PPAR γ partial agonist, KR-62776, inhibits adipocyte differentiation via activation of ERK

Indenone KR-62776 acts as an agonist of PPARγ without inducing obesity in animal models and cells. X-ray crystallography reveals that the indenone occupies the binding pocket in a different manner than rosiglitazone. 2-Dimensional gel-electrophoresis showed that the expression of 42 proteins was altered more than 2.0-fold between KR-62776- or rosiglitazone-treated adipocyte cells and control cells. Rosiglitazone down-regulated the expression of ERK1/2 and suppressed the phosphorylation of ERK1/2 in these cells. However, the expression of ERK1/2 was up-regulated in KR-62776-treated cells. Phosphorylated ERK1/2, activated by indenone, affects the localization of PPARγ, suggesting a mechanism for indenone-inhibition of adipogenesis in 3T3-L1 preadipocyte cells. The preadipocyte cells are treated with ERK1/2 inhibitor PD98059, a large amount of the cells are converted to adipocyte cells. These results support the conclusion that the localization of PPARγ is one of the key factors explaining the biological responses of the ligands. Received 04 March 2009; received after revision 13 March 2009; accepted 17 March 2009     

Methods for backcasting,nowcasting and forecasting using factor‐MIDAS: With an application to Korean GDP

We utilize mixed‐frequency factor‐MIDAS models for the purpose of carrying out backcasting, nowcasting, and forecasting experiments using real‐time data. We also introduce a new real‐time Korean GDP dataset, which is the focus of our experiments. The methodology that we utilize involves first estimating common latent factors (i.e., diffusion indices) from 190 monthly macroeconomic and financial series using various estimation strategies. These factors are then included, along with standard variables measured at multiple different frequencies, in various factor‐MIDAS prediction models. Our key empirical findings as follows. (i) When using real‐time data, factor‐MIDAS prediction models outperform various linear benchmark models. Interestingly, the “MSFE‐best” MIDAS models contain no autoregressive (AR) lag terms when backcasting and nowcasting. AR terms only begin to play a role in “true” forecasting contexts. (ii) Models that utilize only one or two factors are “MSFE‐best” at all forecasting horizons, but not at any backcasting and nowcasting horizons. In these latter contexts, much more heavily parametrized models with many factors are preferred. (iii) Real‐time data are crucial for forecasting Korean gross domestic product, and the use of “first available” versus “most recent” data “strongly” affects model selection and performance. (iv) Recursively estimated models are almost always “MSFE‐best,” and models estimated using autoregressive interpolation dominate those estimated using other interpolation methods. (v) Factors estimated using recursive principal component estimation methods have more predictive content than those estimated using a variety of other (more sophisticated) approaches. This result is particularly prevalent for our “MSFE‐best” factor‐MIDAS models, across virtually all forecast horizons, estimation schemes, and data vintages that are analyzed.     

Interleukin-33 stimulates formation of functional osteoclasts from human CD14+ monocytes

Interleukin (IL)-33 is a recently described pro-inflammatory cytokine. Here we demonstrate IL-33 as a regulator of functional osteoclasts (OCs) from human CD14⁺ monocytes. IL-33 stimulates formation of tartrate-resistant acid phosphatase (TRAP)⁺ multinuclear OCs from monocytes. This action was suppressed by anti-ST2 antibody, suggesting that IL-33 acts through its receptor ST2, but not by the receptor activator of NF-κB ligand (RANKL) decoy, osteoprotegerin, or anti-RANKL antibody. IL-33 stimulated activating phosphorylations of signaling molecules in monocytes that are critical for OC development. These included Syk, phospholipase Cγ2, Gab2, MAP kinases, TAK-1, and NF-κB. IL-33 also enhanced expression of OC differentiation factors including TNF-α receptor-associated factor 6 (TRAF6), nuclear factor of activated T cells cytoplasmic 1, c-Fos, c-Src, cathepsin K, and calcitonin receptor. IL-33 eventually induced bone resorption. This study suggests that the osteoclastogenic property of IL-33 is mediated through TRAF6 as well as the immunoreceptor tyrosine-based activation motif-dependent Syk/PLCγ pathway in human CD14⁺ monocytes.     

