Discovery of macrocyclic inhibitors of apurinic/apyrimidinic endonuclease 1

Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential base excision repair enzyme that is upregulated in a number of cancers, contributes to resistance of tumors treated with DNA-alkylating or -oxidizing agents, and has recently been identified as an important therapeutic target. In this work, we identified hot spots for binding of small organic molecules experimentally in high resolution crystal structures of APE1 and computationally through the use of FTMAP analysis (http://ftmap.bu.edu/). Guided by these hot spots, a library of drug-like macrocycles was docked and then screened for inhibition of APE1 endonuclease activity. In an iterative process, hot-spot-guided docking, characterization of inhibition of APE1 endonuclease, and cytotoxicity of cancer cells were used to design next generation macrocycles. To assess target selectivity in cells, selected macrocycles were analyzed for modulation of DNA damage. Taken together, our studies suggest that macrocycles represent a promising class of compounds for inhibition of APE1 in cancer cells.This work was supported by grants from the National Institutes of Health (Grant R01CA205166 to M.R.K. and M.M.G. and Grant R01CA167291 to M.R.K.) and by the Earl and Betty Herr Professor in Pediatric Oncology Research, Jeff Gordon Children's Foundation, and the Riley Children's Foundation (M.R.K.). Work at the BU-CMD (J.A.P., L.E.B., R.T.) is supported by the National Institutes of Health, Grant R24 GM111625. D.B. and S.V. were supported by the National Institutes of Health, Grant R35 GM118078. (R35 GM118078 - National Institutes of Health; R01CA205166 - National Institutes of Health; R01CA167291 - National Institutes of Health; R24 GM111625 - National Institutes of Health; Earl and Betty Herr Professor in Pediatric Oncology Research; Jeff Gordon Children's Foundation; Riley Children's Foundation)Accepted manuscriptSupporting documentatio

GEO-C:Enabling open cities and the open city toolkit

The GEO-C doctoral programme, entitled “Geoinformatics: Enabling Open Cities”, is funded by the EU Marie Skłodowska-Curie actions (International Training Networks (ITN), European Joint Doctorates) until December 2018, and is managed by three European universities in Germany, Portugal and Spain. 15 doctoral grantholders (Early Stage Researchers) were selected to work on specific three-year projects, all contributing to improving the notion of open cities, and specifically to an Open City Toolkit of methodologies, code, and best practice examples. Contributions include volunteered geographic information (VGI), public information displays, mobility apps to encourage green living, providing open data to immigrant populations, reducing the second-order digital divide, sensing of quality of life, proximity based privacy protection, and spatio-temporal online social media analysis. All doctoral students conducted long-term visits and were embedded in city governments and businesses, to gain experience from multiple perspectives in addition to the researcher and users’ perspective. The projects are situated within three areas: transparency, participation, and collaboration. They took mostly a bottom-up (citizen-centric) approach to (smart) open cities, rather than relying on large IT companies to create smart open cities in a top-down manner. This paper discusses the various contributions to enabling open cities, explains in some detail the Open City Toolkit, and its possible uses and impact on stakeholders. A follow-up doctoral program has been solicited and, if successful, will continue this line of research and will strengthen aspects of privacy, data provenance, and trust, in an effort to improve relations between data (e.g. news) publishers and consumers

Incorporación de residuos derivados de la fabricación cerámica y del vidrio reciclado en el proceso cerámico integral

The following research work shows the results of the introduction of waste generated by the ceramic industry, such as the calcined clay from fired porcelain of stoneware and raw biscuit, sludge and cleaning water, as well as waste from other sectors like the recycling glass. In this way, it can be obtained a stoneware porcelain slab, engobe-glaze and satin glaze that contains high percentage of recyclable raw material

Development of an open sensorized platform in a smart agriculture context: A vineyard support system for monitoring mildew disease

In recent years, some official reports, to produce best products regarding quality, quantity and economic conditions, recommend that the farming sector should benefit with new tools and techniques coming from Information and Communications Technology (ICT) realm. In this way, during last decade the deployment of sensing devices has increased considerably in the field of agriculture. This fact has led to a new concept called smart agriculture, and it contemplates activities such as field monitoring, which offer support to make decisions or perform actions, such as irrigation or fertilization. Apart from sensing devices, which use the Internet protocol to transfer data (Internet of Things), there are the so-called crop models, which are able to provide added value over the data provided by the sensors, with the aim of providing recommendations to farmers in decision-making and thus, increase the quality and quantity of their production. In this scenario, the current work uses a low-cost sensorized platform, capable of monitoring meteorological phenomena following the Internet of Things paradigm, with the goal to apply an alert disease model on the cultivation of the vine. The edge computing paradigm is used to achieve this objective; also our work follows some advances from GIScience to increase interoperability. An example of this platform has been deployed in a vineyard parcel located in the municipality of Vilafamés (Castelló Spain)

High-throughput screening in larval zebrafish identifies novel potent sedative-hypnotics

