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Abstract: Ethnopharmacological relevance: Chaga mushroom (Inonotus obliquus) has been used in folk medicine to treat several disorders through its various biological functions. I. obliquus is claimed to produce general immune-potentiating and strengthening, antiinflammatory, and antitumor properties, but its effects on intestinal inflammation (ulcerative colitis) are clearly not understood. Aim of the study: To determine the effects and mode of action of an aqueous extract of I. obliquus (IOAE) on experimental colitis in mice induced by dextran sulfate sodium (DSS). Materials and methods: Female 5-week-C57BL/6 mice were randomized into groups differing in treatment conditions (prevention and treatment) and doses of IOAE (50 and 100mg/kg body weight). Mice were exposed to DSS (2%) in their drinking water over 7 day to induce acute intestinal inflammation. In colon tissues, we evaluated histological changes by hematoxylin and eosin staining, levels of iNOS by immuno-histochemical staining, and neutrophil influx by myeloperoxidase assay. mRNA expression of pro-inflammatory mediators TNF-α, IL-1β, IL-6, and IFN-γ was determined by RT-PCR. Results: Histological examinations indicated that IOAE suppressed edema, mucosal damage, and the loss of crypts induced by DSS. IOAE markedly attenuated DSS-induced iNOS levels and myeloperoxidase accumulation in colon tissues, demonstrating its suppressive effect on infiltration of immune cells. In addition, IOAE significantly inhibited mRNA expression of pro-inflammatory cytokines induced by DSS in colon tissues. Conclusion: Our results suggest anti-inflammatory effect of IOAE at colorectal sites due to down-regulation of the expression of inflammatory mediators. Suppression of TNF-α and iNOS together with IL-1β by IOAE denotes that it might be a useful supplement in the setting of inflammatory bowel disease. [Copyright &y& Elsevier]

Abstract: In this paper, we design stable and accurate numerical schemes for conservation laws with stiff source terms. A prime example and the main motivation for our study is the reactive Euler equations of gas dynamics. Furthermore, we consider widely studied scalar model equations. We device one-step IMEX (implicit–explicit) schemes for these equations that treats the convection terms explicitly and the source terms implicitly. For the non-linear scalar equation, we use a novel choice of initial data for the resulting Newton solver and obtain correct propagation speeds, even in the difficult case of rarefaction initial data. For the reactive Euler equations, we choose the numerical diffusion suitably in order to obtain correct wave speeds on under-resolved meshes. We prove that our implicit–explicit scheme converges in the scalar case and present a large number of numerical experiments to validate our scheme in both the scalar case as well as the case of reactive Euler equations. Furthermore, we discuss fundamental differences between the reactive Euler equations and the scalar model equation that must be accounted for when designing a scheme. [ABSTRACT FROM AUTHOR]

• Novel machine learning algorithm based on physics informed neural networks (PINNs) for approximating solutions of forward and inverse problems for radiative transfer. • Fast, robust and accurate approach, independent of the equation dimensionality. • Estimates on the generalization error of PINNs for the unsteady and steady forward problem. • Extensive numerical experiments demonstrating the accuracy and efficiency of the proposed algorithm. We propose a novel machine learning algorithm for simulating radiative transfer. Our algorithm is based on physics informed neural networks (PINNs), which are trained by minimizing the residual of the underlying radiative transfer equations. We present extensive experiments and theoretical error estimates to demonstrate that PINNs provide a very easy to implement, fast, robust and accurate method for simulating radiative transfer. We also present a PINN based algorithm for simulating inverse problems for radiative transfer efficiently. [ABSTRACT FROM AUTHOR]

Abstract: We deal with a single conservation law with discontinuous convex–concave type fluxes which arise while considering sign changing flux coefficients. The main difficulty is that a weak solution may not exist as the Rankine–Hugoniot condition at the interface may not be satisfied for certain choice of the initial data. We develop the concept of generalized entropy solutions for such equations by replacing the Rankine–Hugoniot condition by a generalized Rankine–Hugoniot condition. The uniqueness of solutions is shown by proving that the generalized entropy solutions form a contractive semi-group in . Existence follows by showing that a Godunov type finite difference scheme converges to the generalized entropy solution. The scheme is based on solutions of the associated Riemann problem and is neither consistent nor conservative. The analysis developed here enables to treat the cases of fluxes having at most one extrema in the domain of definition completely. Numerical results reporting the performance of the scheme are presented. [Copyright &y& Elsevier]

