Structure-activity relationships based on 3D-QSAR CoMFA/CoMSIA and design of aryloxypropanol-amine agonists with selectivity for the human β3-adrenergic receptor and anti-obesity and anti-diabetic profiles

Indexación: Scopus.Acknowledgments: This work was supported by FONDECYT No. 11130701. We would also like to thank fDoTr CthLeafbr efeora vthaeil afrbeilei tayvoafiltahbeilsitoyf towfa trheer seoqfutwireadret orecqaulciureladt etothcealAcuDla(thet ttph:e/ A/dDt c(lhatbt.pw:/e/dbstc.cloabm.w/seobfst.wcoamre/-stoofotlws aarned-tools and http://teqip.jdvu.ac.in/QSAR_Tools/). SDG. Conflicts of Interest: The authors declare no conflict of interest. Conflicts of Interest: The authors declare no conflict of interest.The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2 ncv = 0.993 and 0.984 and values of r2 test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2 m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561). © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/119

Protective Yeasts Control V. anguillarum Pathogenicity and Modulate the Innate Immune Response of Challenged Zebrafish (Danio rerio) Larvae

Indexación: Web of ScienceWe investigated mechanisms involved in the protection of zebrafish (Danio rerio) larvae by two probiotic candidate yeasts, Debaryornyces hansenii 97 (Dh97) and Yarrowia Iypolitica 242 (YI242), against a Vibrio anguillarum challenge. We determined the effect of different yeast concentrations (10(4)-10(7) CFU/mL) to: (i) protect larvae from the challenge, (ii) reduce the in vivo pathogen concentration and (iii) modulate the innate immune response of the host. To evaluate the role of zebrafish microbiota in protection, the experiments were performed in conventionally raised and germ free larvae. In vitro co-aggregation assays were performed to determine a direct yeast-pathogen interaction. Results showed that both yeasts significantly increased the survival rate of conventionally raised larvae challenged with V. anguillarum. The concentration of yeasts in larvae tended to increase with yeast inoculum, which was more pronounced for Dh97. Better protection was observed with Dh97 at a concentration of 106 CFU/mL compared to 104 CFU/mL. In germ-free conditions V anguillarum reached higher concentrations in larvae and provoked significantly more mortality than in conventional conditions, revealing the protective role of the host microbiota. Interestingly, yeasts were equally (Dh97) or more effective (YI242) in protecting germ-free than conventionally-raised larvae, showing that protection can be exerted only by yeasts and is not necessarily related to modulation of the host microbiota. Although none of the yeasts co aggregated with V anguillarum, they were able to reduce its proliferation in conventionally raised larvae, reduce initial pathogen concentration in germ-free larvae and prevent the upregulation of key components of the inflammatory/anti-inflammatory response (il1b, tnfa, c3, mpx, and il10, respectively). These results show that protection by yeasts of zebrafish larvae challenged with V anguillarum relates to an in vivo anti-pathogen effect, the modulation of the innate immune system, and suggests that yeasts avoid the host-pathogen interaction through mechanisms independent of co-aggregation. This study shows, for the first time, the protective role of zebrafish microbiota against V. anguillarum infection, and reveals mechanisms involved in protection by two non-Saccharomyces yeasts against this pathogen.http://journal.frontiersin.org/article/10.3389/fcimb.2016.00127/ful

A New Kind of Quinonic-Antibiotic Useful Against Multidrug-Resistant S. aureus and E. faecium Infections

Indexación: Scopus.A rapid emergence of resistant bacteria is occurring worldwide, endangering the efficacy of antibiotics and reducing the therapeutic arsenal available for treatment of infectious diseases. In the present study, we developed a new class of compounds with antibacterial activity obtained by a simple, two step synthesis and screened the products for in vitro antibacterial activity against ATCC® strains using the broth microdilution method. The compounds exhibited minimum inhibitory concentrations (MIC) of 1⁻32 μg/mL against Gram-positive ATCC® strains. The structure⁻activity relationship indicated that the thiophenol ring is essential for antibacterial activity and the substituents on the thiophenol ring module, for antibacterial activity. The most promising compounds detected by screening were tested against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF) clinical isolates. We found remarkable activity against VREF for compounds 7 and 16, were the MIC50/90 were 2/4 µg/mL and 4/4 µg/mL, respectively, while for vancomycin the MIC50/90 was 256/512 µg/mL. Neither compound affected cell viability in any of the mammalian cell lines at any of the concentrations tested. These in vitro data show that compounds 7 and 16 have an interesting potential to be developed as new antibacterial drugs against infections caused by VREF.https://www.mdpi.com/1420-3049/23/7/177

A preliminary quantitative mineral resource assessment of undiscovered porphyry copper resources in the Andes mountains of South America