BACKGROUND: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. METHODS: The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. RESULTS: Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. CONCLUSIONS: Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.This work was supported by grants from Shanghai Jiaotong University School of Medicine, Shanghai, China, and the Chinese Medical Association, Beijing, China (both to Dr. Yang). The Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts, supported this work through a Research Scholars Award and an Innovation Grant (both to Dr. Forman). Contributions to this research from the Boston University Center for Molecular Discovery, Boston, Massachusetts (to Drs. Porco, Brown, Schaus, and Xu, and to Mr. Trilles), were supported by a grant from the National Institutes of Health, Bethesda, Maryland (grant No. R24 GM111625). (Shanghai Jiaotong University School of Medicine, Shanghai, China; Chinese Medical Association, Beijing, China; Department of Anesthesia, Critical Care and Pain Medicine of Massachusetts General Hospital, Boston, Massachusetts; R24 GM111625 - National Institutes of Health, Bethesda, Maryland)Accepted manuscript2019-09-0

Internet of things

Manual of Digital Earth / Editors: Huadong Guo, Michael F. Goodchild, Alessandro Annoni .- Springer, 2020 .- ISBN: 978-981-32-9915-3Digital Earth was born with the aim of replicating the real world within the digital world. Many efforts have been made to observe and sense the Earth, both from space (remote sensing) and by using in situ sensors. Focusing on the latter, advances in Digital Earth have established vital bridges to exploit these sensors and their networks by taking location as a key element. The current era of connectivity envisions that everything is connected to everything. The concept of the Internet of Things(IoT)emergedasaholisticproposaltoenableanecosystemofvaried,heterogeneous networked objects and devices to speak to and interact with each other. To make the IoT ecosystem a reality, it is necessary to understand the electronic components, communication protocols, real-time analysis techniques, and the location of the objects and devices. The IoT ecosystem and the Digital Earth (DE) jointly form interrelated infrastructures for addressing today’s pressing issues and complex challenges. In this chapter, we explore the synergies and frictions in establishing an efficient and permanent collaboration between the two infrastructures, in order to adequately address multidisciplinary and increasingly complex real-world problems. Although there are still some pending issues, the identified synergies generate optimism for a true collaboration between the Internet of Things and the Digital Earth

MALDI-TOF MS Enables the Rapid Identification of the Major Molecular Types within the Cryptococcus neoformans/C. gattii Species Complex

BACKGROUND: The Cryptococcus neoformans/C. gattii species complex comprises two sibling species that are divided into eight major molecular types, C. neoformans VNI to VNIV and C. gattii VGI to VGIV. These genotypes differ in host range, epidemiology, virulence, antifungal susceptibility and geographic distribution. The currently used phenotypic and molecular identification methods for the species/molecular types are time consuming and expensive. As Matrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF MS) offers an effective alternative for the rapid identification of microorganisms, the objective of this study was to examine its potential for the identification of C. neoformans and C. gattii strains at the intra- and inter-species level. METHODOLOGY: Protein extracts obtained via the formic acid extraction method of 164 C. neoformans/C. gattii isolates, including four inter-species hybrids, were studied. RESULTS: The obtained mass spectra correctly identified 100% of all studied isolates, grouped each isolate according to the currently recognized species, C. neoformans and C. gattii, and detected potential hybrids. In addition, all isolates were clearly separated according to their major molecular type, generating greater spectral differences among the C. neoformans molecular types than the C. gattii molecular types, most likely reflecting a closer phylogenetic relationship between the latter. The number of colonies used and the incubation length did not affect the results. No spectra were obtained from intact yeast cells. An extended validated spectral library containing spectra of all eight major molecular types was established. CONCLUSIONS: MALDI-TOF MS is a rapid identification tool for the correct recognition of the two currently recognized human pathogenic Cryptococcus species and offers a simple method for the separation of the eight major molecular types and the detection of hybrid strains within this species complex in the clinical laboratory. The obtained mass spectra provide further evidence that the major molecular types warrant variety or even species status

Interactive translation prediction versus conventional post-editing in practice: a study with the CasMaCat workbench

[EN] We conducted a field trial in computer-assisted professional translation to compare interactive translation prediction (ITP) against conventional post-editing (PE) of machine translation (MT) output. In contrast to the conventional PE set-up, where an MT system first produces a static translation hypothesis that is then edited by a professional (hence "post-editing"), ITP constantly updates the translation hypothesis in real time in response to user edits. Our study involved nine professional translators and four reviewers working with the web-based CasMaCat workbench. Various new interactive features aiming to assist the post-editor/translator were also tested in this trial. Our results show that even with little training, ITP can be as productive as conventional PE in terms of the total time required to produce the final translation. Moreover, translation editors working with ITP require fewer key strokes to arrive at the final version of their translation.This work was supported by the European Union’s 7th Framework Programme (FP7/2007–2013) under grant agreement No 287576 (CasMaCat ).Sanchis Trilles, G.; Alabau, V.; Buck, C.; Carl, M.; Casacuberta Nolla, F.; Garcia Martinez, MM.; Germann, U.... (2014). Interactive translation prediction versus conventional post-editing in practice: a study with the CasMaCat workbench. Machine Translation. 28(3-4):217-235. https://doi.org/10.1007/s10590-014-9157-9S217235283-4Alabau V, Leiva LA, Ortiz-Martínez D, Casacuberta F (2012) User evaluation of interactive machine translation systems. 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