Optimization of a class of tryptophan dendrimers that inhibit HIV replication leads to a selective, specific, and low-nanomolar inhibitor of clinical isolates of enterovirus A71

Tryptophan dendrimers that inhibit HIV replication by binding to the HIV envelope glycoproteins gp120 and gp41 have unexpectedly also proven to be potent, specific, and selective inhibitors of the replication of the unrelated enterovirus A71. Dendrimer 12, a consensus compound that was synthesized on the basis of the structure-activity relationship analysis of this series, is 3-fold more potent against the BrCr lab strain and, surprisingly, inhibits a large panel of clinical isolates in the low-nanomolar/high-picomolar range.This work has been supported by the Spanish MINECO (Project SAF2012-39760-C02-01, cofinanced by the FEDER program; Plan Nacional de Cooperación Público-Privada; and Subprograma INNPACTO IPT-2012-0213-060000, cofinanced by the FEDER program) and the Comunidad de Madrid (BIPEDD2-CM-S2010/BMD-2457). This work was also funded by EU FP7 (FP7/2007-2013) Project EUVIRNA under Grant408 Agreement 264286 by EU FP7 SILVER (Contract HEALTH-F3-2010- 260644), a grant from the Belgian Interuniversity Attraction Poles (IAP) Phase VII–P7/45 (BELVIR), and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/MINECO is also acknowledged for a grant to E.R.-B. L.S. was funded by China Scholarship Council (CSC) Grant 201403250056. We also acknowledge Charlotte Vanderheydt for help with the processing of the antiviral data.Peer Reviewe

Recent advances in organic synthesis using light-mediated n-heterocyclic carbene catalysis

The combination of photocatalysis with other ground state catalytic systems have attracted much attention recently due to the enormous synthetic potential offered by a dual activation mode. The use of N-heterocyclic carbene (NHC) as organocatalysts emerged as an important synthetic tool. Its ability to harness umpolung reactivity by the formation of the Breslow intermediate has been employed in the synthesis of thousands of biologically important compounds. However, the available coupling partners are relatively restricted, and its combination with other catalytic systems might improve its synthetic versatility. Thus, merging photoredox and N-heterocyclic carbene (NHC) catalysis has emerged recently as a powerful strategy to develop new transformations and give access to a whole new branch of synthetic possibilities. This review compiles the NHC catalyzed methods mediated by light, either in the presence or absence of an external photocatalyst, that have been described so far, and aims to give an accurate overview of the potential of this activation modeL.M. acknowledges the Autonomous Community of Madrid (CAM) for the financial support (PEJD-2019-PRE/AMB-16640 and SI1/PJI/ 2019-00237) and for an “Atracción de Talento Investigador” contract (2017-T2/AMB-5037

Multivalent Tryptophan‐ and Tyrosine‐Containing [60]Fullerene Hexa‐Adducts as Dual HIV and Enterovirus A71 Entry Inhibitors

Unprecedented 3D hexa-adducts of [60]fullerene peripherally decorated with twelve tryptophan (Trp) or tyrosine (Tyr) residues have been synthesized. Studies on the antiviral activity of these novel compounds against HIV and EV71 reveal that they are much more potent against HIV and equally active against EV71 than the previously described dendrimer prototypes AL-385 and AL-463, which possess the same number of Trp/Tyr residues on the periphery but attached to a smaller and more flexible pentaerythritol core. These results demonstrate the relevance of the globular 3D presentation of the peripheral groups (Trp/Tyr) as well as the length of the spacer connecting them to the central core to interact with the viral envelopes, particularly in the case of HIV, and support the hypothesis that [60]fullerene can be an alternative and attractive biocompatible carbon-based scaffold for this type of highly symmetrical dendrimers. In addition, the functionalized fullerenes here described, which display twelve peripheral negatively charged indole moieties on their globular surface, define a new and versatile class of compounds with a promising potential in biomedical applications

Recent visible light and metal free strategies in [2+2] and [4+2] photocycloadditions

