HNF4α Antagonists Discovered by a High-Throughput Screen for Modulators of the Human Insulin Promoter

Hepatocyte nuclear factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic β cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding.?Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in?vitro and in?vivo, although in?vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.     

Investigating chelating sulfonamides and their use in metalloproteinase inhibitors

Matrix metalloproteinase inhibitors (MMPi) utilize zinc-binding groups (ZBGs) to chelate the catalytic Zn(II) ion resulting in enzyme inhibition. Adapting findings from the literature of Zn(II) ion sensors, we previously reported chelating sulfonamide inhibitors of MMP-2, some of which showed excellent selectivity over other gelatinases (MMP-9). Herein, we greatly expand our investigation of chelating sulfonamides as MMP inhibitors (MMPi) with the synthesis and screening of several new libraries consisting of 2-phenyl-7-sulfonamidobenzimidazole, 2-phenyl-7-sulfonamidobenzoxazole, 7-sulfonamidobenzimidazole, 7-sulfonamidobenzoxazole, and 2-(2-sulfonamidophenyl)-quinoline ZBG derivatives. A novel microwave irradiation synthetic procedure was utilized to rapidly and efficiently prepare these molecules. To better understand the coordination chemistry underlying these ZBGs, crystal structures of representative molecules with several first row transition metals were determined and differences in coordination preferences were considered. Surprisingly, only compounds with the 2-phenyl-7-sulfonamidobenzimidazole ZBG showed inhibition of MMP-2, suggesting that the specific structure of the ZBG can have a pronounced effect of inhibitory activity.     

Influence of different mass absorption coefficient datasets on PIXE yields

Tabulated mass absorption coefficient data from the XCOM, Chantler and ion beam analysis (IBA) Handbook are compared, and differences are shown against X‐ray energy and target atomic number. Over the X‐ray energy range 1–40 keV systematic differences of several tens of percent are noted between these datasets, particularly for the earlier IBA Handbook dataset. The influence of these different mass absorption coefficients on the X‐ray yields for thick target proton‐induced X‐ray emission (PIXE) are investigated and compared as a function of X‐ray energy and target atomic number. For contemporary experimental PIXE users trying to work quantitatively over a broad range of elements and X‐ray energies, differences between PIXE results obtained using these three separate mass attenuation coefficient datasets can be larger than the typical accuracy limits of ±3% to ±5%. There are systematic differences in the mass attenuation coefficients of 5–10% between the XCOM and Chantler, while the differences for the IBA Handbook dataset can be larger (up to 40% and greater) at high X‐ray energies. At this time, we recommend the dataset of Chantler as it is more recent, and the synchrotron experimental results seem to favour it over the older XCOM and IBA Handbook data. Copyright © 2013 John Wiley & Sons, Ltd.     

From shape to randomness: A classification of Langevin stochasticity

The Langevin equation–perhaps the most elemental stochastic differential equation in the physical sciences–describes the dynamics of a random motion driven simultaneously by a deterministic potential field and by a stochastic white noise. The Langevin equation is, in effect, a mechanism that maps the stochastic white-noise input to a stochastic output: a stationary steady state distribution in the case of potential wells, and a transient extremum distribution in the case of potential gradients. In this paper we explore the degree of randomness of the Langevin equation’s stochastic output, and classify it à la Mandelbrot into five states of randomness ranging from “infra-mild” to “ultra-wild”. We establish closed-form and highly implementable analytic results that determine the randomness of the Langevin equation’s stochastic output–based on the shape of the Langevin equation’s potential field.     

Desorption of polymers: role of the stagnant layer

The desorption of polymers is studied theoretically and with Monte Carlo simulations. Two regimes can be distinguished: in one regime the detachment of the polymer from the surface is the slowest process, and in the other it is the diffusion of the polymer away from the surface. In both regimes the desorption rate depends on the thickness H of the stagnant layer, i.e. the layer in which the polymer movement is dominated by diffusion. In the diffusion-limited regime the desorption rate scales as H ^{? 2}, as expected for diffusive processes. In the detachment-limited regime the desorption rate scales as H ^{? 1}. The importance of the thickness of the stagnant layer in the detachment-limited regime is due to the fact that the polymer, after it has detached, will most likely readsorb soon after: the probability that the polymer does not readsorb, but crosses the stagnant layer, is inversely proportional to the thickness of the stagnant layer.     

