Stroke is the third cause of death worldwide and the main cause of chronic, severe adult disability. We focus on acute ischaemic stroke, which accounts for approximately 80% of all strokes. The ...current therapy aims at restoring cerebral blood flow within a narrow time window in order to prevent damaging the "penumbra" which surrounds the infarct core. Intravenous thrombolysis remains the fundamental treatment worldwide, though not ideal for various restrictions and complications, limiting to 10% or less the percentage of patients treated within the appropriate time window. Neuroprotection is an alternative or adjunct approach to thrombolysis, targeting cerebral parenchyma in the acute ischaemic phase. Furthermore, neurorepair attempts to restore neuronal function in the after-stroke phase in those patients (treated or untreated) with significant impairment. In the past decades, the efficacy and safety of numerous candidate neuroprotective agents were shown in various animal stroke models. However, in clinical trials, promising pre-clinical studies have not been translated into positive outcomes. Our review will analyse the possible reasons for this failure and the new approaches and recommendations to overcome it, as well as novel strategies targeting additional events in ischaemia cascade. The combination of thrombolysis with pharmacological and non-pharmacological neuroprotective approaches has also been tested. Finally, the neurorepair strategy will be described with special emphasis on the role of cell-based therapies and ischaemic conditioning. Hopefully, the future therapy of ischaemic stroke will encompass a combination of neuroprotection (to stabilise penumbra), thrombolysis, antithrombotics (for secondary prevention) and neurorepair based on cell therapy plus rehabilitation.
This review summarizes the information on biochemical and biological activity of the main
mycotoxins, focusing on toxicological aspects in terms of species-specific effects. Both in vitro and in vivo ...studies have centered on the peculiarity of the responses to mycotoxins, demonstrating that toxicokinetics, bioavailability and the mechanisms of action of these substances vary depending on the species involved, but additional studies are needed to better understand the specific responses. The aim of this review is to summarize the toxicological responses of the main species affected by
mycotoxins.
The Fusarium incarnatum-equiseti species complex (FIESC) comprises 33 phylogenetically distinct species that have been recovered from diverse biological sources, but have been most often isolated ...from agricultural plants and soils. Collectively, members of FIESC can produce diverse mycotoxins. However, because the species diversity of FIESC has been recognized only recently, the potential of species to cause mycotoxin contamination of crop plants is unclear. In this study, therefore, we used comparative genomics to investigate the distribution of and variation in genes and gene clusters responsible for the synthesis of mycotoxins and other secondary metabolites (SMs) in FIESC.
We examined genomes of 13 members of FIESC that were selected based primarily on their phylogenetic diversity and/or occurrence on crops. The presence and absence of SM biosynthetic gene clusters varied markedly among the genomes. For example, the trichothecene mycotoxin as well as the carotenoid and fusarubin pigment clusters were present in all genomes examined, whereas the enniatin, fusarin, and zearalenone mycotoxin clusters were present in only some genomes. Some clusters exhibited discontinuous patterns of distribution in that their presence and absence was not correlated with the phylogenetic relationships of species. We also found evidence that cluster loss and horizontal gene transfer have contributed to such distribution patterns. For example, a combination of multiple phylogenetic analyses suggest that five NRPS and seven PKS genes were introduced into FIESC from other Fusarium lineages.
Our results suggest that although the portion of the genome devoted to SM biosynthesis has remained similar during the evolutionary diversification of FIESC, the ability to produce SMs could be affected by the different distribution of related functional and complete gene clusters.
This article addresses the bi-objective integer cutting stock problem in one dimension. This problem has great importance and use in various industries, including steel mills. The bi-objective model ...considered aims to minimize the frequency of cutting patterns to meet the minimum demand for each item requested and the number of different cutting patterns to be used, being these conflicting objectives. In this study, we apply three classic methods of scalarization: weighted sum, Chebyshev metric and ε-Constraint. This last method is developed to obtain all of the efficient solutions. Also, we propose and test a fourth method, modifying the Chebyshev metric, without the insertion of additional variables in the formulation of the sub-problems. The computational experiments with randomly generated real size instances illustrate and attest the suitability of the bi-objective model for this problem, as well as the applicability of all the proposed exact algorithms, thus showing that they are useful tools for decision makers in this area. Moreover, the modified metric method improved with respect to the performance of the classical version in the tests.
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•Shows how the stowage planning and quay crane scheduling problems are interrelated.•Helps the charterer to not be charged for the extra use of the vessel.•Shows number of movement’s ...minimization does not minimize the ship stay time in port.•Explains a long term tendency of continuous increasing on container ship size.
