Structure-Activity Relationship and Crystallographic Studies on 4-Hydroxypyrimidine HIF Prolyl Hydroxylase Domain Inhibitors

The 2-oxoglutarate-dependent hypoxia inducible factor prolyl hydroxylases (PHDs) are targets for treatment of a variety of diseases including anaemia. One PHD inhibitor is approved for use for the treatment of renal anaemia and others are in late stage clinical trials. The number of reported templates for PHD inhibition is limited. We report structure–activity relationship and crystallographic studies on a promising class of 4-hydroxypyrimidine-containing PHD inhibitors.     

Instant Cyclohexene Epoxidation Over Ni-TUD-1 Under Ambient Conditions

Catalysis Letters - To avoid the aggregation problem and activity loss of nickel oxide (NiO) nanoparticles (NPs) in organic reactions, NiO NPs were incorporated into TUD-1 mesoporous material....     

Enabling resilient P2P video streaming: survey and analysis

Peer-to-Peer (P2P) techniques for multimedia streaming have been shown to be a good enhancement to the traditional client/server methods when trying to reduce costs and increase robustness. Due to the fact that P2P systems are highly dynamic, the main challenge that has to be addressed remains supporting the general resilience of the system. Various challenges arise when building a resilient P2P streaming system, such as network failures and system dynamics. In this paper, we first classify the different challenges that face P2P streaming and then present and analyze the possible countermeasures. We classify resilience mechanisms as either core mechanisms, which are part of the system, or as cross-layer mechanisms that use information from different communication layers, which might inflict additional costs. We analyze and present resilience mechanisms from an engineering point of view, such that a system engineer can use our analysis as a guide to build a resilient P2P streaming system with different mechanisms and for various application scenarios.     

Numerical solution of the potential due to dipole sources in volumeconductors with arbitrary geometry and conductivity

The integral conservation equation for biological volume conductors with general geometry and arbitrary distribution of electrical conductivity is solved using a finite volume method. An effective conductivity was defined for the boundaries between regions with abrupt change of the conductivity to allow the simultaneous solution of the entire domain although the derivatives are not continuous. The geometrical singularities arising from the spherical topology of the coordinate system are removed using the conservation law. The resulting finite volume solution method is efficient both in central processing unit (CPU) time and memory requirements, allowing the solution of the volume conductor equation using a large number of mesh points (of the order of 10⁵) even on small workstations (like SGI Indigo). It results in very accurate solutions, as several comparisons with analytical solutions of head models reveal. The proposed finite volume method is an attractive alternative to the finite element and boundary element methods that are more common in bioelectric applications     

Lysine‐241 Has a Role in Coupling 2OG Turnover with Substrate Oxidation During KDM4‐Catalysed Histone Demethylation

The JmjC histone lysyl demethylases (KDMs) play important roles in modulating histone methylation states and have the potential to be regulated by oxygen availability. Lys241 of the KDM4 subfamily is proposed to be important in oxygen binding by KDM4A. We report evidence that, although Lys241 is unlikely to be directly involved in oxygen binding, it has an important role in coupling 2‐oxoglutarate cosubstrate oxidation with lysine demethylase activity. The results suggest that compounds promoting the uncoupling of substrate oxidation are of interest as JmjC‐KDM inhibitors.     

Characterization of insulin-like growth factor binding proteins and regulation of IGFBP3 in human mesangial cells

IGF-I regulates renal growth and development. Insulin-like growth factor binding proteins (IGFBPs) are synthesized by the kidney and may modulate the local autocrine and/or paracrine actions of IGF-I. We have previously demonstrated that mesangial cells (MC) release IGF-I and IGF-binding activity; however, the specific IGFBPs produced by these cells and the factors involved in their regulation are unknown. We examined MC for expression of IGFBP-1 to -6 mRNAs and proteins. RNase protection assays using total RNA demonstrated that MC express all of the IGFBPs. [125I]IGF-I Western ligand blot of conditioned medium demonstrated that MC release IGFBPs of 24, 29, 32 kDa, and a doublet at 46 kDa, consistent with IGFBP-4, -5, -2 and -3, respectively. IGFBP species of 28 and 34 kDa were also detected. Since IGF-I and TGF-beta are implicated in glomerular hypertrophy and matrix expansion, we tested their effect on IGFBPs released by MC. IGF-I (100 ng/ml), TGF-beta (2 ng/ml) and forskolin (10(-5) M) differentially regulated the abundance of IGFBPs released in the conditioned medium in a time-dependent manner. IGF-I and TGF-beta were potent inducers of the release of IGFBP3 protein; however, TGF-beta, but not IGF-I, increased IGFBP3 mRNA levels. Recombinant IGFBP3 was tested for its effect on IGF-I-induced mitogenesis. IGFBP3 inhibited IGF-I-stimulated DNA synthesis in a dose-dependent manner with a peak effect observed at 50 nM IGFBP3. Although TGF-beta is a potent inhibitor of IGF-I-stimulated DNA synthesis, this effect is not mediated via IGFBPs. Expression of IGFBP-1 to -6 by MC suggests that these proteins may modulate IGF-I bioavailability in the glomerulus. IGF-I itself, TGF-beta and cAMP agonists may indirectly modulate the effects of IGF-I via the release of IGFBPs by MC.     

Hemodynamic sequelae of regression of experimental atherosclerosis

Regression of experimental atherosclerosis is characterized by decreased intimal thickness and luminal enlargement, but intimal fibrosis becomes more dense. We tested the hypothesis that fibrosis of arteries during regression might limit vasodilator capacity and restrict hemodynamic improvement despite luminal improvement. We studied limb, coronary, and cerebral hemodynamics in 11 normal cynomolgus monkeys, 10 monkeys given an atherogenic diet for 20 mo and 8 monkeys given a regression diet for an additional 18 mo. The atherogenic diet induced lesions of moderate severity (50-60% stenosis); owing to characteristic vessel growth during the atherogenic period, luminal size did not decrease correspondingly. Regression monkeys showed typical changes of regression with luminal enlargement but increased fibrosis. The iliac artery was perfused at constant blood flow and maximal vasodilatation was produced with papaverine. Blood flow was measured with microspheres during maximal vasodilatation in the coronary bed (adenosine) and cerebral bed (hypercapnia). In normal monkeys, minimal vascular resistances were 1.95 +/- 0.19 mm Hg/ml/min X 100 g (mean +/- SE) (limb), 0.13 +/- 0.01 (coronary), and 0.44 +/- 0.02 (cerebral). In atherosclerotic monkeys minimal resistance increased (P less than 0.05) 108, 62, and 166% in the limb, coronary, and cerebral beds, respectively. In regression monkeys, minimal resistance increased from values found in atherosclerotic animals in the limb (+22%), decreased inconsistently in the coronary bed (-19%), and decreased significantly in the cerebral bed (-44%, P less than 0.05). Thus morphologic regression was accompanied by significant hemodynamic improvement during maximal dilatation only in cerebral vessels. We conclude that increases in luminal size during regression of atherosclerotic lesions may not be associated with increases in vasodilator capacity, as intimal fibrosis may limit physiologically important hemodynamic improvement.