We present a novel active learning algorithm, termed as iterative surrogate model optimization (ISMO), for robust and efficient numerical approximation of PDE constrained optimization problems. This algorithm is based on deep neural networks and its key feature is the iterative selection of training data through a feedback loop between deep neural networks and any underlying standard optimization algorithm. Numerical examples for optimal control, parameter identification and shape optimization problems for PDEs are provided to demonstrate that ISMO significantly outperforms a standard deep neural network based surrogate optimization algorithm as well as standard optimization algorithms. [ABSTRACT FROM AUTHOR]

We derive bounds on the error, in high-order Sobolev norms, incurred in the approximation of Sobolev-regular as well as analytic functions by neural networks with the hyperbolic tangent activation function. These bounds provide explicit estimates on the approximation error with respect to the size of the neural networks. We show that tanh neural networks with only two hidden layers suffice to approximate functions at comparable or better rates than much deeper ReLU neural networks. • Explicit bounds for function approximation in Sobolev norms by tanh neural networks. • Tanh networks with 2 hidden layers are at least as expressive as deeper ReLU networks. • Improved convergence rate for neural network approximation of analytic functions. [ABSTRACT FROM AUTHOR]

In the present study, we developed a novel drug-like self-micellizing anticancer lipid (SMAL), and investigated its anticancer activity and effects on cell death pathways in human colorectal cancer (CRC) cell lines. Three self-assembled nanoparticles were prepared, namely, SMAL102 (lauramide derivative), SMAL104 (palmitamide derivative), and SMAL108 (stearamide derivative) by a thin-film hydration technique, and were characterized for physicochemical and biological parameters. SMAL102 were nanosized (160.23 ± 8.11 nm) with uniform spherical shape, while SMAL104 and SMAL108 did not form spherical shape but formed large size nanoparticles and irregular in shape. Importantly, SMAL102 showed a cytotoxic effect towards CRC cell lines (HCT116 and HT-29), and less toxicity to a normal colon fibroblast cell line (CCD-18Co). Conversely, SMAL104 and SMAL108 did not have an anti-proliferative effect on CRC cell lines. SMAL102 nanoparticles were actively taken up by CRC cell lines, localized in the cell membrane, and exhibited remarkable cytotoxicity in a concentration-dependent manner. The normal colon cell line showed significantly less cellular uptake and non-cytotoxicity as compared with the CRC cell lines. SMAL102 nanoparticles induced caspase-3, caspase-9, and PARP cleavage in HT-29 cells, indicating the induction of apoptosis; whereas LC3B was activated in HCT116 cells, indicating autophagy-induced cell death. Collectively, these results demonstrate that SMAL102 induced cell death via activation of apoptosis and autophagy in CRC cell lines. The present study could be a pioneer for further preclinical and clinical development of such compounds. [ABSTRACT FROM AUTHOR]

Aim of the study In this study, we examined the effect of different fractions and components of Chaga mushroom (Inonotus Obliquus) on viability and apoptosis of colon cancer cells. Among them, one component showed the most effective growth inhibition and was identified as ergosterol peroxide by NMR analysis. We investigated the anti-proliferative and apoptosis mechanisms of ergosterol peroxide associated with its anti-cancer activities in human colorectal cancer (CRC) cell lines and tested its anti-tumor effect on colitis-induced CRC developed by Azoxymethane (AOM)/Dextran sulfate sodium (DSS) in a mouse model. Materials and methods We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, Western blot analysis, colony formation assays, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and AOM/DSS mouse models to study the molecular mechanism of metastatic activities in CRC cells. Results Ergosterol peroxide inhibited cell proliferation and also suppressed clonogenic colony formation in HCT116, HT-29, SW620 and DLD-1 CRC cell lines. The growth inhibition observed in these CRC cell lines was the result of apoptosis, which was confirmed by FACS analysis and Western blotting. Ergosterol peroxide inhibited the nuclear levels of β-catenin, which ultimately resulted in reduced transcription of c-Myc, cyclin D1, and CDK-8. Ergosterol peroxide administration showed a tendency to suppress tumor growth in the colon of AOM/DSS-treated mice, and quantification of the IHC staining showed a dramatic decrease in the Ki67-positive staining and an increase in the TUNEL staining of colonic epithelial cells in AOM/DSS-treated mice by ergosterol peroxide for both prevention and therapy. Conclusion Our data suggest that ergosterol peroxide suppresses the proliferation of CRC cell lines and effectively inhibits colitis-associated colon cancer in AOM/DSS-treated mice. Ergosterol peroxide down-regulated β-catenin signaling, which exerted anti-proliferative and pro-apoptotic activities in CRC cells. These properties of ergosterol peroxide advocate its use as a supplement in colon cancer chemoprevention. [ABSTRACT FROM AUTHOR]

