Bisindolylmaleimides New Ligands of CaM Protein Sosa-Peinado, Alejandro; Fructuoso-García, Karina; Vásquez-Bochm, L. X. ...
Molecules (Basel, Switzerland),
10/2022, Letnik:
27, Številka:
21
Journal Article
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In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide ...compounds are drug prototypes derived from Staurosporine, an alkaloid with activity for cancer treatment. Bisindolylmaleimide compounds II, IV, VII, X, and XI, are proposed and reported as possible inhibitors of calmodulin protein for the first time. For the above, a biotechnological device was used (fluorescent biosensor hCaM M124C-mBBr) to directly determine binding parameters experimentally (Kd and stoichiometry) of these compounds, and molecular modeling tools (Docking, Molecular Dynamics, and Chemoinformatic Analysis) to carry out the theoretical studies and complement the experimental data. The results indicate that this compound binds to calmodulin with a Kd between 193–248 nM, an order of magnitude lower than most classic inhibitors. On the other hand, the theoretical studies support the experimental results, obtaining an acceptable correlation between the ΔGExperimental and ΔGTheoretical (r2 = 0.703) and providing us with complementary molecular details of the interaction between the calmodulin protein and the Bisindolylmaleimide series. Chemoinformatic analyzes bring certainty to Bisindolylmaleimide compounds to address clinical steps in drug development. Thus, these results make these compounds attractive to be considered as possible prototypes of new calmodulin protein inhibitors.
Although epidemiological cutoff values (ECVs) have been established for Candida spp. and the triazoles, they are based on MIC data from a single laboratory. We have established ECVs for eight Candida ...species and fluconazole, posaconazole, and voriconazole based on wild-type (WT) MIC distributions for isolates of C. albicans (n=11,241 isolates), C. glabrata (7,538), C. parapsilosis (6,023), C. tropicalis (3,748), C. krusei (1,073), C. lusitaniae (574), C. guilliermondii (373), and C. dubliniensis (162). The 24-h CLSI broth microdilution MICs were collated from multiple laboratories (in Canada, Brazil, Europe, Mexico, Peru, and the United States). The ECVs for distributions originating from ≥6 laboratories, which included ≥95% of the modeled WT population, for fluconazole, posaconazole, and voriconazole were, respectively, 0.5, 0.06 and 0.03 μg/ml for C. albicans, 0.5, 0.25, and 0.03 μg/ml for C. dubliniensis, 8, 1, and 0.25 μg/ml for C. glabrata, 8, 0.5, and 0.12 μg/ml for C. guilliermondii, 32, 0.5, and 0.25 μg/ml for C. krusei, 1, 0.06, and 0.06 μg/ml for C. lusitaniae, 1, 0.25, and 0.03 μg/ml for C. parapsilosis, and 1, 0.12, and 0.06 μg/ml for C. tropicalis. The low number of MICs (<100) for other less prevalent species (C. famata, C. kefyr, C. orthopsilosis, C. rugosa) precluded ECV definition, but their MIC distributions are documented. Evaluation of our ECVs for some species/agent combinations using published individual MICs for 136 isolates (harboring mutations in or upregulation of ERG11, MDR1, CDR1, or CDR2) and 64 WT isolates indicated that our ECVs may be useful in distinguishing WT from non-WT isolates.
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•Chemical properties of 148 ash samples from across the globe were analysed.•Ash chemical composition varied greatly amongst, but also within, ecosystems.•Burn severity and ...post-rainfall sampling strongly affected ash chemical composition.•Some ashes were high in metal concentrations of concern for humans and ecosystems.•The approach can serve as initial standardization of sampling and analysis protocols.
The mobilisation of potentially harmful chemical constituents in wildfire ash can be a major consequence of wildfires, posing widespread societal risks. Knowledge of wildfire ash chemical composition is crucial to anticipate and mitigate these risks.
