A Multiple Classifier System Identifies Novel Cannabinoid CB2 Receptor Ligands

open access articleDrugs have become an essential part of our lives due to their ability to improve people’s health and quality of life. However, for many diseases, approved drugs are not yet available or existing drugs have undesirable side effects, making the pharmaceutical industry strive to discover new drugs and active compounds. The development of drugs is an expensive process, which typically starts with the detection of candidate molecules (screening) for an identified protein target. To this end, the use of high-performance screening techniques has become a critical issue in order to palliate the high costs. Therefore, the popularity of computer-based screening (often called virtual screening or in-silico screening) has rapidly increased during the last decade. A wide variety of Machine Learning (ML) techniques has been used in conjunction with chemical structure and physicochemical properties for screening purposes including (i) simple classifiers, (ii) ensemble methods, and more recently (iii) Multiple Classifier Systems (MCS). In this work, we apply an MCS for virtual screening (D2-MCS) using circular fingerprints. We applied our technique to a dataset of cannabinoid CB2 ligands obtained from the ChEMBL database. The HTS collection of Enamine (1.834.362 compounds), was virtually screened to identify 48.432 potential active molecules using D2-MCS. This list was subsequently clustered based on circular fingerprints and from each cluster, the most active compound was maintained. From these, the top 60 were kept, and 21 novel compounds were purchased. Experimental validation confirmed six highly active hits (>50% displacement at 10 μM and subsequent Ki determination) and an additional five medium active hits (>25% displacement at 10 μM). D2-MCS hence provided a hit rate of 29% for highly active compounds and an overall hit rate of 52%

Revan-degree indices on random graphs

Given a simple connected non-directed graph $G=(V(G),E(G))$, we consider two families of graph invariants: $RX_\Sigma(G) = \sum_{uv \in E(G)} F(r_u,r_v)$ (which has gained interest recently) and $RX_\Pi(G) = \prod_{uv \in E(G)} F(r_u,r_v)$ (that we introduce in this work); where $uv$ denotes the edge of $G$ connecting the vertices $u$ and $v$, $r_u$ is the Revan degree of the vertex $u$, and $F$ is a function of the Revan vertex degrees. Here, $r_u = \Delta + \delta - d_u$ with $\Delta$ and $\delta$ the maximum and minimum degrees among the vertices of $G$ and $d_u$ is the degree of the vertex $u$. Particularly, we apply both $RX_\Sigma(G)$ and R$X_\Pi(G)$ on two models of random graphs: Erd\"os-R\'enyi graphs and random geometric graphs. By a thorough computational study we show that \left and \left, normalized to the order of the graph, scale with the average Revan degree \left; here \left denotes the average over an ensemble of random graphs. Moreover, we provide analytical expressions for several graph invariants of both families in the dense graph limit.Comment: 16 pages, 10 figure

Cooperative Electronic and Structural Regulation in a Bioinspired Allosteric Photoredox Catalyst

Herein, we report the first allosteric photoredox catalyst regulated via constructively coupled structural and electronic control. While often synergistically exploited in nature, these two types of control mechanisms have only been applied independently in the vast majority of allosteric enzyme mimics and receptors in the literature. By embedding a model of photosystem II in a supramolecular coordination complex that responds to chloride as an allosteric effector, we show that distance and electronic control of light harvesting can be married to maximize allosteric regulation of catalytic activity. This biomimetic system is composed of a Bodipy photoantenna, which is capable of transferring excited-state energy to a photoredox pair, wherein the excitation energy is used to generate a catalytically active charge-separated state. The structural aspect of allosteric regulation is achieved by toggling the coordination chemistry of an antenna-functionalized hemilabile ligand via partial displacement from a RhI structual node using chloride. In doing so, the distance between the antenna and the central photoredox catalyst is increased, lowering the inherent efficiency of through-space energy transfer. At the same time, coordination of chloride lowers both the charge of the Rh^I node and the reduction potential of the Rh^(II/I) couple, to the extent that electronic quenching of the antenna excited state is possible via photoinduced electron transfer from the metal center. Compared to a previously developed system that operates solely via electronic regulation, the present system demonstrates that coupling electronic and structural approaches to allosteric regulation gives rise to improved switching ratios between catalytically active and inactive states. Contributions from both structural and electronic control mechanisms are probed via nuclear magnetic resonance, X-ray diffraction, electrochemical, spectroelectrochemical, and transient absorption studies. Overall, this work establishes that intertwined electronic and structural regulatory mechanisms can be borrowed from nature to build stimuli-responsive inorganic materials with potential applications in sensing, catalysis, and photonic devices