Quantitative information on the probable locations and amounts of undiscovered porphyry copper resources of the world is important to international exploration managers, land-use and environmental planners, economists, and policy makers. The U.S. Geological Survey is organizing and facilitating a cooperative assessment, in collaboration with interested geological surveys and geological organizations, of the likely global distribution, quantity, and quality of selected undiscovered nonfuel mineral resources. This report on undiscovered porphyry copper deposits of the Andes Mountains was produced jointly with the geological surveys of Argentina, Chile, Colombia, and Peru, and is a summary of the more extensive report (>300 pages) that will be published soon. Reports on undiscovered copper resources of other regions of the world are being prepared and will be followed by assessments of the global undiscovered resources of platinum-group minerals and potash

Doing marine spatial zoning in coastal marine tropics: Palawan’s Environmental Critical Areas Network (ECAN)

This is the final version. Available from Elsevier via the DOI in this record. Zoning is an important tool in marine spatial planning (MSP) for balancing the multi-uses of the marine environment. Whilst mainly developed conceptually and implemented in Europe and North America, marine zoning is becoming a popular tool for addressing diverse coastal marine issues in the tropics. However, we know little about how it is being implemented in practice in that context. In this study, we analysed the factors and strategies that enable and hinder the establishment of marine zoning in the low-income tropics through a case study of the 26-year history of the development of the Environmental Critical Areas Network (ECAN) in Palawan, Philippines. We employed two participatory methods: Innovation Histories to investigate how implementation barriers and opportunities change over time, and the Net-Map method to reveal the social relations and power distributions that enabled, blocked, and stalled its implementation. We found that MSP can be durable in these contexts when institutionalised in national law and adopted by local co-coordinative bodies, yet it remains an externally-driven agenda. Our study shows that the scaling up of zoning does not necessarily help resolve conflicts around marine and coastal space, and highlights the importance and influence of the political economy on MSP implementation and outcomes. We conclude that MSP's insensitivity to contextual power relations and politics raises concerns over social inclusivity, equity and justice. Moving forward, MSP implemented in the tropics needs to make conflicts, trade-offs and power distributions explicit at the outset through participatory decision-making that involves and empowers all stakeholders from the early stages of initiatives.United Kingdom Research and InnovationGlobal Challenges Research Fun

A hypoperfusion context may aid to interpret hyperlactatemia in sepsis-3 septic shock patients: a proof-of-concept study

__Background:__ Persistent hyperlactatemia is particularly difficult to interpret in septic shock. Besides hypoperfusion, adrenergic-driven lactate production and impaired lactate clearance are important contributors. However, clinical recognition of different sources of hyperlactatemia is unfortunately not a common practice and patients are treated with the same strategy despite the risk of over-resuscitation in some. Indeed, pursuing additional resuscitation in non-hypoperfusion-related cases might lead to the toxicity of fluid overload and vasoactive drugs. We hypothesized that two different clinical patterns can be recognized in septic shock patients through a multimodal perfusion monitoring. Hyperlactatemic patients with a hypoperfusion context probably represent a more severe acute circulatory dysfunction, and the absence of a hypoperfusion context is eventually associated with a good outcome. We performed a retrospective analysis of a database of septic shock patients with persistent hyperlactatemia after initial resuscitation. __Results:__ We defined hypoperfusion context by the presence of a ScvO2 < 70%, or a P(cv-a)CO2 ≥6 mmHg, or a CRT ≥4 s together with hyperlactatemia. Ninety patients were included, of whom seventy exhibited a hypoperfusion-related pattern and 20 did not. Although lactate values were comparable at baseline (4.8 ± 2.8 vs. 4.7 ± 3.7 mmol/L), patients with a hypoperfusion context exhibited a more severe circulatory dysfunction with higher vasopressor requirements, and a trend to longer mechanical ventilation days, ICU stay, and more rescue therapies. Only one of the 20 hyperlactatemic patients without a hypoperfusion context died (5%) compared to 11 of the 70 with hypoperfusion-related hyperlactatemia (16%). __Conclusions:__ Two different clinical patterns among hyperlactatemic septic shock patients may be identified according to hypoperfusion context. Patients with hyperlactatemia plus low ScvO2, or high P(cv-a)CO2, or high CRT values exhibited a more severe circulatory dysfunction. This provides a starting point to launch further prospective studies to confirm if this approach can lead to a more selective resuscitation strategy

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Evolutionary Origin and Phylogeography of the Diploid Obligate Parthenogen Artemia parthenogenetica (Branchiopoda: Anostraca)

Background: Understanding the evolutionary origin and the phylogeographic patterns of asexual taxa can shed light on the origin and maintenance of sexual reproduction. We assessed the geographic origin, genetic diversity, and phylogeographic history of obligate parthenogen diploid Artemia parthenogenetica populations, a widespread halophilic crustaceanPeer reviewe