Multiprotein Dynamic Combinatorial Chemistry: A Strategy for the Simultaneous Discovery of Subfamily‐Selective Inhibitors for Nucleic Acid Demethylases FTO and ALKBH3

Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self‐assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic “thermal tag” with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily‐selective probes against two clinically important epigenetic enzymes: FTO (7 ; IC_{50} = 2.6 μm ) and ALKBH3 (8 ; IC_{50} = 3.7 μm ). To date, this is the first report of a subfamily‐selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest

Homogeneous Gold Catalysis through Relativistic Effects: Addition of Water to Propyne

In the catalytic addition of water to propyne the Au(III) catalyst is not stable under non-relativistic conditions and dissociates into a Au(I) compound and Cl2. This implies that one link in the chain of events in the catalytic cycle is broken and relativity may well be seen as the reason why Au(III) compounds are effective catalysts.Comment: 12 pages, 3 figures, 1 tabl

Mitochondrial DNA Copy Number Is Associated with Breast Cancer Risk

Mitochondrial DNA (mtDNA) copy number in peripheral blood is associated with increased risk of several cancers. However, data from prospective studies on mtDNA copy number and breast cancer risk are lacking. We evaluated the association between mtDNA copy number in peripheral blood and breast cancer risk in a nested case-control study of 183 breast cancer cases with pre-diagnostic blood samples and 529 individually matched controls among participants of the Singapore Chinese Health Study. The mtDNA copy number was measured using real time PCR. Conditional logistic regression analyses showed that there was an overall positive association between mtDNA copy number and breast cancer risk (Ptrend = 0.01). The elevated risk for higher mtDNA copy numbers was primarily seen for women with <3 years between blood draw and cancer diagnosis; ORs (95% CIs) for 2nd, 3rd, 4th, and 5th quintile of mtDNA copy number were 1.52 (0.61, 3.82), 2.52 (1.03, 6.12), 3.12 (1.31, 7.43), and 3.06 (1.25, 7.47), respectively, compared with the 1st quintile (Ptrend = 0.004). There was no association between mtDNA copy number and breast cancer risk among women who donated a blood sample ≥3 years before breast cancer diagnosis (Ptrend = 0.41). This study supports a prospective association between increased mtDNA copy number and breast cancer risk that is dependent on the time interval between blood collection and breast cancer diagnosis. Future studies are warranted to confirm these findings and to elucidate the biological role of mtDNA copy number in breast cancer risk. © 2013 Thyagarajan et al

Selective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic Approaches†

Ferrous ion and 2-oxoglutarate (2OG) oxygenases catalyze the demethylation of N(epsilon)-methylated lysine residues in histones. Here we report studies on the inhibition of the JMJD2 subfamily of histone demethylases, employing binding analyses by nondenaturing mass spectrometry (MS), dynamic combinatorial chemistry coupled to MS, turnover assays, and crystallography. The results of initial binding and inhibition assays directed the production and analysis of a set of N-oxalyl-d-tyrosine derivatives to explore the extent of a subpocket at the JMJD2 active site. Some of the inhibitors were shown to be selective for JMJD2 over the hypoxia-inducible factor prolyl hydroxylase PHD2. A crystal structure of JMJD2A in complex with one of the potent inhibitors was obtained; modeling other inhibitors based on this structure predicts interactions that enable improved inhibition for some compounds

A computational study of the heterogeneous synthesis of hydrazine on Co3Mo3N

Periodic and molecular density functional theory calculations have been applied to elucidate the associative mechanism for hydrazine and ammonia synthesis in the gas phase and hydrazine formation on Co3Mo3N. We find that there are two activation barriers for the associative gas phase mechanism with barriers of 730 and 658 kJ/mol, corresponding to a hydrogenation step from N2 to NNH2 and H2NNH2 to H3NNH3, respectively. The second step of the mechanism is barrierless and an important intermediate, NNH2, can also readily form on Co3Mo3N surfaces via the Eley–Rideal chemisorption of H2 on a pre-adsorbed N2 at nitrogen vacancies. Based on this intermediate a new heterogeneous mechanism for hydrazine synthesis is studied. The highest relative barrier for this heterogeneous catalysed process is 213 kJ/mol for Co3Mo3N containing nitrogen vacancies, clearly pointing towards a low-energy process for the synthesis of hydrazine via a heterogeneous catalysis route

Photochemistry of Furyl- and Thienyldiazomethanes: Spectroscopic Characterization of Triplet 3-Thienylcarbene

