Harmful and Beneficial Role of ROS

Reactive oxygen species (ROS) are an unavoidable byproduct of oxygen metabolism and their cellular concentrations are determined by the balance between their rates of production and their rates of clearance by various antioxidant compounds and enzymes. For a long time ROS were thought to cause exclusively toxic effects which were associated with various pathologies, including carcinogenesis, neurodegeneration, atherosclerosis, diabetes, and aging. However, to date, it is known that while prolonged exposure to high ROS concentrations may lead to various disorders, low ROS concentrations exert beneficial effects regulating cell signaling cascades

On the Legendre differential equation with uncertainties at the regular-singular point 1: Lp random power series solution and approximation of its statistical moments

"This is the peer reviewed version of the following article: Calatayud, J, Cortés, J-;C, Jornet, M. On the Legendre differential equation with uncertainties at the regular-singular point 1: Lp random power series solution and approximation of its statistical moments. Comp and Math Methods. 2019; 1:e1045. https://doi.org/10.1002/cmm4.1045 , which has been published in final form at https://doi.org/10.1002/cmm4.1045. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] In this paper, we construct two linearly independent response processes to the random Legendre differential equation on (-1,1)U(1,3), consisting of Lp(omega) convergent random power series around the regular¿singular point 1. A theorem on the existence and uniqueness of Lp(omega) solution to the random Legendre differential equation on the intervals (-1,1) and (1,3) is obtained. The hypotheses assumed are simple: initial conditions in Lp(omega) and random input A in L infinite(omega) (this is equivalent to A having absolute moments that grow at most exponentially). Thus, this paper extends the deterministic theory to a random framework. Uncertainty quantification for the solution stochastic process is performed by truncating the random series and taking limits in Lp(omega). In the numerical experiments, we approximate its expectation and variance for certain forms of the differential equation. The reliability of our approach is compared with Monte Carlo simulations and generalized polynomial chaos expansions.Spanish Ministerio de Economía y Competitividad, Grant/Award Number: MTM2017-89664-P; Programa de Ayudas de Investigación y Desarrollo; Universitat Politècnica de ValènciaCalatayud-Gregori, J.; Cortés, J.; Jornet-Sanz, M. (2019). On the Legendre differential equation with uncertainties at the regular-singular point 1: Lp random power series solution and approximation of its statistical moments. Computational and Mathematical Methods. 1(4):1-12. https://doi.org/10.1002/cmm4.1045S11214Calbo, G., Cortés, J.-C., Jódar, L., & Villafuerte, L. (2011). Solving the random Legendre differential equation: Mean square power series solution and its statistical functions. Computers & Mathematics with Applications, 61(9), 2782-2792. doi:10.1016/j.camwa.2011.03.045Villafuerte, L., Braumann, C. A., Cortés, J.-C., & Jódar, L. (2010). Random differential operational calculus: Theory and applications. Computers & Mathematics with Applications, 59(1), 115-125. doi:10.1016/j.camwa.2009.08.061Wong, E., & Hajek, B. (1985). Stochastic Processes in Engineering Systems. Springer Texts in Electrical Engineering. doi:10.1007/978-1-4612-5060-9Nouri, K., & Ranjbar, H. (2014). Mean Square Convergence of the Numerical Solution of Random Differential Equations. Mediterranean Journal of Mathematics, 12(3), 1123-1140. doi:10.1007/s00009-014-0452-8Lupulescu, V., O’Regan, D., & ur Rahman, G. (2014). Existence results for random fractional differential equations. Opuscula Mathematica, 34(4), 813. doi:10.7494/opmath.2014.34.4.813Villafuerte, L., & Chen-Charpentier, B. M. (2012). A random differential transform method: Theory and applications. Applied Mathematics Letters, 25(10), 1490-1494. doi:10.1016/j.aml.2011.12.033Licea, J. A., Villafuerte, L., & Chen-Charpentier, B. M. (2013). Analytic and numerical solutions of a Riccati differential equation with random coefficients. Journal of Computational and Applied Mathematics, 239, 208-219. doi:10.1016/j.cam.2012.09.040Lang, S. (1997). Undergraduate Analysis. Undergraduate Texts in Mathematics. doi:10.1007/978-1-4757-2698-5Cortés, J.-C., Romero, J.-V., Roselló, M.-D., Santonja, F.-J., & Villanueva, R.-J. (2013). Solving Continuous Models with Dependent Uncertainty: A Computational Approach. Abstract and Applied Analysis, 2013, 1-10. doi:10.1155/2013/983839Calatayud, J., Cortés, J. C., Jornet, M., & Villanueva, R. J. (2018). Computational uncertainty quantification for random time-discrete epidemiological models using adaptive gPC. Mathematical Methods in the Applied Sciences, 41(18), 9618-9627. doi:10.1002/mma.531