When aiming to synthesize molecules with elevated molecular complexity starting from relatively simple starting materials, photochemical transformations represent an open avenue to circumvent analogous multistep procedures. Specifically, light-mediated cycloadditions remain as powerful tools to generate new bonds begotten from non-very intuitive disconnections, that alternative thermal protocols would not offer. In response to the current trend in both industrial and academic research pointing towards green and sustainable processes, several strategies that meet these requirements are currently available in the literature. This Minireview summarizes [2+2] and [4+2] photocycloadditions that do not require the use of metal photocatalysts by means of alternative strategies. It is segmented according to the cycloaddition type in order to give the reader a friendly approach and we primarily focus on the most recent developments in the field carried out using visible light, a general overview of the mechanism in each case is offered as wellFinancial support was provided by the European Research Council (ERC-CoG, Contract Number: 647550), the Spanish Government (RTI2018-095038-B-I00), the ‘Comunidad de Madrid’ and European Structural Funds (S2018/NMT-4367). R. I. R thanks Fundación Carolina for a graduate fellowshi

Multimessenger NuEM Alerts with AMON

The Astrophysical Multimessenger Observatory Network (AMON), has developed a real-time multi-messenger alert system. The system performs coincidence analyses of datasets from gamma-ray and neutrino detectors, making the Neutrino-Electromagnetic (NuEM) alert channel. For these analyses, AMON takes advantage of sub-threshold events, i.e., events that by themselves are not significant in the individual detectors. The main purpose of this channel is to search for gamma-ray counterparts of neutrino events. We will describe the different analyses that make-up this channel and present a selection of recent results

Search for Spatial Correlations of Neutrinos with Ultra-high-energy Cosmic Rays

For several decades, the origin of ultra-high-energy cosmic rays (UHECRs) has been an unsolved question of high-energy astrophysics. One approach for solving this puzzle is to correlate UHECRs with high-energy neutrinos, since neutrinos are a direct probe of hadronic interactions of cosmic rays and are not deflected by magnetic fields. In this paper, we present three different approaches for correlating the arrival directions of neutrinos with the arrival directions of UHECRs. The neutrino data are provided by the IceCube Neutrino Observatory and ANTARES, while the UHECR data with energies above ∼50 EeV are provided by the Pierre Auger Observatory and the Telescope Array. All experiments provide increased statistics and improved reconstructions with respect to our previous results reported in 2015. The first analysis uses a high-statistics neutrino sample optimized for point-source searches to search for excesses of neutrino clustering in the vicinity of UHECR directions. The second analysis searches for an excess of UHECRs in the direction of the highest-energy neutrinos. The third analysis searches for an excess of pairs of UHECRs and highest-energy neutrinos on different angular scales. None of the analyses have found a significant excess, and previously reported overfluctuations are reduced in significance. Based on these results, we further constrain the neutrino flux spatially correlated with UHECRs

Searching for VHE gamma-ray emission associated with IceCube neutrino alerts using FACT, H.E.S.S., MAGIC, and VERITAS

The realtime follow-up of neutrino events is a promising approach to searchfor astrophysical neutrino sources. It has so far provided compelling evidencefor a neutrino point source: the flaring gamma-ray blazar TXS 0506+056 observedin coincidence with the high-energy neutrino IceCube-170922A detected byIceCube. The detection of very-high-energy gamma rays (VHE, $\mathrm{E} >100\,\mathrm{GeV}$) from this source helped establish the coincidence andconstrained the modeling of the blazar emission at the time of the IceCubeevent. The four major imaging atmospheric Cherenkov telescope arrays (IACTs) -FACT, H.E.S.S., MAGIC, and VERITAS - operate an active follow-up program oftarget-of-opportunity observations of neutrino alerts sent by IceCube. Thisprogram has two main components. One are the observations of known gamma-raysources around which a cluster of candidate neutrino events has been identifiedby IceCube (Gamma-ray Follow-Up, GFU). Second one is the follow-up of singlehigh-energy neutrino candidate events of potential astrophysical origin such asIceCube-170922A. GFU has been recently upgraded by IceCube in collaborationwith the IACT groups. We present here recent results from the IACT follow-upprograms of IceCube neutrino alerts and a description of the upgraded IceCubeGFU system.<br

Modifications in the branched arms of a class of dual inhibitors of HIV and EV71 replication expand their antiviral spectrum

