Unveiling the mechanism of action of 7α-acetoxy-6β-hydroxyroyleanone on an mrsa/visa strain: Membrane and cell wall interactions

UIDB/00100/2020 PTDC/MED-QUI/29036/2017 CEECIND/03414/2018 UIDB/04378/2020 PTDC/BIA-MIC/31645/2017 UID/DTP/04138/2019 UID/DTP/04567/2019 CBIOS/PRUID/BI1/2017 UIDB/04567/2020 UID/AMB/50017 UIDP/50017/2020 UIDB/50017/2020The number of cases of failure in the treatment of infections associated with resistant bacteria is on the rise, due to the decreasing efficacy of current antibiotics. Notably, 7α-Acetoxy-6β-hydroxyroyleanone (AHR), a diterpene isolated from different Plectranthus species, showed antibacterial activity, namely against Methicillin-resistant Staphylococcus aureus (MRSA) strains. The high antibacterial activity and low cytotoxicity render this natural compound an interesting alternative against resistant bacteria. The aim of this study is to understand the mechanism of action of AHR on MRSA, using the MRSA/Vancomycin-intermediate S. aureus (VISA) strain CIP 106760, and to study the AHR effect on lipid bilayers and on the cell wall. Although AHR interacted with lipid bilayers, it did not have a significant effect on membrane passive permeability. Alternatively, bacteria treated with this royleanone displayed cell wall disruption, without revealing cell lysis. In conclusion, the results gathered so far point to a yet undescribed mode of action that needs further investigation.publishersversionpublishe

Hypothalamic Inhibition Of Acetyl-coa Carboxylase Stimulates Hepatic Counter-regulatory Response Independent Of Ampk Activation In Rats.

Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability. In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation. Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.8e6266

The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies

Genetic-neuroimaging paradigms could provide insights regarding the pathophysiology of bipolar disorder (BD). Nevertheless, findings have been inconsistent across studies. A systematic review of gene-imaging studies involving individuals with BD was conducted across electronic major databases from inception until January 9th, 2017. Forty-four studies met eligibility criteria (N=2122 BD participants). Twenty-six gene variants were investigated across candidate gene studies and 4 studies used a genome-wide association approach. Replicated evidence (i.e. in >2 studies) suggests that individuals with BD carrying the BDNF Val66Met risk allele could have reduced hippocampal volumes compared to non-carriers. This review underscores the potential of gene-neuroimaging paradigms to provide mechanistic insights for BD. However, this systematic review found a single replicated finding. Suggestions to improve the reproducibility of this emerging field are provided, including the adoption of a trans-diagnostic approac

One-year timeline kinetics of cytokine-mediated cellular immunity in dogs vaccinated against visceral leishmaniasis

BACKGROUND: The main control strategy for visceral leishmaniasis in Brazil has been based on the elimination of seropositive dogs, although this is not widely accepted. In this context, the use of a long-lasting protective vaccine against canine visceral leishmaniasis (CVL) has been highly expected. The aim of this work was to determine the timeline kinetics of the cytokine microenvironment derived from circulating leukocytes as supportive immunological biomarkers triggered by Leishmune® vaccine. Cross-sectional kinetic analysis of cellular immunity cytokines was carried out at three times (1, 6 and 12 months) after primovaccination with Leishmune®. In vitro short-term whole blood cultures were stimulated with Leishmania infantum soluble antigen (SLAg). The secreted cytokine signatures and their major sources were determined. RESULTS: At six months after vaccination, Leishmune® induced an increase in IL-8, IFN-γ, IL-17a and TNF-α levels and a decrease in IL-10. Cytokine signature analysis revealed a shift in the microenvironment towards a pro-inflammatory profile mediated by IL-8 and IFN-γ. Both, CD4(+) (↑TNF-α(+) and ↑IFN-γ (+)) and CD8(+) (↑IL-17a and ↓IL-4) T-cells contributed to the acquired immune responses observed after stimulation with SLAg. CONCLUSIONS: The changes observed in the cytokine profile suggested that Leishmune® was able to induce an effective response at six months after primovaccination. After one year, it returned to baseline suggesting the need of additional boosting

The New Generation Atlas of Quasar Spectral Energy Distributions from Radio to X-rays

We have produced the next generation of quasar spectral energy distributions (SEDs), essentially updating the work of Elvis et al. (1994) by using high-quality data obtained with several space and ground-based telescopes, including NASA's Great Observatories. We present an atlas of SEDs of 85 optically bright, non-blazar quasars over the electromagnetic spectrum from radio to X-rays. The heterogeneous sample includes 27 radio-quiet and 58 radio-loud quasars. Most objects have quasi-simultaneous ultraviolet-optical spectroscopic data, supplemented with some far-ultraviolet spectra, and more than half also have Spitzer mid-infrared IRS spectra. The X-ray spectral parameters are collected from the literature where available. The radio, far-infrared, and near-infrared photometric data are also obtained from either the literature or new observations. We construct composite spectral energy distributions for radio-loud and radio-quiet objects and compare these to those of Elvis et al., finding that ours have similar overall shapes, but our improved spectral resolution reveals more detailed features, especially in the mid and near-infrared.Comment: 46 pages, 10 figures, 10 tables, Accepted by ApJS. Composite SED data files for radio-loud and radio-quiet quasars (rlmsedMR.txt, rqmsedMR.txt) are included in the source (Other formats -> Source). Supplemental figures are not include

The Brazilian Developments on the Regional Atmospheric Modeling System (BRAMS 5.2): An Integrated Environmental Model Tuned for Tropical Areas

We present a new version of the Brazilian developments on the Regional Atmospheric Modeling System where different previous versions for weather, chemistry and carbon cycle were unified in a single integrated software system. The new version also has a new set of state-of-the-art physical parameterizations and greater computational parallel and memory usage efficiency. Together with the description of the main features are examples of the quality of the transport scheme for scalars, radiative fluxes on surface and model simulation of rainfall systems over South America in different spatial resolutions using a scale-aware convective parameterization. Besides, the simulation of the diurnal cycle of the convection and carbon dioxide concentration over the Amazon Basin, as well as carbon dioxide fluxes from biogenic processes over a large portion of South America are shown. Atmospheric chemistry examples present model performance in simulating near-surface carbon monoxide and ozone in Amazon Basin and Rio de Janeiro megacity. For tracer transport and dispersion, it is demonstrated the model capabilities to simulate the volcanic ash 3-d redistribution associated with the eruption of a Chilean volcano. Then, the gain of computational efficiency is described with some details. BRAMS has been applied for research and operational forecasting mainly in South America. Model results from the operational weather forecast of BRAMS on 5 km grid spacing in the Center for Weather Forecasting and Climate Studies, INPE/Brazil, since 2013 are used to quantify the model skill of near surface variables and rainfall. The scores show the reliability of BRAMS for the tropical and subtropical areas of South America. Requirements for keeping this modeling system competitive regarding on its functionalities and skills are discussed. At last, we highlight the relevant contribution of this work on the building up of a South American community of model developers