Effect of pressure on an intramolecular electron-transfer reaction induced by pulse-radiolysis

Abstract

The pressure dependence of an intramolecular electron-transfer reaction between p-nitrobenzoate and the pentaamminecobalt (III) species was studied with the aid of a combined high-pressure pulse-radiolysis technique. The resulting volume of activation of +7.5±0.3 cm³mol^?1 is ascribed to an intrinsic volume increase due to the reduction of Co(III) to Co(II) and some desolvation of the coordinated ligand during the electron-transfer process. The results are compared with related data obtained using conventional kinetic techniques.     

Four calculus qualms

In the teaching of calculus, some misunderstandings can arise, which can be alleviated by slightly deeper investigation, to be shared with students as occasions demand. In this note, four such explorations are described: (1) the Fundamental Theorem of Calculus is not stated and then proven, but calculated. (2) The integral calculus could conceivably be developed before the diff erential calculus. (3) The Taylor series about any point for any ‘good’ function is not stated and then proven, but calculated from scratch. (4) The graphing of the functions b?x and x?b (for any given b > 0) on the same set of axes is done more accurately, and more interestingly.     

Dynamic consistency for stochastic optimal control problems

For a sequence of dynamic optimization problems, we aim at discussing a notion of consistency over time. This notion can be informally introduced as follows. At the very first time step?t ₀, the decision maker formulates an optimization problem that yields optimal decision rules for all the forthcoming time steps?t ₀,t ₁,??,T; at the next time step?t ₁, he is able to formulate a new optimization problem starting at time?t ₁ that yields a new sequence of optimal decision rules. This process can be continued until the final time?T is reached. A?family of optimization problems formulated in this way is said to be dynamically consistent if the optimal strategies obtained when solving the original problem remain optimal for all subsequent problems. The notion of dynamic consistency, well-known in the field of economics, has been recently introduced in the context of risk measures, notably by Artzner et al. (Ann. Oper. Res. 152(1):5?C22, 2007) and studied in the stochastic programming framework by Shapiro (Oper. Res. Lett. 37(3):143?C147, 2009) and for Markov Decision Processes (MDP) by Ruszczynski (Math. Program. 125(2):235?C261, 2010). We here link this notion with the concept of ??state variable?? in MDP, and show that a significant class of dynamic optimization problems are dynamically consistent, provided that an adequate state variable is chosen.     

Capturing Ridge Functions in High Dimensions from Point Queries

Constructing a good approximation to a function of many variables suffers from the “curse of dimensionality”. Namely, functions on ℝ ^N with smoothness of order s can in general be captured with accuracy at most O(n ^−s/N ) using linear spaces or nonlinear manifolds of dimension n. If N is large and s is not, then n has to be chosen inordinately large for good accuracy. The large value of N often precludes reasonable numerical procedures. On the other hand, there is the common belief that real world problems in high dimensions have as their solution, functions which are more amenable to numerical recovery. This has led to the introduction of models for these functions that do not depend on smoothness alone but also involve some form of variable reduction. In these models it is assumed that, although the function depends on N variables, only a small number of them are significant. Another variant of this principle is that the function lives on a low dimensional manifold. Since the dominant variables (respectively the manifold) are unknown, this leads to new problems of how to organize point queries to capture such functions. The present paper studies where to query the values of a ridge function f(x)=g(a⋅x) when both a∈ℝ ^N and g∈C[0,1] are unknown. We establish estimates on how well f can be approximated using these point queries under the assumptions that g∈C ^s [0,1]. We also study the role of sparsity or compressibility of a in such query problems.     

Experimental and theoretical evidence for pressure-induced metallization in FeO with rocksalt-type structure

Electrical conductivity of FeO was measured up to 141 GPa and 2480 K in a laser-heated diamond-anvil cell. The results show that rock-salt (B1) type structured FeO metallizes at around 70 GPa and 1900 K without any structural phase transition. We computed fully self-consistently the electronic structure and the electrical conductivity of B1 FeO as a function of pressure and temperature, and found that although insulating as expected at ambient condition, B1 FeO metallizes at high temperatures, consistent with experiments. The observed metallization is related to spin crossover.