Photolysis (λ \u3e 543 nm) of 3-thienyldiazomethane (1), matrix isolated in Ar or N2 at 10 K, yields triplet 3-thienylcarbene (13) and α-thial-methylenecyclopropene (9). Carbene 13 was characterized by IR, UV/vis, and EPR spectroscopy. The conformational isomers of 3-thienylcarbene (s-E and s-Z) exhibit an unusually large difference in zero-field splitting parameters in the triplet EPR spectrum (|D/hc| = 0.508 cm–1, |E/hc| = 0.0554 cm–1; |D/hc| = 0.579 cm–1, |E/hc| = 0.0315 cm–1). Natural Bond Orbital (NBO) calculations reveal substantially differing spin densities in the 3-thienyl ring at the positions adjacent to the carbene center, which is one factor contributing to the large difference in D values. NBO calculations also reveal a stabilizing interaction between the sp orbital of the carbene carbon in the s-Z rotamer of 13 and the antibonding σ orbital between sulfur and the neighboring carbon—an interaction that is not observed in the s-E rotamer of 13. In contrast to the EPR spectra, the electronic absorption spectra of the rotamers of triplet 3-thienylcarbene (13) are indistinguishable under our experimental conditions. The carbene exhibits a weak electronic absorption in the visible spectrum (λmax = 467 nm) that is characteristic of triplet arylcarbenes. Although studies of 2-thienyldiazomethane (2), 3-furyldiazomethane (3), or 2-furyldiazomethane (4) provided further insight into the photochemical interconversions among C5H4S or C5H4O isomers, these studies did not lead to the spectroscopic detection of the corresponding triplet carbenes (2-thienylcarbene (11), 3-furylcarbene (23), or 2-furylcarbene (22), respectively)

Do RCAN1 proteins link chronic stress with neurodegeneration?

It has long been suspected that chronic stress can exacerbate, or even cause, disease. We now propose that the RCAN1 gene, which can generate several RCAN1 protein isoforms, may be at least partially responsible for this phenomenon. We review data showing that RCAN1 proteins can be induced by multiple stresses, and present new data also implicating psychosocial/emotional stress in RCAN1 induction. We further show that transgenic mice overexpressing the RCAN1-1L protein exhibit accumulation of hyperphosphorylated tau protein (AT8 antibody), an early precursor to the formation of neurofibrillary tangles and neurodegeneration of the kind seen in Alzheimer disease. We propose that, although transient induction of the RCAN1 gene might protect cells against acute stress, persistent stress may cause chronic RCAN1 overexpression, resulting in serious side effects. Chronically elevated levels of RCAN1 proteins may promote or exacerbate various diseases, including tauopathies such as Alzheimer disease. We propose that the mechanism by which stress can lead to these diseases involves the inhibition of calcineurin and the induction of GSK-3 beta by RCAN1 proteins. Both inhibition of calcineurin and induction of GSK-3 beta contribute to accumulation of phosphorylated tau, formation of neurofibrillary tangles, and eventual neurodegeneration.-Ermak, G., Pritchard, M. A., Dronjak, S., Niu, B., Davies, K. J. A. Do RCAN1 proteins link chronic stress with neurodegeneration? FASEB J. 25, 3306-3311 (2011). www.fasebj.or

State-dependent distributed-delay model of orthogonal cutting

In this paper we present a model of turning operations with state-dependent distributed time delay. We apply the theory of regenerative machine tool chat- ter and describe the dynamics of the tool-workpiece sys- tem during cutting by delay-diferential equations. We model the cutting-force as the resultant of a force sys- tem distributed along the rake face of the tool, which results in a short distributed delay in the governing equation superimposed on the large regenerative de- lay. According to the literature on stress distribution along the rake face, the length of the chip-tool inter- face, where the distributed cutting-force system is act- ing, is function of the chip thickness, which depends on the vibrations of the tool-workpiece system due to the regenerative efect. Therefore, the additional short de- lay is state-dependent. It is shown that involving state- dependent delay in the model does not afect linear sta- bility properties, but does afect the nonlinear dynamics of the cutting process. Namely, the sense of the Hopf bi- furcation along the stability boundaries may turn from sub- to supercritical at certain spindle speed regions

Molecular excitation in the Interstellar Medium: recent advances in collisional, radiative and chemical processes

We review the different excitation processes in the interstellar mediumComment: Accepted in Chem. Re