Multi-omic data integration elucidates Synechococcus adaptation mechanisms to fluctuations in light intensity and salinity

Synechococcus sp. PCC 7002 is a fast-growing cyanobacterium which flourishes in freshwater and marine environments, owing to its ability to tolerate high light intensity and a wide range of salinities. Harnessing the properties of cyanobacteria and understanding their metabolic efficiency has become an imperative goal in recent years owing to their potential to serve as biocatalysts for the production of renewable biofuels. To improve characterisation of metabolic networks, genome-scale models of metabolism can be integrated with multi-omic data to provide a more accurate representation of metabolic capability and refine phenotypic predictions. In this work, a heuristic pipeline is constructed for analysing a genome-scale metabolic model of Synechococcus sp. PCC 7002, which utilises flux balance analysis across multiple layers to observe flux response between conditions across four key pathways. Across various conditions, the detection of significant patterns and mechanisms to cope with fluctuations in light intensity and salinity provides insights into the maintenance of metabolic efficiency

Temporal trends of molecular markers associated with artemether- lumefantrine tolerance/resistance in Bagamoyo district, Tanzania

Background: Development and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) constitutes a major threat to recent global malaria control achievements. Surveillance of molecular markers could act as an early warning system of ACT-resistance before clinical treatment failures are apparent. The aim of this study was to analyse temporal trends of established genotypes associated with artemether-lumefantrine tolerance/resistance before and after its deployment as first-line treatment for uncomplicated malaria in Tanzania 2006. Methods: Single nucleotide polymorphisms in the P. falciparum multidrug resistance gene 1 (pfmdr1) N86Y, Y184F, D1246Y and P. falciparum chloroquine transporter gene (pfcrt) K76T were analysed from dried blood spots collected during six consecutive studies from children with uncomplicated P. falciparum malaria in Fukayosi village, Bagamoyo District, Tanzania, between 2004-2011. Results: There was a statistically significant yearly increase of pfmdr1 N86, 184F, D1246 and pfcrt K76 between 2006-2011 from 14% to 61% (yearly OR = 1.38 [95% CI 1.25-1.52] p \u3c 0.0001), 14% to 35% (OR = 1.17 [95% CI 1.07-1.30] p = 0.001), 54% to 85% (OR = 1.21 [95% CI 1.03-1.42] p = 0.016) and 49% to 85% (OR = 1.33 [95% CI 1.17-1.51] p \u3c 0.0001), respectively. Unlike for the pfmdr1 SNP, a significant increase of pfcrt K76 was observed already between 2004-2006, from 26% to 49% (OR = 1.68 [95% CI 1.17-2.40] p = 0.005). From 2006 to 2011 the pfmdr1 NFD haplotype increased from 10% to 37% (OR = 1.25 [95% CI 1.12-1.39] p \u3c 0.0001), whereas the YYY haplotype decreased from 31% to 6% (OR = 0.73 [95% CI 0.56-0.98] p = 0.018). All 390 successfully analysed samples had one copy of the pfmdr1 gene. Conclusion: The temporal selection of molecular markers associated with artemether-lumefantrine tolerance/resistance may represent an early warning sign of impaired future drug efficacy. This calls for stringent surveillance of artemether-lumefantrine efficacy in Tanzania and emphasizes the importance of molecular surveillance as a complement to standard in vivo trials. © 2013 Malmberg et al.; licensee BioMed Central Ltd

Toll-like receptor pre-stimulation protects mice against lethal infection with highly pathogenic influenza viruses

<p>Abstract</p> <p>Since the beginning of the 20th century, humans have experienced four influenza pandemics, including the devastating 1918 'Spanish influenza'. Moreover, H5N1 highly pathogenic avian influenza (HPAI) viruses are currently spreading worldwide, although they are not yet efficiently transmitted among humans. While the threat of a global pandemic involving a highly pathogenic influenza virus strain looms large, our mechanisms to address such a catastrophe remain limited. Here, we show that pre-stimulation of Toll-like receptors (TLRs) 2 and 4 increased resistance against influenza viruses known to induce high pathogenicity in animal models. Our data emphasize the complexity of the host response against different influenza viruses, and suggest that TLR agonists might be utilized to protect against lethality associated with highly pathogenic influenza virus infection in humans.</p