Here we present a comprehensive dataset on the chemical characteristics of a wide range of wildfire ashes (42 types and a total of 148 samples) from wildfires across the globe and examine their potential societal and environmental implications. An extensive review of studies analysing chemical composition in ash was also performed to complement and compare our ash dataset.
Most ashes in our dataset had an alkaline reaction (mean pH 8.8, ranging between 6 and 11.2). Important constituents of wildfire ash were organic carbon (mean: 204 g kg−1), calcium, aluminium, and iron (mean: 47.9, 17.9 and 17.1 g kg−1). Mean nitrogen and phosphorus ranged between 1 and 25 g kg−1, and between 0.2 and 9.9 g kg−1, respectively. The largest concentrations of metals of concern for human and ecosystem health were observed for manganese (mean: 1488 mg kg−1; three ecosystems > 1000 mg kg−1), zinc (mean: 181 mg kg−1; two ecosystems > 500 mg kg−1) and lead (mean: 66.9 mg kg−1; two ecosystems > 200 mg kg−1). Burn severity and sampling timing were key factors influencing ash chemical characteristics like pH, carbon and nitrogen concentrations. The highest readily dissolvable fractions (as a % of ash dry weight) in water were observed for sodium (18 %) and magnesium (11.4 %). Although concentrations of elements of concern were very close to, or exceeded international contamination standards in some ashes, the actual effect of ash will depend on factors like ash loads and the dilution into environmental matrices such as water, soil and sediment. Our approach can serve as an initial methodological standardisation of wildfire ash sampling and chemical analysis protocols.
Abstract
Sierra Negra (SN) is a high summit (4580 m asl) inside the Pico de Orizaba National Park in eastern Mexico (coordinates 18.98N, 97.46W). Its location is favourable for astrophysical ...observations, therefore it has been selected as the site of various observatories. In this work, the behaviour of several atmospheric parameters (pressure, temperature, wind speed and relative humidity) was performed for the period 2012 July to 2015 October. The parameters chosen are known to have some influence in the time variability of the cosmic ray flux from the top of the atmosphere to the observation place. This study will help a proper characterization of the atmosphere. Moreover, a comparison with a similar study done a decade ago by Carrasco et al. allows us to analyse the evolution of the parameters with time and assess the stability of the atmospheric conditions of the site. Similarities and differences with the Carrasco et al. study are discussed.
Clinical and Laboratory Standards Institute (CLSI) conditions for testing the susceptibilities of pathogenic
species to antifungal agents are based on a collaborative study that evaluated five ...clinically relevant isolates of
and some antifungal agents. With the advent of molecular identification, there are two basic needs: to confirm the suitability of these testing conditions for all agents and
species and to establish species-specific epidemiologic cutoff values (ECVs) or breakpoints (BPs) for the species. We collected available CLSI MICs/minimal effective concentrations (MECs) of amphotericin B, five triazoles, terbinafine, flucytosine, and caspofungin for 301
, 486
, 75
, and 13
molecularly identified isolates. Data were obtained in 17 independent laboratories (Australia, Europe, India, South Africa, and South and North America) using conidial inoculum suspensions and 48 to 72 h of incubation at 35°C. Sufficient and suitable data (modal MICs within 2-fold concentrations) allowed the proposal of the following ECVs for
and
, respectively: amphotericin B, 4 and 4 μg/ml; itraconazole, 2 and 2 μg/ml; posaconazole, 2 and 2 μg/ml; and voriconazole, 64 and 32 μg/ml. Ketoconazole and terbinafine ECVs for
were 2 and 0.12 μg/ml, respectively. Insufficient or unsuitable data precluded the calculation of ketoconazole and terbinafine (or any other antifungal agent) ECVs for
, as well as ECVs for
and
These ECVs could aid the clinician in identifying potentially resistant isolates (non-wild type) less likely to respond to therapy.
