Straddling For Market Space: Transforming Estonian State-Owned Enterprises Toward A Free-Market Orientation

This paper examines the dynamics of transformation of three Estonian state-owned enterprises – Eesti Gaas, Eesti Energia and Eesti Telefon - toward a free market orientation following the Estonia’s decision to separate from the USSR. The difficulties of such transformation are first examined from a theoretical perspective. It is argued that organizations attempting such transformation are likely to be stuck in a state of dynamic equilibrium between the old static mode and the emerging free-market mode until some key factor causes it to tip over into one or the other of these modes. Four major transformational challenges - strategic orientation, resource and competency acquisition logic, workforce and organizational configuration - are discussed by examining the dynamics of transformation of three Estonian state-owned enterprises

Structure-based predictions broadly link transcription factor mutations to gene expression changes in cancers

© 2014 The Author(s). Thousands of unique mutations in transcription factors (TFs) arise in cancers, and the functional and biological roles of relatively few of these have been characterized. Here, we used structure-based methods developed specifically for DNA-binding proteins to systematically predict the consequences of mutations in several TFs that are frequently mutated in cancers. The explicit consideration of protein-DNA interactions was crucial to explain the roles and prevalence of mutations in TP53 and RUNX1 in cancers, and resulted in a higher specificity of detection for known p53-regulated genes among genetic associations between TP53 genotypes and genome-wide expression in The Cancer Genome Atlas, compared to existing methods of mutation assessment. Biophysical predictions also indicated that the relative prevalence of TP53 missense mutations in cancer is proportional to their thermodynamic impacts on protein stability and DNA binding, which is consistent with the selection for the loss of p53 transcriptional function in cancers. Structure and thermodynamics-based predictions of the impacts of missense mutations that focus on specific molecular functions may be increasingly useful for the precise and large-scale inference of aberrant molecular phenotypes in cancer and other complex diseases

Informal Action—Adjudication—Rule Making: Some Recent Developments in Federal Administrative Law

Direct energy consumption of ICT hardware is only “half the story.” In order to get the “whole story,” energy consumption during the entire life cycle has to be taken into account. This chapter is a first step toward a more comprehensive picture, showing the “grey energy” (i.e., the overall energy requirements) as well as the releases (into air, water, and soil) during the entire life cycle of exemplary ICT hardware devices by applying the life cycle assessment method. The examples calculated show that a focus on direct energy consumption alone fails to take account of relevant parts of the total energy consumption of ICT hardware as well as the relevance of the production phase. As a general tendency, the production phase is more and more important the smaller (and the more energy-efficient) the devices are. When in use, a tablet computer is much more energy-efficient than a desktop computer system with its various components, so its production phase has a much greater relative importance. Accordingly, the impacts due to data transfer when using Internet services are also increasingly relevant the smaller the end-user device is, reaching up to more than 90 % of the overall impact when using a tablet computer.QC 20140825</p

Genetic and transcriptomic analysis of transcription factor genes in the model halophilic Archaeon: coordinate action of TbpD and TfbA

<p>Abstract</p> <p>Background</p> <p>Archaea are prokaryotic organisms with simplified versions of eukaryotic transcription systems. Genes coding for the general transcription factors TBP and TFB are present in multiple copies in several Archaea, including <it>Halobacterium </it>sp. NRC-1. Multiple TBP and TFBs have been proposed to participate in transcription of genes via recognition and recruitment of RNA polymerase to different classes of promoters.</p> <p>Results</p> <p>We attempted to knock out all six TBP and seven TFB genes in <it>Halobacterium </it>sp. NRC-1 using the <it>ura</it>3-based gene deletion system. Knockouts were obtained for six out of thirteen genes, <it>tbp</it>CDF and <it>tfb</it>ACG, indicating that they are not essential for cell viability under standard conditions. Screening of a population of 1,000 candidate mutants showed that genes which did not yield mutants contained less that 0.1% knockouts, strongly suggesting that they are essential. The transcriptomes of two mutants, Δ<it>tbp</it>D and Δ<it>tfb</it>A, were compared to the parental strain and showed coordinate down regulation of many genes. Over 500 out of 2,677 total genes were regulated in the Δ<it>tbp</it>D and Δ<it>tfb</it>A mutants with 363 regulated in both, indicating that over 10% of genes in both strains require the action of both TbpD and TfbA for normal transcription. Culturing studies on the Δ<it>tbp</it>D and Δ<it>tfb</it>A mutant strains showed them to grow more slowly than the wild-type at an elevated temperature, 49°C, and they showed reduced viability at 56°C, suggesting TbpD and TfbA are involved in the heat shock response. Alignment of TBP and TFB protein sequences suggested the expansion of the TBP gene family, especially in <it>Halobacterium </it>sp. NRC-1, and TFB gene family in representatives of five different genera of haloarchaea in which genome sequences are available.</p> <p>Conclusion</p> <p>Six of thirteen TBP and TFB genes of <it>Halobacterium </it>sp. NRC-1 are non-essential under standard growth conditions. TbpD and TfbA coordinate the expression of over 10% of the genes in the NRC-1 genome. The Δ<it>tbp</it>D and Δ<it>tfb</it>A mutant strains are temperature sensitive, possibly as a result of down regulation of heat shock genes. Sequence alignments suggest the existence of several families of TBP and TFB transcription factors in <it>Halobacterium </it>which may function in transcription of different classes of genes.</p

Differential Effects of Leptin on the Invasive Potential of Androgen-Dependent and -Independent Prostate Carcinoma Cells

Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP) cells as well as androgen-insensitive (PC-3 and DU-145) cells. At a concentration of 200 nm, LNCaP cells showed a significant increase (20% above control; P < .0001) in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P < .01 to P < .0001) dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity

Microarray Analysis in the Archaeon Halobacterium salinarum Strain R1

Background: Phototrophy of the extremely halophilic archaeon Halobacterium salinarum was explored for decades. The research was mainly focused on the expression of bacteriorhodopsin and its functional properties. In contrast, less is known about genome wide transcriptional changes and their impact on the physiological adaptation to phototrophy. The tool of choice to record transcriptional profiles is the DNA microarray technique. However, the technique is still rarely used for transcriptome analysis in archaea. Methodology/Principal Findings: We developed a whole-genome DNA microarray based on our sequence data of the Hbt. salinarum strain R1 genome. The potential of our tool is exemplified by the comparison of cells growing under aerobic and phototrophic conditions, respectively. We processed the raw fluorescence data by several stringent filtering steps and a subsequent MAANOVA analysis. The study revealed a lot of transcriptional differences between the two cell states. We found that the transcriptional changes were relatively weak, though significant. Finally, the DNA microarray data were independently verified by a real-time PCR analysis. Conclusion/Significance: This is the first DNA microarray analysis of Hbt. salinarum cells that were actually grown under phototrophic conditions. By comparing the transcriptomics data with current knowledge we could show that our DNA microarray tool is well applicable for transcriptome analysis in the extremely halophilic archaeon Hbt. salinarum. The reliability of our tool is based on both the high-quality array of DNA probes and the stringent data handling including MAANOVA analysis. Among the regulated genes more than 50% had unknown functions. This underlines the fact that haloarchaeal phototrophy is still far away from being completely understood. Hence, the data recorded in this study will be subject to future systems biology analysis

Protection against LPS-induced cartilage inflammation and degradation provided by a biological extract of Mentha spicata

<p>Abstract</p> <p>Background</p> <p>A variety of mint [<it>Mentha spicata</it>] has been bred which over-expresses Rosmarinic acid (RA) by approximately 20-fold. RA has demonstrated significant anti-inflammatory activity <it>in vitro </it>and in small rodents; thus it was hypothesized that this plant would demonstrate significant anti-inflammatory activity <it>in vitro</it>. The objectives of this study were: a) to develop an <it>in vitro </it>extraction procedure which mimics digestion and hepatic metabolism, b) to compare anti-inflammatory properties of High-Rosmarinic-Acid <it>Mentha spicata </it>(HRAM) with wild-type control <it>M. spicata </it>(CM), and c) to quantify the relative contributions of RA and three of its hepatic metabolites [ferulic acid (FA), caffeic acid (CA), coumaric acid (CO)] to anti-inflammatory activity of HRAM.</p> <p>Methods</p> <p>HRAM and CM were incubated in simulated gastric and intestinal fluid, liver microsomes (from male rat) and NADPH. Concentrations of RA, CA, CO, and FA in simulated digest of HRAM (HRAM_sim) and CM (CM_sim) were determined (HPLC) and compared with concentrations in aqueous extracts of HRAM and CM. Cartilage explants (porcine) were cultured with LPS (0 or 3 μg/mL) and test article [HRAM_sim(0, 8, 40, 80, 240, or 400 μg/mL), or CM_sim(0, 1, 5 or 10 mg/mL), or RA (0.640 μg/mL), or CA (0.384 μg/mL), or CO (0.057 μg/mL) or FA (0.038 μg/mL)] for 96 h. Media samples were analyzed for prostaglandin E₂(PGE₂), interleukin 1β (IL-1), glycosaminoglycan (GAG), nitric oxide (NO) and cell viability (differential live-dead cell staining).</p> <p>Results</p> <p>RA concentration of HRAM_simand CM_simwas 49.3 and 0.4 μg/mL, respectively. CA, FA and CO were identified in HRAM_simbut not in aqueous extract of HRAM. HRAM_sim(≥ 8 μg/mL) inhibited LPS-induced PGE₂and NO; HRAM_sim(≥ 80 μg/mL) inhibited LPS-induced GAG release. RA inhibited LPS-induced GAG release. No anti-inflammatory or chondroprotective effects of RA metabolites on cartilage explants were identified.</p> <p>Conclusions</p> <p>Our biological extraction procedure produces a substance which is similar in composition to post-hepatic products. HRAM_simis an effective inhibitor of LPS-induced inflammation in cartilage explants, and effects are primarily independent of RA. Further research is needed to identify bioactive phytochemical(s) in HRAM_sim.</p

NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus

The PIDDosome (PIDD–RAIDD–caspase-2 complex) is considered to be the primary signaling platform for caspase-2 activation in response to genotoxic stress. Yet studies of PIDD-deficient mice show that caspase-2 activation can proceed in the absence of PIDD. Here we show that DNA damage induces the assembly of at least two distinct activation platforms for caspase-2: a cytoplasmic platform that is RAIDD dependent but PIDD independent, and a nucleolar platform that requires both PIDD and RAIDD. Furthermore, the nucleolar phosphoprotein nucleophosmin (NPM1) acts as a scaffold for PIDD and is essential for PIDDosome assembly in the nucleolus after DNA damage. Inhibition of NPM1 impairs caspase-2 processing, apoptosis, and caspase-2–dependent inhibition of cell growth, demonstrating that the NPM1-dependent nucleolar PIDDosome is a key initiator of the caspase-2 activation cascade. Thus we have identified the nucleolus as a novel site for caspase-2 activation and function