In grapevine, anthocyanins and proanthocyanidins are the main flavonoids in berries, which are associated to organoleptic properties in red wine such as color and astringency. Flavonoid pathway is ...specifically regulated at transcriptional level and several R2R3-MYB proteins have shown to act as positive regulators. However, some members of this family have shown to repress the flavonoid biosynthesis. In this work, we present the characterization of VvMYB4-like gene, which encodes a putative transcriptional factor highly expressed in the skin of berries at the pre veraison stage in grapevine. Its over-expression in tobacco resulted in the loss of pigmentation in flowers due a decrease in anthocyanin accumulation. Severity in anthocyanin suppression observed in petals could be associated with the expression level of the VvMYB4-like transgene. Expression analysis of flavonoid structural genes revealed the strong down-regulation of the flavonoid-related genes anthocyanidin synthase (ANS) and dihydroflavonol reductase (DFR) genes and also the reduction of the anthocyanin-related gene UDP glucose:flavonoid 3-O-glucosyl transferase (UFGT), which was dependent of the transgene expression. In addition, expression of VvMYB4-like in the model plant Arabidopsis showed similar results, with the higher down-regulation observed in the AtDFR and AtLDOX genes. These results suggest that VvMYB4-like may play an important role in regulation of anthocyanin biosynthesis in grapevine acting as a transcriptional repressor of flavonoid structural genes.
Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ...ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7β (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7β-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.
Population ageing is associated with an increase in hospital admissions. Defining the factors that affect the risk of hospital readmission could identify individuals at high risk and enable targeted ...interventions to be designed. This aim of this study was to identify the risk factors for hospital readmission in elderly people. A systematic review of the literature published in English or Spanish was performed by electronically searching EMBASE, MEDLINE, CINAHL, SCI and SSCI. Some keywords were aged, elder, readmission, risk, etc. Selection criteria were: prospective cohort studies with suitable statistical analysis such as logistic regression, that explored the relationship between the risk of readmission with clinical, socio-demographic or other factors in elderly patients (aged at least 75 years) admitted to hospital. Studies that fulfilled these criteria were reviewed and data were extracted by two reviewers. We assessed the methodological quality of the studies and prepared a narrative synthesis. We included 12 studies: 11 were selected from 1392 articles identified from the electronic search and one additional reference was selected by manual review. Socio-demographic factors were only explanatory in a few models, while prior admissions and duration of hospital stay were frequently relevant factors in others. Morbidity and functional disability were the most common risk factors. The results demonstrate the need for increased vigilance of elderly patients who are admitted to hospital with specific characteristics that include previous hospital admissions, duration of hospital stay, morbidity and functional disability.
Microtubule-targeting agents that bind at the colchicine-site of tubulin are of particular interest in antitumoral therapy due to their dual mechanism of action as antimitotics and vascular ...disrupting agents. Cyclohexanediones derivatives have been described as a new family of colchicine-domain binders with an association constant to tubulin similar to that of colchicine. Here, the high-resolution structures of tubulin in complex with cyclohexanediones TUB015 and TUB075 were solved by X-ray crystallography. A detailed analysis of the tubulin-TUB075 interaction by means of computational affinity maps allowed the identification of two additional regions at the binding site that were addressed with the design and synthesis of a new series of cyclohexanediones with a distal 2-substituted benzofurane. These new compounds showed potent antiproliferative activity with IC
values in the nM range, arrested cell cycle progression at the G
/M phase and induced apoptosis at sub μM concentrations. Moreover, they caused the destruction of a preformed vascular network in vitro and inhibited the migration of endothelial cells at non-toxic concentrations. Finally, these compounds displayed high affinity for tubulin as substantiated by a K
value of 2.87 × 10
M
which, to the best of our knowledge, represents the highest binding constant measured to date for a colchicine-domain ligand.
•A Hamiltonian scheme is proposed for the Higgs boson equation for the first time.•The model is a generalization of the Higgs boson equation in the de Sitter space-time.•Generalized potential and ...fractional spatial diffusion are considered.•The scheme is mathematically analyzed both variationally and numerically.•Also, a simpler linear scheme is analyzed, and a Matlab implementation is proposed.
The present work is the first paper in the literature to report on a Hamiltonian discretization of the (fractional) Higgs boson equation in the de Sitter space-time, and its theoretical analysis. More precisely, we design herein a numerically efficient finite-difference Hamiltonian technique for the solution of a fractional extension of the Higgs boson equation in the de Sitter space-time. The model under investigation is a multidimensional equation with generalized potential and Riesz space-fractional derivatives of orders in (1,2. An energy integral for the model is readily available, and we propose a nonlinear, implicit and consistent numerical technique based on fractional-order centered differences, with similar Hamiltonian properties in the discrete scenario. A fractional energy approach is used then to prove the properties of stability and convergence of the technique. For simulation purposes, we consider both the classical and the fractional Higgs real-valued scalar fields in the de Sitter space-time, and find results qualitatively similar to those available in the literature. For the sake of convenience, we provide the Matlab code of an alternative linear discretization of the method presented in this work. This linear implicit approach is thoroughly analyzed also.
Climate change is expected to enhance weather conditions prone to wildfires. Climate regionalized projections for the Canary Islands were performed, using as boundary conditions some of the results ...provided by the Coupled Model Intercomparison Project (CMIP5) initiative, and covering the recent past (1980-2009) and future (2070-2099) periods, under two Representative Concentration Pathways, 4.5 and 8.5. All fire risk indicators derived from the Canadian Forest Fire Weather Index (FWI) are foreseen to worsen by the end of the century. The fire season could increase its length up to 75 days per year, being more noticeable as altitude increases. The extreme risk days (FWI > 60) show an average increase of 58%, reaching 12 days a year, and the area with high risk could increase by 44%. Analyzing the contribution of the different meteorological variables, it is observed that the main parameter in the fire danger index result is the temperature (currently weights 46%). However, in the future, the importance of precipitation will increase, since the rainfall reduction in some areas could reach 41%. The high dependence of the expected changes on land height, and the small size of the islands, demonstrates the necessity of using high-resolution climate regionalizations.
There is a significant number of funerary contexts for the Early Neolithic in the Iberian Peninsula, and the body of information is much larger for the Late Neolithic. In contrast, the archaeological ...information available for the period in between (ca. 4800-4400/4200 cal BC) is scarce. This period, generally called Middle Neolithic, is the least well-known of the peninsular Neolithic sequence, and at present there is no specific synthesis on this topic at the peninsular scale. In 2017, an exceptional funerary context was discovered at Dehesilla Cave (Sierra de C#225;diz, Southern Iberian Peninsula), providing radiocarbon dates which place it at the beginning of this little-known Middle Neolithic period, specifically between ca. 4800-4550 cal BC. Locus 2 is a deposition constituted by two adult human skulls and the skeleton of a very young sheep/goat, associated with stone structures and a hearth, and a number of pots, stone and bone tools and charred plant remains. The objectives of this paper are, firstly, to present the new archaeological context documented at Dehesilla Cave, supported by a wide range of data provided by interdisciplinary methods. The dataset is diverse in nature: stratigraphic, osteological, isotopic, zoological, artifactual, botanical and radiocarbon results are presented together. Secondly, to place this finding within the general context of the contemporaneous sites known in the Iberian Peninsula through a systematic review of the available evidence. This enables not only the formulation of explanations of the singular new context, but also to infer the possible ritual funerary behaviours and practices in the 5.sup.th millennium cal BC in the Iberian Peninsula.
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