We have previously reported a new class of dendrimers with tryptophan (Trp) residues on the surface that show dual antiviral activities against HIV and enterovirus EV71. The prototype compound of this family is a derivative of pentaerythritol with 12 peripheral Trp groups and trivalent spacer arms. Here a novel series of dendrimers with divalent and tetravalent branched arms, instead of the trivalent ones present on the prototype, has been synthesized and its activity against HIV, EV71 and a panel of 16 different viruses and other pathogens has been determined. Convergent or divergent approaches have been used for the synthesis of these compounds. Our findings demonstrate that only compounds with tetravalent branched arms showed the same anti-HIV and anti-EV71 activity of the prototype (low micromolar) and even gain significant antiviral activity against new pathogens such as HSV-2, adenovirus-2, human corona virus and respiratory syncytial virus, being the first members of the Trp dendrimer family that showed activity against those viruses. As the prototype, these compounds also showed low-nanomolar activity against a representative EV71 clinical isolate. Experimental work carried on to determine the mode of action of the most potent IIa, containing tetravalent branched arms, demonstrated that it interacts with the viral envelopes of HIV, EV71 and HSV-2 and thus may prevent virus attachment to the host cell. These results support the interest of this new series of Trp dendrimers and qualify them as useful prototypes for the development of novel inhibitors of viral entry with broad antiviral spectrum.This work has been supported by the Spanish Ministerio de Economía, Industria y Competitividad (MINECO) [project SAF2015- 64629-C2-1-R (MINECO/FEDER)], the Spanish Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC, Project CSIC201680E079), “The Centers of Excellence” of the KU Leuven (EF- 05/15 and PF-10/18), EU FP7 (FP7/2007–2013) Project EUVIRNA (Grant 408 Agreement 264286), EU FP7 SILVER (Contract HEALTH-F3- 2010-260644), a grant from the Belgian Interuniversity Attraction Poles (IAP) Phase VII–P7/45 (BELVIR) and the EU FP7 Industry-Academia Partnerships and Pathways Project AIROPICO. The Spanish MEC/ MINECO is also acknowledged for a grant to B.M.G and the China Scholarship Council (Grant 201403250056) for a grant to L.S. We also thank Charlotte Vanderheydt, Caroline Collard, Kim Donckers, Sandra Claes and Evelyne Van Kerckhove for help with the processing of the antiviral data and Arnaud Boonen and Sam Noppen with the generation of the SPR data.Peer Reviewe

Physical activity among Spanish adolescents: Relationship with their relatives' physical activity - The AVENA Study

Identifying factors related to physical activity levels in young people is important for a more efficient health promotion. The aims of this study were to assess physical activity levels in a national sample of urban Spanish adolescents, and to examine the association between significant others' physical activity (father, mother, brother, sister, and close friends) and that of the adolescents. The present study comprised 2260 adolescents (1157 boys, 1103 girls) aged 13.0-18.5 years participating in the AVENA Study. Both the adolescents' physical activity and that of their relatives and close friends was assessed by questionnaire. The odds of being active were higher in boys than girls (odds ratio = 2.79, 95% confidence interval = 2.34-3.33) and tended to decrease across age groups in both boys and girls. Father's and older brother's physical activity was associated with boys' physical activity, while that of any significant other was associated with girls' physical activity. When both parents reported being active, boys had nearly two times higher odds of being active and girls had nearly three times higher odds of being active. The physical activity levels of Spanish adolescents are in line with those previously reported. Physical activity levels in girls are strongly related to the physical activity of any significant other, whereas physical activity levels in boys are only related to their male relatives' physical activity. © 2011 Taylor & Francis.Peer Reviewe

Galloyl Carbohydrates with Antiangiogenic Activity Mediated by Capillary Morphogenesis Gene 2 (CMG2) Protein Binding

We previously showed that a small molecule of natural origin, 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose (PGG), binds to capillary morphogenesis gene 2 (CMG2) with a submicromolar IC and also has antiangiogenic activity in vitro and in vivo. In this work, we synthetized derivatives of PGG with different sugar cores and phenolic substituents and tested these as angiogenesis inhibitors. In a high-throughput Förster resonant energy transfer-based binding assay, we found that one of our synthetic analogues (1,2,3,4,6-penta-O-galloyl-β-d-mannopyranose (PGM)), with mannose as central core and galloyl substituents, exhibit higher (up to 10×) affinity for CMG2 than the natural glucose prototype PGG and proved to be a potent angiogenesis inhibitor. These findings demonstrate that biochemical CMG2 binding in vitro predicts inhibition of endothelial cell migration ex vivo and antiangiogenic activity in vivo. The molecules herein described, and in particular PGM, might be useful prototypes for the development of novel agents for angiogenesis-dependent diseases, including blinding eye disease and cancer.This work was supported by the Spanish MINECO [Project SAF2015-64629-C2-1-R (MINECO/FEDER)], the Spanish Agencia Estatal Consejo Superior de Investigaciones Cientif́ - icas (CSIC, Project CSIC201680E079), and NIH R01 EY018829. The Spanish MINECO is also acknowledged for a grant to B.M.-G.Peer Reviewe