurons and neuromuscular junctions. This was mediated by the (i) activation of an antioxidant response and generation of an anti-inflammatory environment in the spinal cord; (ii) activation of the PI3K-Akt pro-survival pathway in the spinal cord and sciatic nerves; (iii) reduced demyelination of the sciatic nerves; and (iv) elevation of peripheral CD4+/Foxp3+ T regulatory cell numbers. RNS60 did not show the same effects in 129Sv-SOD1 G93A mice, which are unable to activate a protective immune response. Conclusion: RNS60 demonstrated significant therapeutic efficacy in C57BL/6-SOD1 G93A mice by virtue of its effects on multiple disease mechanisms in motor neurons, glial cells, and peripheral immune cells. These findings, together with the excellent clinical safety profile, make RNS60 a promising candidate for ALS therapy and support further studies to unravel its molecular mechanism of action. In addition, the differences in efficacy of RNS60 in SOD1 G93A mice of different strains may be relevant for identifying potential markers to predict efficacy in clinical trials

Chaos for the Hyperbolic Bioheat Equation

The Hyperbolic Heat Transfer Equation describes heat processes in which extremely short periods of time or extreme temperature gradients are involved. It is already known that there are solutions of this equation which exhibit a chaotic behaviour, in the sense of Devaney, on certain spaces of analytic functions with certain growth control. We show that this chaotic behaviour still appears when we add a source term to this equation, i.e. in the Hyperbolic Bioheat Equation. These results can also be applied for the Wave Equation and for a higher order version of the Hyperbolic Bioheat Equation.The authors are supported in part by MEC and FEDER, Projects MTM2010-14909 and MTM2013-47093-P.Conejero, JA.; Ródenas Escribá, FDA.; Trujillo Guillen, M. (2015). Chaos for the Hyperbolic Bioheat Equation. Discrete and Continuous Dynamical Systems - Series A. 35(2):653-668. doi:10.3934/dcds.2015.35.653S65366835

Distributionally chaotic families of operators on Fréchet spaces

This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Communications on Pure and Applied Analysis (CPAA) following peer review. The definitive publisher-authenticated version Conejero, J. A., Kostić, M., Miana, P. J., & Murillo-Arcila, M. (2016). Distributionally chaotic families of operators on Fréchet spaces.Communications on Pure and Applied Analysis, 2016, vol. 15, no 5, p. 1915-1939, is available online at: http://dx.doi.org/10.3934/cpaa.2016022The existence of distributional chaos and distributional irregular vectors has been recently considered in the study of linear dynamics of operators and C-0-semigroups. In this paper we extend some previous results on both notions to sequences of operators, C-0-semigroups, C-regularized semigroups, and alpha-timesintegrated semigroups on Frechet spaces. We also add a study of rescaled distributionally chaotic C-0-semigroups. Some examples are provided to illustrate all these results.The first and fourth authors are supported in part by MEC Project MTM2010-14909, MTM2013-47093-P, and Programa de Investigacion y Desarrollo de la UPV, Ref. SP20120700. The second author is partially supported by grant 174024 of Ministry of Science and Technological Development, Republic of Serbia. The third author has been partially supported by Project MTM2013-42105-P, DGI-FEDER, of the MCYTS; Project E-64, D.G. Aragon, and Project UZCUD2014-CIE-09, Universidad de Zaragoza. The fourth author is supported by a grant of the FPU Program of Ministry of education of Spain.Conejero, JA.; Kostic, M.; Miana Sanz, PJ.; Murillo Arcila, M. (2016). Distributionally chaotic families of operators on Fréchet spaces. Communications on Pure and Applied Analysis. 15(5):1915-1939. https://doi.org/10.3934/cpaa.2016022S1915193915

R497K polymorphism in epidermal growth factor receptor gene is associated with the risk of acute coronary syndrome

<p>Abstract</p> <p>Background</p> <p>Previous studies suggested that genetic polymorphisms in the epidermal growth factor receptor (EGFR) gene had been implicated in the susceptibility to some tumors and inflammatory diseases. EGFR has been recently implicated in vascular pathophysiological processes associated with excessive remodeling and atherosclerosis. Acute coronary syndrome (ACS) is a clinical manifestation of preceding atherosclerosis. Our purpose was to investigate the association of the EGFR polymorphism with the risk of ACS. In this context, we analyzed the HER-1 R497K and EGFR intron 1 (CA)_nrepeat polymorphisms in 191 patients with ACS and 210 age- and sex-matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy and direct sequencing.</p> <p>Results</p> <p>There were significant differences in the genotype and allele distribution of R497K polymorphism of the EGFR gene between cases and controls. The <it>Lys </it>allele had a significantly increased risk of ACS compared with the <it>Arg </it>allele (adjusted OR = 1.49, 95% CI: 1.12–1.98, adjusted <it>P </it>= 0.006). However, no significant relationship between the number of (CA)_nrepeats of EGFR intron 1 (both alleles < 20 or any allele ≥ 20) and the risk of ACS was observed (adjusted OR = 0.97, 95% CI: 0.58–1.64, adjusted <it>P </it>= 0.911). Considering these two polymorphisms together, there was no statistically significant difference between the two groups.</p> <p>Conclusion</p> <p>R497K polymorphism of the EGFR gene is significantly associated with the risk of ACS. Our data suggests that R497K polymorphism may be used as a genetic susceptibility marker of the ACS.</p