The operational efficiency of a port depends on proper container movement planning, called “stowage planning”, especially because unloading and loading container ships demands time, and this has a cost. Thus, the optimization of operations through stages is important to avoid blockage activities. This paper proposes a framework for solving the 3D stowage planning (3D SP) problem for container ships integrated with the scheduling of quay cranes (SQC) problem. 3D SP and SQC problems are interrelated and combinatorial, justifying the applications of meta-heuristics like a genetic algorithm combined with simulation and representation by rules. The robustness of the developed approach is attested in problems with 30 ports, 1500 TEUs ship or 15 ports and 22,000 TEUs ship and two quay cranes. These studies showed that the addition of the SQC problem leads to a 45.82% increase in load/unload time for the 3D SP problem solution, on average. This could help the charterer to avoid paying charges to the shipowner due to its an extra unplanned use of the vessel. Additionally, the developed methodology also helps to explain a long term phenomena of continuous increasing in container ship capacity since 1950s.
, the main aflatoxin B₁ producing fungal species,
, a deoxynivalenol producer, and the fumonisin-producing species
and
are the main toxigenic fungi (TF) that colonize maize. Several strategies are ...available to control TF and related mycotoxins, such as chemical control. However, there is poor knowledge on the efficacy of fungicides on maize plants since few molecules are registered. The sensitivity of
,
,
, and
to eleven fungicides, selected based on their different modes of action, was evaluated in both in vitro assays and, after selection, in the field. In vitro, demethylation inhibitors (DMI) showed excellent performances, followed by thiophanate-methyl and folpet. Among the succinate dehydrogenase inhibitors (SDHI), isopyrazam showed a higher effectiveness against Fusarium species than boscalid, which was ineffective against Fusarium, like the phenyl-pyrrole fludioxonil. Furthermore, both SDHIs and fludioxonil were more active against
than Fusarium species. In field trials, prothioconazole and thiophanate-methyl were confirmed to be effective to reduce
(52% and 48%) and
contamination (44% and 27%). On the other hand, prothioconazole and boscalid could reduce
contamination at values of 75% and 56%, respectively.
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Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia ...are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy.
The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM.
This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.
Background: Tumor necrosis factor‐α (TNF‐α) plays a central role in the molecular pathogenesis of periodontal disease. However, the epigenetic regulation attributable to microbial and inflammatory ...signals at the biofilm–gingival interface are poorly understood. In this study, the DNA methylation alteration within the TNFA promoter in human gingival biopsies from different stages of periodontal disease is investigated and the regulatory mechanism of TNFA transcription by DNA methylation is explored.
Methods: Gingival biopsies were obtained from 17 patients with chronic periodontitis (CP) and 18 periodontally healthy individuals. Another 11 individuals participated in an experimentally induced gingivitis study, and gingival biopsies were collected at the baseline, induction, and resolution phase. To confirm that TNFA promoter methylation modulated TNFA transcription, THP.1 cells were treated with a DNA methyltransferase inhibitor, 5‐Aza‐2‐deoxycytidine (5‐Aza‐2dC), and an RAW294.7 cell line transfected with a TNFA promoter‐specific luciferase reporter system with or without methylation was used.
Results: In gingival biopsies from individuals with severe CP, two individual cytosine‐guanine dinucleotides (CpG sites) within the TNFA promoter (at −163 and −161 bp) displayed increased methylation in CP samples compared to those with gingival health (16.1% ± 5.1% versus 11.0% ± 4.6%, P = 0.02 and 19.8% ± 4.1% versus 15.4% ± 3.6%, P = 0.04, respectively). The methylation level at −163 bp was inversely associated with the transcription level of TNFA (P = 0.018). However, no significant difference in the TNFA promoter methylation pattern was observed in samples biopsied during the induction or resolution phase of experimentally induced gingivitis, which represented a reversible periodontal lesion. THP.1 cells treated with 5‐Aza‐2dC demonstrated a time‐dependent increase in TNFA messenger level. It was also found that the luciferase activity decreased 2.6‐fold in a construct containing an in vitro methylated TNFA promoter when compared to the unmethylated insert (P = 0.03).
Conclusion: Although the biopsy samples represented a mixed cell population, the change in promoter methylation status in chronic periodontal disease suggested that DNA methylation may be an important regulatory mechanism in controlling TNFA transcriptional expression in periodontal disease.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2-4 years from the time of diagnosis. Although ...IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.
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