Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

Divalent metal transporter-1 (SLC11A2/DMT1) uses the H+ electrochemical gradient as the driving force to transport divalent metal ions such as Fe2+, Mn2+ and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H+-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H+-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20 μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment.

Linked Data for sharing, discovery and re-use of Language Resources at a Web scale

Conferencia por invitación, impartida el 31 d mayo de 2014 en el Workshop on Language Technology Service Platforms: Synergies, Standards, Sharing at LREC2014

Gene discovery and gene function assignment in filamentous fungi

Filamentous fungi are a large group of diverse and economically important microorganisms. Large-scale gene disruption strategies developed in budding yeast are not applicable to these organisms because of their larger genomes and lower rate of targeted integration (TI) during transformation. We developed transposon-arrayed gene knockouts (TAGKO) to discover genes and simultaneously create gene disruption cassettes for subsequent transformation and mutant analysis. Transposons carrying a bacterial and fungal drug resistance marker are used to mutagenize individual cosmids or entire libraries in vitro. Cosmids are annotated by DNA sequence analysis at the transposon insertion sites, and cosmid inserts are liberated to direct insertional mutagenesis events in the genome. Based on saturation analysis of a cosmid insert and insertions in a fungal cosmid library, we show that TAGKO can be used to rapidly identify and mutate genes. We further show that insertions can create alterations in gene expression, and we have used this approach to investigate an amino acid oxidation pathway in two important fungal phytopathogens.

The synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: Curative effects of desoxyepothilones B and F against human tumor xenografts in nude mice

We have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone B (dEpoB), and 12,13-desoxyepothilone F (dEpoF). The concentrations required for 50% growth inhibition (IC50) for a variety of anticancer agents were measured in CCRF-CEM/VBL1000 cells (2,048-fold resistance to vinblastine). By using dEpoB, dEpoF, aza-EpoB, and paclitaxel, the IC50 values were 0.029, 0.092, 2.99, and 5.17 μM, respectively. These values represent 4-, 33.5-, 1,423- and 3,133-fold resistance, respectively, when compared with the corresponding IC50 in the parent [nonmultiple drug-resistant (MDR)] CCRF-CEM cells. We then produced MDR human lung carcinoma A549 cells by continuous exposure of the tumor cells to sublethal concentrations of dEpoB (1.8 yr), vinblastine (1.2 yr), and paclitaxel (1.8 yr). This continued exposure led to the development of 2.1-, 4,848-, and 2,553-fold resistance to each drug, respectively. The therapeutic effect of dEpoB and paclitaxel was also compared in vivo in a mouse model by using various tumor xenografts. dEpoB is much more effective in reducing tumor sizes in all MDR tumors tested. Analysis of dEpoF, an analog possessing greater aqueous solubility than dEpoB, showed curative effects similar to dEpoB against K562, CCRF-CEM, and MX-1 xenografts. These results indicate that dEpoB and dEpoF are efficacious antitumor agents with both a broad chemotherapeutic spectrum and wide safety margins.

Terminology and French-Spanish business translation: evaluating terminology resources for the translation of accounting documents

This article is the English version of “Terminología y traducción económica francés-español: evaluación de recursos terminológicos en el ámbito contable” by Daniel Gallego Hernández. It was not published on the print version of MonTI for reasons of space. The online version of MonTI does not suffer from these limitations, and this is our way of promoting plurilingualism.

Journal and orderly book : manuscript, 1758 May-Oct

Copied orders and narrative entries of a military expedition to Schenectady and the Oneida station.

Nares Strait region, Canada and Greenland, 1853 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Chart exhibiting the discoveries of the second American-Grinnell-Expedition in search of Sir John Franklin : unrevised from the original material and projected on the spot by E.K. Kane. It was published by Lith of J. Bien in [1855]. Scale [ca. 1:400,000]. Covers the Nares Strait region, Greenland and Canada. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'NAD 1983 CSRS UTM Zone 19 North' projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows coastal features such as drainage, islands, capes, bays, tides, lines of ice, camps, and more. Relief shown by hachures. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

