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Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.

Thyroid hormones (THs) operate numerous physiological processes through the nuclear thyroid hormone receptors and several other proteins. Here we report direct peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) activation by the T4 metabolite TETRAC at nanomolar affinity. We demonstrate that TETRAC is a highly active PPARγ agonist promoting PPARγ signaling in cell-free, cellular and in vivo settings suggesting that TETRAC and other THs are activators of PPARγ linking TH and PPAR signaling.

The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme, containing a peptidase and a hydrolase activity both activities having opposing functions regulating inflammatory response. The hydrolase activity is responsible for the conversion of leukotriene A4 to pro-inflammatory leukotriene B4, and hence, selective inhibitors of the hydrolase activity are of high pharmacological interest. Here we present the thermodynamic characterization of structurally distinct inhibitors of the LTA4H that occupy different regions of the binding site using different biophysical methods. An in silico method for the determination of stabilized water molecules in the binding site of the apo structure of LTA4H is used to interpret the measured thermodynamic data and provided insights for design of novel LTA4H inhibitors.

Taking generative software development as our point of departure, we introduce generative software complexity as a measure for quantifying the structural complexity of software. After explaining that it is the same as Kolmogorov complexity, we discuss its merits from the viewpoint of software understanding. The results obtained are in many ways unsatisfactory, but sufficiently intriguing to warrant further work. Introduction of a software complexity metric underlying software generation.Generative software complexity is the Kolmogorov complexity of software.Discussion of generative complexity as an understandability metric.Explanation of the emergence of domain-specific concepts.

The architecture of three of the latest 16-bit microprocessors, viz. the Intel 8086, the Zilog Z800 and the Motorola MC68000, are discussed. The various technical issues confronting the user of a 16-bit micro, such as high-level languages, portability of hardware and software, inter-processor communication, and functional off-loading, are used as a framework for the discussion.