• Cardiac arrhythmias, atrial filtration and ventricular tachycardia, mainly caused by the autonomic nervous system. • Conventional strategies have been overcome using parasympathetic and sympathetic stimulation. • Therapeutic modalities associated with VNS, tragus stimulation, RDN, BAT and CSD may be promising. • Heart rate variability, skin sympathetic nerve activity using microneurography, and alternans are a few autonomic tone evaluation techniques. The pathophysiology of atrial fibrillation and ventricular tachycardia that result in cardiac arrhythmias is related to the sustained complicated mechanisms of the autonomic nervous system. Atrial fibrillation is when the heart beats irregularly, and ventricular arrhythmias are rapid and inconsistent heart rhythms, which involves many factors including the autonomic nervous system. It's a complex topic that requires careful exploration. Cultivation of speculative knowledge on atrial fibrillation; the irregular rhythm of the heart and ventricular arrhythmias; rapid oscillating waves resulting from mistakenly inconsistent P waves, and the inclusion of an autonomic nervous system is an inconceivable approach toward clinical intricacies. Autonomic modulation, therefore, acquires new expansions and conceptions of appealing therapeutic intelligence to prevent cardiac arrhythmia. Notably, autonomic modulation uses the neural tissue's flexibility to cause remodeling and, hence, provide therapeutic effects. In addition, autonomic modulation techniques included stimulation of the vagus nerve and tragus, renal denervation, cardiac sympathetic denervation, and baroreceptor activation treatment. Strong preclinical evidence and early human studies support the annihilation of cardiac arrhythmias by sympathetic and parasympathetic systems to transmigrate the cardiac myocytes and myocardium as efficient determinants at the cellular and physiological levels. However, the goal of this study is to draw attention to these promising early pre-clinical and clinical arrhythmia treatment options that use autonomic modulation as a therapeutic modality to conquer the troublesome process of irregular heart movements. Additionally, we provide a summary of the numerous techniques for measuring autonomic tone such as heart rate oscillations and its association with cutaneous sympathetic nerve activity appear to be substitute indicators and predictors of the outcome of treatment. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease affecting people of all ages worldwide. Side effects of antiepileptic drugs and their association with oxidative stress stimulate the search for new drugs, which would be more affordable with fewer adverse effects. Accordingly, the aim of the present work is to evaluate the anticonvulsant effect of anacardic acid (AA), a natural compound extracted from cashew liquid ( Anacardium occidentalis ), in murine models, as well as its antioxidant actions in Saccharomyces cerevisiae . AA (>90% purity) was tested, in vivo , in male Swiss mice (25–30 g) with four convulsive models, (1) pentylenetetrazole, (2) pilocarpine, (3) electroshock, and (4) kainic acid, at doses of 25, 50, and 100 mg/kg, body weight (B.W.) Additionally, the effective dose, toxic dose, and protective index studies were also performed. Results revealed that AA exhibits anticonvulsive effects in models 1, 3, and 4, with a mean effective dose (ED 50 ) of 39.64 (model 1) >100 mg/kg, B.W. (model 2), and 38.36 (model 3); furthermore, AA displays a protection index of 1.49 (model 1), <0.6 (model 2, and 1.54 (model 3). In addition, AA showed antioxidant activities in S. cerevisiae mutated for superoxide dismutases (SOD). In conclusion, these results show that AA exhibits significant anticonvulsant and antioxidant activities and may be used as a promising natural product for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Omeprazole (OME) is a proton pump inhibitor used for the treatment of various gastric and intestinal disease; however, studies on its effects on the genetic materials are still restricted. The present study aimed to evaluate possible toxicogenic effects of OME in Allium cepa meristems with the application of cytogenetic biomarkers for DNA damage, mutagenic, toxic and cytotoxic effects. Additionally, retinol palmitate (RP) and ascorbic acid (AA) were also co-treated with OME to evaluate possible modulatory effects of OME-induced cytogenetic damages. OME was tested at 10, 20 and 40 μg/mL, while RP and AA at 55 μg/mL and 352.2 μg/mL, respectively. Copper sulphate (0.6 μg/mL) and dechlorinated water were used as positive control and negative control, respectively. The results suggest that OME induced genotoxicity and mutagenicity in A. cepa at all tested concentrations. It was noted that cotreatment of OME with the antioxidant vitamins RP and/or AA significantly (p < 0.05) inhibited and/or modulated all toxicogenic damages induced by OME. These observations demonstrate their antigenotoxic, antimutagenic, antitoxic and anticitotoxic effects in A. cepa . This study indicates that application of antioxidants may be useful tools to overcome OME-induced toxic effects. [ABSTRACT FROM AUTHOR]