South America, 1739 (Image 1 of 2) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Carte du Perou, pour servir à l'histoire des Incas et à celle de l'etat present de cette province, dressée par Philippe Buache, sur les observations astronomiq[es] faites aux environs de l'équateur et communiquées à l'Académie depuis l'an 1736 jusqu'en 1739 par M.M. Godin, Bouguer et de la Condaminede l'Acad. R[le] des Sciences Assujetie por les autres parties aux observations du P. Feuillée et de M. Frezier aux routes et remarques geographiques de divers voyageurs. It is part of a two sheet map set: [Carte du Peru]. It was published sur le Quay de la Megisserie avec privilege du Roy in 1739. Scale [ca. 1:195,000]. Covers the territory of the former Inca Empire, South America. This layer is image 1 of 2 total images of the two sheet source map representing the northern portion of the map. Map in French and Spanish. The image inside the map neatline is georeferenced to the surface of the earth and fit to a non-standard 'World Sinusoidal' projection with the central meridian at 75 degrees west. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, cities and other human settlements, territorial boundaries, shoreline features, and more. Relief shown pictorially. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

South America, 1739 (Image 2 of 2) (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Carte de la partie meridionale du Perou : pour servir à l'histoire des Incas et à celle de l'etat present de cette province, dressée par Philippe Buache. It is part of a two sheet map set: [Carte du Peru]. It was published sur le Quay de la Megisserie avec privilege du Roy in 1739. Scale [ca. 1:195,000]. Covers the territory of the former Inca Empire, South America. This layer is image 2 of 2 total images of the two sheet source map representing the southern portion of the map. Map in French and Spanish. The image inside the map neatline is georeferenced to the surface of the earth and fit to a non-standard 'World Sinusoidal' projection with the central meridian at 75 degrees west. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, cities and other human settlements, territorial boundaries, shoreline features, and more. Relief shown pictorially. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

Eastern Africa showing expedition route of Speke and Grant, 1863 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Map of the route explored by Captns. Speke & Grant from Zanzibar to Egypt : showing the outfall of the Nile from the Victoria Nyanza (Lake) and the various Negro territories discovered by them. It was published by Edward Stanford in 1863. Scale [ca. 1:5,800,000]. Covers portions of north and eastern Africa including parts of Sudan, Eritrea, Ethiopia, Uganda, Kenya, Rwanda, Burundi, and Tanzania. The image inside the map neatline is georeferenced to the surface of the earth and projected to the 'World Mercator' projection. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as drainage, expedition routes of John Speke and James Grant, cities and other human settlements, tribe and territorial boundaries, and more. Relief is shown by hachures. Includes location map and text. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

James Cook Expeditions, Pacific Ocean, 1776-1779 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Mapa que demuestra el derrotero q[ue] : hizo M. Cook en 1776, 1777, 1778, y 1779 en su tercero y ultimo viaje. It was published by Libreria de Copin in [1780]. Scale [ca. 1:600,000]. Map in Spanish. The image inside the map neatline is georeferenced to the surface of the earth and fit to a non-standard 'Mercator' projection with the central meridian at 180 degrees west. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. Note: The central meridian of this map is not the same as the Prime Meridian and may wrap the International Date Line or overlap itself when displayed in GIS software. This map shows features such as drainage, cities and other human settlements, shoreline features, and more. Relief shown pictorially. Shows the route of James Cook's Pacific Ocean expeditions in the HMS Resolution, 1776-1779. Includes notes. This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.

Bering Sea and Arctic Ocean Region, 1882 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Behring's Sea and Arctic Ocean : from surveys of the U.S. North Pacific Surveying Expedition in 1855, Commander John Rodgers U.S.N. commanding and from Russian and English authorities, J.C.P. de Kraft, commodore U.S.N. Hydrographer to the Bureau of Navigation ; compiled by E.R. Knorr ; drawn by Louis Waldecker. Corr. & additions to Jan. 1882. It was published by U.S. Navy, Hydrographic Office in 1882. Scale [ca. 1:4,400,000]. Covers the Bering Sea and Arctic Ocean region. The image inside the map neatline is georeferenced to the surface of the earth and fit to a non-standard 'Mercator' projection with the central meridian at 180 degrees west. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. Note: The central meridian of this map is not the same as the Prime Meridian and may wrap the International Date Line or overlap itself when displayed in GIS software. This map shows features such as drainage, cities and other human settlements, territorial boundaries, expedition routes, shoreline features, bays, harbors, islands, rocks, and more. Relief shown by hachures and spot heights. Depths shown by soundings. Includes drawing of Wrangel Island "as seen from Bark Nile of New London ... ; 15 to 18 miles distant". This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection and the Harvard University Library as part of the Open Collections Program at Harvard University project: Organizing Our World: Sponsored Exploration and Scientific Discovery in the Modern Age. Maps selected for the project correspond to various expeditions and represent a range of regions, originators, ground condition dates, scales, and purposes.