Reflections on Pandemic (H1N1) 2009 and the International Response

Gabriel Leung and Angus Nicoll provide their reflections on the international response to the 2009 H1N1 influenza pandemic, including what went well and what changes need to be made in anticipation of future flu pandemics

saeRS and sarA Act Synergistically to Repress Protease Production and Promote Biofilm Formation in Staphylococcus aureus

Mutation of the staphylococcal accessory regulator (sarA) limits biofilm formation in diverse strains of Staphylococcus aureus, but there are exceptions. One of these is the commonly studied strain Newman. This strain has two defects of potential relevance, the first being mutations that preclude anchoring of the fibronectin-binding proteins FnbA and FnbB to the cell wall, and the second being a point mutation in saeS that results in constitutive activation of the saePQRS regulatory system. We repaired these defects to determine whether either plays a role in biofilm formation and, if so, whether this could account for the reduced impact of sarA in Newman. Restoration of surface-anchored FnbA enhanced biofilm formation, but mutation of sarA in this fnbA-positive strain increased rather than decreased biofilm formation. Mutation of sarA in an saeS-repaired derivative of Newman (P18L) or a Newman saeRS mutant (ΔsaeRS) resulted in a biofilm-deficient phenotype like that observed in clinical isolates, even in the absence of surface-anchored FnbA. These phenotypes were correlated with increased production of extracellular proteases and decreased accumulation of FnbA and/or Spa in the P18L and ΔsaeRS sarA mutants by comparison to the Newman sarA mutant. The reduced accumulation of Spa was reversed by mutation of the gene encoding aureolysin, while the reduced accumulation of FnbA was reversed by mutation of the sspABC operon. These results demonstrate that saeRS and sarA act synergistically to repress the production of extracellular proteases that would otherwise limit accumulation of critical proteins that contribute to biofilm formation, with constitutive activation of saeRS limiting protease production, even in a sarA mutant, to a degree that can be correlated with increased enhanced capacity to form a biofilm. Although it remains unclear whether these effects are mediated directly or indirectly, studies done with an sspA::lux reporter suggest they are mediated at a transcriptional level

Early Induction of Oxidative Stress in Mouse Model of Alzheimer Disease with Reduced Mitochondrial Superoxide Dismutase Activity

While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5–7 months of age) and old (25–30 months of age) mice with the four genotypes, wild-type (Sod2+/+), hemizygous Sod2 (Sod2+/−), hAPP/wild-type (Sod2+/+), and hAPP/hemizygous (Sod2+/−) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2+/+ or Sod2+/−. Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2+/− mice may contribute to the pathological and behavioral changes seen in this animal model

Paradoxical regulation of Bcl-2 family proteins by 17β-oestradiol in human breast cancer cells MCF-7

Tumorigenesis is related to the dysregulation of cell growth or cell death pathways. Hence, elucidation of the mechanisms involved in the modulation of pro- or anti-apoptotic proteins is important in furthering understanding of breast cancer aetiology and may aid in designing prevention and treatment strategies. In the present study, we examined the role of 17β-oestradiol on the regulation of apoptosis in the breast cancer cell line MCF-7. Using multi-probe RNAase protection assays, we found changes in the mRNA levels of several Bcl-2 family proteins upon treatment of MCF-7 cells with 17β-oestradiol. Unexpectedly, we found a paradoxical effects of 17β-oestradiol on two anti-apoptotic proteins Bcl-2 and Bcl-x. Treatment with 17β-oestradiol resulted in up-regulation of Bcl-2 mRNA and protein, but down-regulated Bcl-x(L) mRNA and protein. The effect of 17β-oestradiol on Bcl-x(L) occurred at concentration-dependent fashion. The effect was specific to 17β-oestradiol since other steroid hormones exert no effect on Bcl-x(L). Tamoxifen, an anti-oestrogen, blocked the down-regulation of Bcl-x(L) by 17β-oestradiol demonstrating this effect is oestrogen receptor-dependent. We speculate that different members of the Bcl-2 family proteins may be regulated through different pathway and these pathways may be modulated by 17β-oestradiol. © 1999 Cancer Research Campaig