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Author(s): Matthew N. Poy [1]; Lena Eliasson [3]; Jan Krutzfeldt [1]; Satoru Kuwajima [1]; Xiaosong Ma [3]; Patrick E. MacDonald [3]; Sébastien Pfeffer [1]; Thomas Tuschl [1]; Nikolaus Rajewsky [4]; [...]

Defects in pancreatic [beta]-cell function contribute to the development of type 2 diabetes, a polygenic disease that is characterized by insulin resistance and compromised insulin secretion. Hepatocyte nuclear factors (HNFs) -1[alpha], -3[beta], -4[alpha], and Pdx-1 contribute in the complex transcriptional circuits within the pancreas that are involved in [beta]-cell development and function. In mice, a heterozygous mutation in Pdx-1 alone, but not Hnf-1[[alpha].sup.+/-], Hnf-3[[beta].sup.+/-], or Hnf-4[[alpha].sup.+/-], causes impaired glucose-stimulated insulin secretion in mice. To investigate the possible functional relationships between these transcription factors on [beta]-cell activity in vivo, we generated mice with the following combined heterozygous mutations: Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-], Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-], Pdx-[1.sup.+/-]/Hnf-4[[alpha].sup.+/-, Hnf-1[[alpha].sup.+/-]/Hnf-4[[alpha].sup.+/-], and Hnf-3[[beta].sup.+/-]/Hnf-4[[alpha].sup.+/-]. The greatest loss in function was in combined heterozygous null alleles of Pdx-1 and Hnf-1[alpha](Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-]), or Pdx-1 and Hnf-3[beta](Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-]). Both double mutants develop progressively impaired glucose tolerance and acquire a compromised first- and second-phase insulin secretion profile in response to glucose compared with Pdx-[1.sup.+/-] mice alone. The loss in [beta]-cell function in Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-] mice was associated with decreased expression of Nkx-6.1, glucokinase (Gck), aldolase B (aldo-B), and insulin, whereas Nkx2.2, Nkx-6.1, Glut-2, Gck, aldo-B, the liver isoform of pyruvate kinase, and insulin expression was reduced in Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-] mice. The islet cell architecture was also abnormal in Pdx-[1.sup.+/-]/Hnf-3[[beta].sup.+/-] and Pdx-[1.sup.+/-]/Hnf-1[[alpha].sup.+/-] mice, with glucagon-expressing cells scattered throughout the islet, a defect that may be connected to decreased E-cadherin expression. Our data suggest that functional interactions between key islet regulatory factors play an important role in maintaining islet architecture and [beta]-cell function. These studies also established polygenic mouse models for investigating the mechanisms contributing to [beta]-cell dysfunction in diabetes. hepatocyte nuclear factors | diabetes mellitus | insulin secretion | pancreatic islets

A novel free-energy perturbation method is developed for the computation of the free energy of transferring a molecule between fluid phases. The methodology consists in drawing a free-energy profile of the target molecule moving across a binary-phase structure built in the computer. The novelty of the method lies in the difference of the definition of the free-energy profile from the common definition. As an important element of the method, the process of making a correction to the transfer free energy with respect to the cutoff of intermolecular forces is elucidated. In order to examine the performance of the method in the application to fluid-phase equilibrium properties, molecular-dynamics computations are carried out for the evaluation of gas solubility and vapor pressure of liquid n-hexane at 298.15 K. The gas species treated are methane, ethane, propane, and n-butane, with the gas solubility expressed as Henry’s constant. It is shown that the method works fine and calculated results are generally in good agreement with experiments. It is found that the cutoff correction is strikingly large, constituting a dominant part of the calculated transfer free energy at the cutoff of 8 Å. [ABSTRACT FROM AUTHOR]

The Ewald method, which is known as a method for evaluating electrostatic interactions in periodic systems, is extended to nonperiodic systems. A general way of applying the Ewald method to nonperiodic systems is described and a detailed application is demonstrated for the treatment of ions immersed in dipolar solvent molecules. As a preliminary test, electric fields produced by point dipoles forming a simple cubic lattice are calculated, both by the new Ewald treatment and by the conventional cutoff (truncation) method. These test calculations not only demonstrate the advantage of the new Ewald method but also reveal inherent problems associated with the cutoff method. [ABSTRACT FROM AUTHOR]

Examines the molecular dynamics simulation of water diffusion in atactic polypropylene (aPP) and isotactic polypropylene (iPP) models. Comparison between iPP and aPP on density; Formation of water cluster in aPP model; Maintenance of aggregated structure in iPP.

Molecular-dynamics (MD) simulation of the diffusion of water in amorphous polyethylene has been performed. In order to obtain information about the fundamental diffusion behavior of water, the constant particle number, constant pressure, and constant temperature (NPT) MD was employed for three model systems differing in the number of water molecules and methylene group in the polyethylene chains. Time duration beyond 10 ns showed that the water molecules came together forming water clusters of various sizes. Although the self-diffusion coefficient Dself estimated from the mean-square displacement curve scattered considerably in the order from 10-8–10-5 cm2/s, Dself for the water cluster is generally one order lower in magnitude than that of a single water. However, the linearity of the mean-square curve for the larger system which contained 4000 carbon atoms was very good, and Dself obtained for ten water molecules up to 11 ns duration showed 7.1×10-7 cm2/s which was in good agreement with the experimental value. © 1997 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We have previously shown that a forkhead transcription factor Foxal interacts with androgen signaling and controls prostate differentiated response. Here, we show the mouse Foxal expression marks the entire embryonic urogenital sinus epithelium (UGE), contrasting with Shh and Foxa2, which are restricted to the basally located cells during prostate budding. The Foxal-deficient mouse prostate shows a severely altered ductal pattern that resembles primitive epithelial cords surrounded by thick stromal layers. Characterization of these mutant cells indicates a population of basal-like cells similar to those found in the embryonic UGE, whereas no differentiated or mature luminal epithelial cells are found in Foxal-deficient epithelium. These phenotypic changes are accompanied with molecular aberrations, including focal epithelial activation of Shh and elevated Foxa2 and Notchl in the null epithelium. Perturbed epithelial-stromal interactions induced by Foxal-deficient epithelium is evident, as demonstrated by the expansion of surrounding smooth muscle and elevated levels of stromal factors (Bmp4, Fgf7, Fgf10 and Gli). The prostatic homeobox protein Nkx3.1, a known proliferation inhibitor, was downregulated in Foxal-deficient epithelial cells, while several prostate-specific androgen-regulated markers, including a novel Foxal target, are absent in the null prostate. These data indicate that Foxal plays a pivotal role in controlling prostate morphogenesis and cell differentiation. [ABSTRACT FROM AUTHOR]