Extensive antimicrobial resistance mobilization via Multicopy Plasmid Encapsidation mediated by temperate phages

Objectives: To investigate the relevance of multicopy plasmids in antimicrobial resistance and assess their mobilization mediated by phage particles Methods: Several databases with complete sequences of plasmids and annotated genes were analysed. The 16S methyltransferase gene armA conferring high-level aminoglycoside resistance was used as a marker in eight different plasmids, from different incompatibility groups, and with differing sizes and plasmid copy numbers. All plasmids were transformed into Escherichia coli bearing one of four different lysogenic phages. Upon induction, encapsidation of armA in phage particles was evaluated using qRT-PCR and Southern blotting. Results: Multicopy plasmids carry a vast set of emerging clinically important antimicrobial resistance genes. However, 60% of these plasmids do not bear mobility (MOB) genes. When carried on these multicopy plasmids, mobilization of a marker gene armA into phage capsids was up to 10000 times more frequent than when it was encoded by a large plasmid with a low copy number. Conclusions: Multicopy plasmids and phages, two major mobile genetic elements (MGE) in bacteria, represent a novel high-efficiency transmission route of antimicrobial resistance genes that deserves further investigation

Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging

Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.Y.-H.O. received fellowships from Alborada Scholar-ship (University of Cambridge), Trinity-Henry Barlow Scholarship (Universityof Cambridge), and R.O.C. Government Scholarship to Study Abroad (GSSA). A.G.G. received fellowships from the Ramon Areces Foundationand the LaCaixa Foundation. C.K. was supported by Marie Curie Career Inte-gration (H2020-MSCA-IF-2015-70841). S.M.-F. was supported by Red TerCel (ISCIII-Spanish Cell Therapy Network). V.A. is supported by grants from theSpanish Ministerio de Economıa,Industria y Competitividad (MEIC) with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER, ‘‘Una manerade hacer Europa’’) (SAF2016-79490-R), the Instituto de Salud Carlos III (AC16/00091 and AC17/00067), the Fundacio Marato TV3 (122/C/2015), and the Progeria Research Foundation (Established Investigator Award 2014–52). TheCNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia, Innovacion y Universidades (MCIU), and the Pro CNIC Foundation,and is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work wassupported by core support grants from the Wellcome Trust and the MRC to theCambridge Stem Cell Institute, MEIC (SAF-2011-30308), Ramon y Cajal Program Grant (RYC-2009-04703), ConSEPOC-Comunidad de Madrid (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC-2014-CoG-64765 and MarieCurie Career Integration grant FP7-PEOPLE-2011-RG-294096), and a Programme Foundation Award from Cancer Research UK to S.M.-F., who wasalso supported in part by an International Early Career Scientist grant fromthe Howard Hughes Medical Institute.S

Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis

Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.This work-was supported by the Marie Curie activities of the European Commission (Oncotrain program; fellowship to P.W), the Spanish Ministry of Economy and Competitiveness (MINECO; fellowship to A.G.-L.), the CENIT AMIT Project "Advanced Molecular Imaging Technologies" (TEC2008-06715-C02-1, RD07/0014/2009 to F.M.), the Red de investigacion Cardiovascular (RIC), cofunded by FEDER (grant RD12/004240022 to J.M.R.; grant RD12/0042/0056 to L.J.J.-B), Fundacio La Marato TV3 (grant 20151331 to J.M.R.), the Castilla-Leon Autonomous Government (BIO/SA01/15, CS049U16 to X.R.B.), the Solorzano and Ramon Areces Foundations (to X.R.B.), MINECO (grants RD12/0036/0002 and SAF2015-64556-R to X.R.B.; SAF2015-63633-R to J.M.R.; and SAF2015-69920-R to M.M.), Consolider-Ingenio 2010 Programme (grant SAF2014-57791-REDC to M.M.), Red Tematica CellSYS (grant BFU2014-52125-REDT to M.M.), Comunidad de Madrid (OncoCycle Programme; grant S2010/BMD-2470 to M.M.), Worldwide Cancer Research (grants 14-1248 to X.R.B., and 15-0278 to M.M.) and the MitoSys project (European Union Seventh Framework Programme; grant HEALTH-F5-2010-241548 to M.M.). CNIC is supported by MINECO and the Pro-CNIC Foundation. CNIO and CNIC are Severo Ochoa Centers of Excellence (MINECO awards SEV-2015-0510 and SEV-2015-0505, respectively).S

A larger brown fat volume and lower radiodensity are related to a greater cardiometabolic risk, especially in young men

Objectives: Brown adipose tissue (BAT) is important in the maintenance of cardiometabolic health in rodents. Recent reports appear to suggest the same in humans, although if this is true remains elusive partly because of the methodological bias that affected previous research. This cross-sectional work reports the relationships of cold-induced BAT volume, activity (peak standardized uptake, SUVpeak), and mean radiodensity (an inverse proxy of the triacylglycerols content) with the cardiometabolic and inflammatory profile of 131 young adults, and how these relationships are influenced by sex and body weight.Design: This is a cross-sectional study.Methods: Subjects underwent personalized cold exposure for 2 h to activate BAT, followed by static F-18-fluorodeoxyglucose PET-CT scanning to determine BAT variables. Information on cardiometabolic risk (CMR) and inflammatory markers was gathered, and a CMR score and fatty liver index (FLI) were calculated.Results: In men, BAT volume was positively related to homocysteine and liver damage markers concentrations (independently of BMI and seasonality) and the FLI (all P 0.05).Conclusions: A larger BAT volume and a lower BAT mean radiodensity are related to a higher CMR, especially in young men, which may support that BAT acts as a compensatory organ in states of metabolic disruption.</p

The use of the CNIC-Polypill in real-life clinical practice: opportunities and challenges in patients at very high risk of atherosclerotic cardiovascular disease – expert panel meeting report

Although the cardiovascular (CV) polypill concept is not new and several guidelines state that a CV polypill should be considered an integral part of a comprehensive CV disease (CVD) prevention strategy, there are still some barriers to its implementation in the real-world setting, mainly in secondary CV prevention. As the CNIC-polypill is the only one approved for secondary CV prevention in patients with atherosclerotic CVD in 27 countries worldwide, a panel of four discussants and 30 participants from 18 countries conveyed in a virtual meeting on April 21, 2022, to discuss key clinical questions regarding the practical use of the CNIC-Polypill and barriers to its implementation. Data presented showed that, although the use of the CV polypill is not explicitly mentioned in the current 2021 European Society of Cardiology guidelines on CVD prevention, it may be used in any patient for secondary CVD prevention tolerating all their components to improve outcomes through different aspects. The favourable results of the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial now reinforce this recommendation. The panellists presented algorithms on how to switch from any baseline regimen when starting treatment with the CNIC-polypill in different situations, including patients with hypertension, dyslipidaemia, and a previous CV event; at discharge after a cardiovascular event; in chronic ischemic conditions; and in cases of polypharmacy. The panellists and expert discussants did agree that available studies conducted so far with the CNIC-polypill demonstrate that it is as efficacious as the monocomponents, equipotent drugs, or other therapies; reduces the risk of experiencing recurrent major CV events; improves medication adherence; reduces health care costs and resources compared to patients treated with loose drugs; and the patients prefer it over the multipill strategy. In conclusion, the data presented by the participants provided the evidence behind the use of the CNIC-polypill to help fulfil the goal of encouraging its adoption by physicians.info:eu-repo/semantics/publishedVersio