In association with the X28 solar flare on November 4, 2003, the muon telescope installed in Mexico City observed an enhancement in its counting rate between 19:55 and 20:00 UT. Based on a numerical ...simulation, we found that the entry of a high-energy solar neutron, with energy range from 0.2 to 2 GeV, is capable of producing muon flux that reach the atmospheric depth of Mexico City. Furthermore, we also found that this muon flux is of the order of 3% with respect to the average muon flux recorded by the telescope. Therefore it is very likely that the excess signals observed in the muon telescope are due to muons generated by solar neutrons in the Earth’s atmosphere.
The objective of the present study was to assess the predictive ability of subsets of single nucleotide polymorphism (SNP) markers for development of low-cost, low-density genotyping assays in dairy ...cattle. Dense SNP genotypes of 4,703 Holstein bulls were provided by the USDA Agricultural Research Service. A subset of 3,305 bulls born from 1952 to 1998 was used to fit various models (training set), and a subset of 1,398 bulls born from 1999 to 2002 was used to evaluate their predictive ability (testing set). After editing, data included genotypes for 32,518 SNP and August 2003 and April 2008 predicted transmitting abilities (PTA) for lifetime net merit (LNM$), the latter resulting from progeny testing. The Bayesian least absolute shrinkage and selection operator method was used to regress August 2003 PTA on marker covariates in the training set to arrive at estimates of marker effects and direct genomic PTA. The coefficient of determination (R2) from regressing the April 2008 progeny test PTA of bulls in the testing set on their August 2003 direct genomic PTA was 0.375. Subsets of 300, 500, 750, 1,000, 1,250, 1,500, and 2,000 SNP were created by choosing equally spaced and highly ranked SNP, with the latter based on the absolute value of their estimated effects obtained from the training set. The SNP effects were re-estimated from the training set for each subset of SNP, and the 2008 progeny test PTA of bulls in the testing set were regressed on corresponding direct genomic PTA. The R2 values for subsets of 300, 500, 750, 1,000, 1,250, 1,500, and 2,000 SNP with largest effects (evenly spaced SNP) were 0.184 (0.064), 0.236 (0.111), 0.269 (0.190), 0.289 (0.179), 0.307 (0.228), 0.313 (0.268), and 0.322 (0.291), respectively. These results indicate that a low-density assay comprising selected SNP could be a cost-effective alternative for selection decisions and that significant gains in predictive ability may be achieved by increasing the number of SNP allocated to such an assay from 300 or fewer to 1,000 or more.
•Solar neutron flux.•Simulations.•Olar neutron telescope.
We performed simulations of the solar neutron (ns) flux in the Earth's atmosphere associated with three significant flares (X17 of September ...07, 2005, X1.3 of September 07, 2017 and M2.9 of September 08, 2017). The input of the simulations was calculated on the basis of ns signals detected at ground level by the Solar Neutron Telescope of Sierra Negra (SNT-SN), in Mexico, and by the FIB scintillator of the Space Environment Data Acquisition-Attached Payload on board of the International Space Station. Since ns can produce Extensive Air Showers (EAS) in the Earth's atmosphere, we used the CORSIKA code and FLUKA subroutines to simulate the particle fluxes associated with the X17, X1.3 and M2.9 flares. We studied the average longitudinal variations of particle flux and energy loss through the atmosphere to estimate the ns flux impinging on the SNT-SN. The results of the simulated interactions and multiplicities of the particles, as a function of their energy, showed that 11–13% of the ns, released by the X17 flare, could overcome the atmospheric attenuation and propagate from the top of the atmosphere to the SNT-SN (4580 m a.s.l.) without producing EAS. On the other hand, ns associated with the X1.3 and M2.9 flares were lost due to atmospheric attenuation and the production of new particles; therefore, they were not detected at ground level by the SNT- SN. The characterization of these events allowed to develop an automatic tool for the analysis of ns emissions associated with solar flares.
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