Multispecies-compatible antitumor effects of a cross-species small-interfering RNA against mammalian target of rapamycin

Successful development of sequence-specific siRNA (small interfering RNA)-based drugs requires an siRNA design that functions consistently in different organisms. Utilizing the CAPSID program previously developed by our group, we here designed siRNAs against mammalian target of rapamycin (mTOR) that are entirely complementary among various species and investigated their multispecies-compatible gene-silencing properties. The mTOR siRNAs markedly reduced mTOR expression at both the mRNA and protein levels in human, mouse, and monkey cell lines. The reduction in mTOR expression resulted in inactivation of both mTOR complex I and II signaling pathways, as confirmed by reduced phosphorylation of p70S6K (70-kDa ribosomal protein S6 kinase), 4EBP1 (eIF4E-binding protein 1), and AKT, and nuclear accumulation of FOXO1 (forkhead box O1), with consequent cell-cycle arrest, proliferation inhibition, and autophagy activation. Moreover, interfering with mTOR activity in vivo using mTOR small-hairpin RNA-expressing recombinant adeno-associated virus led to significant antitumor effects in xenograft and allograft models. Thus, the present study demonstrates that cross-species siRNA successfully silences its target and readily produces multispecies-compatible phenotypic alterations-antitumor effects in the case of mTOR siRNA. Application of cross-species siRNA should greatly facilitate the development of siRNA-based therapeutic agents.     

Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer

Human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR frequently respond to treatment with EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, but responses are not durable, as tumors acquire resistance. Secondary mutations in EGFR (such as T790M) or upregulation of the MET kinase are found in over 50% of resistant tumors. Here, we report increased activation of AXL and evidence for epithelial-to-mesenchymal transition (EMT) in multiple in vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to erlotinib in the absence of the EGFR p.Thr790Met alteration or MET activation. Genetic or pharmacological inhibition of AXL restored sensitivity to erlotinib in these tumor models. Increased expression of AXL and, in some cases, of its ligand GAS6 was found in EGFR-mutant lung cancers obtained from individuals with acquired resistance to TKIs. These data identify AXL as a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to EGFR TKIs in individuals with EGFR-mutant lung cancer.     

Birds of a Feather Protest Together: Theorizing Self-Organizing Political Protests with Flock Theory

The current research theorizes decentralized and self-organized political protests via flock theory (Rosen 2002), a theory of emergent self-organization in communicative human interaction. Flock theory draws from a theoretical basis of emergence and self-organizing systems, and is presented as a theory of decentralized communication structures. Focusing on the optimization of decentralized networks and roadmap based coordination of organizationally homopholous foci; the current theory poses a model of human interaction that captures the potentially egalitarian effects of cooperative evolution and collective action. Case studies of two separate decentralized political protests against Korean government and FARC are offered as evidences of such phenomena.     

Electroluminescence from single monolayers of nanocrystals in molecular organic devices

The integration of organic and inorganic materials at the nanometre scale into hybrid optoelectronic structures enables active devices that combine the diversity of organic materials with the high-performance electronic and optical properties of inorganic nanocrystals. The optimization of such hybrid devices ultimately depends upon the precise positioning of the functionally distinct materials. Previous studies have already emphasized that this is a challenge, owing to the lack of well-developed nanometre-scale fabrication techniques. Here we demonstrate a hybrid light-emitting diode (LED) that combines the ease of processability of organic materials with the narrow-band, efficient luminescence of colloidal quantum dots (QDs). To isolate the luminescence processes from charge conduction, we fabricate a quantum-dot LED (QD-LED) that contains only a single monolayer of QDs, sandwiched between two organic thin films. This is achieved by a method that uses material phase segregation between the QD aliphatic capping groups and the aromatic organic materials. In our devices, where QDs function exclusively as lumophores, we observe a 25-fold improvement in luminescence efficiency (1.6 cd A(-1) at 2,000 cd m(-2)) over the best previous QD-LED results. The reproducibility and precision of our phase-segregation approach suggests that this technique could be widely applicable to the fabrication of other hybrid organic/inorganic devices.     

The chick ovomucoid gene contains at least six intervening sequences.

A 15-kilobase pair EcoRI chick DNA fragment, containing both the termination codon UGA and the 5'-portion of the structural ovomucoid gene, has been cloned in lambda phage Charon 4A by in vitro packaging. Restriction mapping and electron microscopic analyses of this cloned DNA have revealed that the structural ovomucoid gene sequences are separated by at least six intervening sequences.