Citrinin (CIT) is a mycotoxin which causes contamination in the food and is associated with different toxic effects. A web search on CIT has been conducted covering the timespan since 1946. The accumulated data indicate that CIT is produced by several fungal strains belonging to Penicillium, Aspergillus and Monascus genera, and is usually found together with another nephrotoxic mycotoxin, ochratoxin A. Although, it is evident that CIT exposure can exert toxic effects on the heart, liver, kidney, as well as reproductive system, the mechanism of CIT-induced toxicity remains largely elusive. It is still controversial what are the genotoxic and mutagenic effects of CIT. Until now, its toxic effect has been linked to the CIT-mediated oxidative stress and mitochondrial dysfunction in biological systems. However, the toxicity strongly depends on its concentration, route, frequency and time of exposure, as well as from the used test systems. Besides the toxic effects, CIT is also reported to possess a broad spectrum of bioactivities, including antibacterial, antifungal, and potential anticancer and neuro-protective effects in vitro. This systematic review presents the current state of CIT research with emphasis on its bioactivity profile. [ABSTRACT FROM AUTHOR]

• [6]-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] is a phenolic substance with several pharmacological properties. • [6]-Gingerol showed antitumoral effects in primary cells of Sarcoma 180 as well as in peripheral blood lymphocytes of mice. • [6]-Gingerol induced cytogenetic changes in S-180 cells, biomarkers of genotoxicity, mutagenicity, apoptosis and necrosis. • [6]-Gingerol may be an antitumoral agent with mechanisms associated with reducing genetic instability inducing apoptosis. [6]-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] is a phenolic substance reported for several ethnopharmacological usage by virtue of its antioxidant, antiemetic, anti-inflammatory and anticancer properties. This study assessed the antitumoral effects of [6]-Gingerol in primary cells of Sarcoma 180 as well as in peripheral blood lymphocytes of mice. The effect of [6]-Gingerol was assessed by applying cytogenetic biomarkers as indicative of genotoxicity, mutagenicity and apoptosis. Ascitic liquid cells were treated with [6]-Gingerol at concentrations of 21.33, 42.66 and 85.33 μM and subjected to the cytotoxicity assays using Trypan blue test and the comet assay, as well as the cytokinesis-block micronucleus assay. Doxorubicin (6 μM) and hydrogen peroxide (85.33 μM) were used as positive controls. [6]-Gingerol, especially at concentrations of 42.66 and 85.33 μM, showed notable cytotoxicity in Sarcoma 180 cells by reducing cell viability and cell division rates via induction of apoptosis. Genotoxicity at the concentrations used was punctuated by the increase in the index and frequency of DNA damage in tested groups. [6]-Gingerol, at all concentrations tested, did not induce significant aneugenic and/or clastogenic effects. It did, however, induced other nuclear abnormalities, such as nucleoplasmic bridges, nuclear buds and apoptosis. The genotoxic effects observed in the cotreatment with H 2 O 2 (challenge assay) employing neoplastic and healthy cells, indicated that [6]-Gingerol may induce oxidative stress. Observations suggest that [6]-Gingerol may be a candidate for pharmaceutical antitumoral formulations due to its cytotoxicity and to mechanisms associated with genetic instability generated by nuclear alterations especially by apoptosis. [ABSTRACT FROM AUTHOR]