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.

Hours with the Bible; or, The scriptures in the light of modern discovery and knowledge.

Mode of access: Internet.

Hours with the Bible: or, The Scriptures in the light of modern discovery and knowledge,

v.1. From creation to the patriarchs.--v.2. From Moses to the judges.--v.3. From Samson to Solomon.--v.4. Rehoboam to Hezekiah.--v.5. From Menasseth to Zedekia and contemporary prophets.--v.6. From the exile to Malachi.

Hours with the Bible : or, The Scriptures in the light of modern discovery and knowledge ... /

Mode of access: Internet.

Discovery; the popular journal of knowledge.

Editors: Jan. 1920-June 1921, A.S. Russell.---July 1921-Dec. 1923, Edward Liveing.---Jan.-Apr. 1924, R.J.V. Pulvertaft.---May 1924-Mar. 1926, H.B.C. Pollard.---Apr. 1926-1931, J.A. Benn.---1932-34, Bernard Lintern.---1934-Mar. 1938, L.R. Muirhead.---Apr. 1938-1940, C.P. Snow.

Database and narratological representation of Australian Aboriginal knowledge as information visualisation using a game engine

Current database technologies do not support contextualised representations of multi-dimensional narratives. This paper outlines a new approach to this problem using a multi-dimensional database served in a 3D game environment. Preliminary results indicate it is a particularly efficient method for the types of contextualised narratives used by Australian Aboriginal peoples to tell their stories about their traditional landscapes and knowledge practices. We discuss the development of a tool that complements rather than supplants direct experience of these traditional knowledge practices.