S6K1 Phosphorylation of H2B Mediates EZH2 Trimethylation of H3: A Determinant of Early Adipogenesis

Yi, S.,Um, S.,Lee, J.,Yoo, J.,Bang, S.,Park, E.,Lee, M.,Nam, K.,Jeon, Y.,Park, J.,You, J.,Lee, S.J.,Bae, G.U.,Rhie, J.,Kozma, Sara C.,Thomas, G.,Han, J.W. Cell Press 2016 Molecular Cell Vol.62 No.3

S6K1 has been implicated in a number of key metabolic responses, which contribute to obesity. Critical among these is the control of a transcriptional program required for the commitment of mesenchymal stem cells to the adipocytic lineage. However, in contrast to its role in the cytosol, the functions and targets of nuclear S6K1 are unknown. Here, we show that adipogenic stimuli trigger nuclear translocation of S6K1, leading to H2BS36 phosphorylation and recruitment of EZH2 to H3, which mediates H3K27 trimethylation. This blocks Wnt gene expression, inducing the upregulation of PPARγ and Cebpa and driving increased adipogenesis. Consistent with this finding, white adipose tissue from S6K1-deficient mice exhibits no detectable H2BS36 phosphorylation or H3K27 trimethylation, whereas both responses are highly elevated in obese humans or in mice fed a high-fat diet. These findings define an S6K1-dependent mechanism in early adipogenesis, contributing to the promotion of obesity.

Involvement of S6K1 in mitochondria function and structure in HeLa cells

Park, J.,Tran, Q.,Mun, K.,Masuda, K.,Kwon, S.H.,Kim, S.H.,Kim, D.H.,Thomas, G.,Park, J. Pergamon Press ; Elsevier Science Ltd 2016 Cellular signalling Vol.28 No.12

The major biological function of mitochondria is to generate cellular energy through oxidative phosphorylation. Apart from cellular respiration, mitochondria also play a key role in signaling processes, including aging and cancer metabolism. It has been shown that S6K1-knockout mice are resistant to obesity due to enhanced beta-oxidation, with an increased number of large mitochondria. Therefore, in this report, the possible involvement of S6K1 in regulating mitochondria dynamics and function has been investigated in stable lenti-shS6K1-HeLa cells. Interestingly, S6K1-stably depleted HeLa cells showed phenotypical changes in mitochondria morphology. This observation was further confirmed by detailed image analysis of mitochondria shape. Corresponding molecular changes were also observed in these cells, such as the induction of mitochondrial fission proteins (Drp1 and Fis1). Oxygen consumption is elevated in S6K1-depeleted HeLa cells and FL5.12 cells. In addition, S6K1 depletion leads to enhancement of ATP production in cytoplasm and mitochondria. However, the relative ratio of mitochondrial ATP to cytoplasmic ATP is actually decreased in lenti-shS6K1-HeLa cells compared to control cells. Lastly, induction of mitophagy was found in lenti-shS6K1-HeLa cells with corresponding changes of mitochondria shape on electron microscope analysis. Taken together, our results indicate that S6K1 is involved in the regulation of mitochondria morphology and function in HeLa cells. This study will provide novel insights into S6K1 function in mitochondria-mediated cellular signaling.

S6K1 Plays a Critical Role in Early Adipocyte Differentiation

Carnevalli, Larissa S.,Masuda, Kouhei,Frigerio, Francesca,Le Bacquer, Olivier,Um, Sung Hee,Gandin, Valentina,Topisirovic, Ivan,Sonenberg, Nahum,Thomas, George,Kozma, Sara C. Elsevier 2010 Developmental cell Vol.18 No.5

<P><B>Summary</B></P><P>Earlier, we reported that <I>S6K1</I><SUP>−/−</SUP> mice have reduced body fat mass, have elevated rates of lipolysis, have severely decreased adipocyte size, and are resistant to high fat diet (HFD)-induced obesity. Here we report that adipocytes of <I>S6K1</I><SUP>−/−</SUP> mice on a HFD have the capacity to increase in size to a degree comparable to that of wild-type (WT) mice, but not in number, indicating an unexpected lesion in adipogenesis. Tracing this lesion revealed that S6K1 is dispensable for terminal adipocyte differentiation, but is involved in the commitment of embryonic stem cells to early adipocyte progenitors. We further show that absence of S6K1 attenuates the upregulation of transcription factors critical for commitment to adipogenesis. These results led to the conclusion that a lack of S6K1 impairs the generation of de novo adipocytes when mice are challenged with a HFD, consistent with a reduction in early adipocyte progenitors.</P> <P><B>Graphical Abstract</B></P><P><ce:figure></ce:figure></P>

Export Market Size Matters: The Effect of the Market Size of Export Destinations on Manufacturing Growth

Goda Thomas,Sánchez González Santiago 한국국제경제학회 2024 International Economic Journal Vol.38 No.1

Literature contends that the manufacturing sector is crucial for economic development, and it is conventional wisdom that exports drive manufacturing growth. However, it has yet to be established empirically whether the market size of export destinations is an essential factor in explaining diverging regional and sectoral manufacturing growth patterns. This article argues that accessing a few large external markets reduces entry costs, increases expectations of economies of scale, and fosters capital formation. To test this hypothesis, we construct a novel Relative Export Market Size (REMS) index that measures whether the share of sectoral exports destined to large economies in one region is higher than in other regions. Using a PVAR model with fixed effects, we verify the impact of the REMS index on value added, employment, and capital accumulation of 129 manufacturing sectors in 23 regions in Colombia from 1992 to 2017. The obtained results show that exporting to larger markets positively impacts employment, capital formation, and value added per capita of manufacturing sectors at a regional level. This finding indicates that exporting to the world’s largest market helps develop competitive manufacturing sectors.

microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells

Marcais, Antoine,Blevins, Rory,Graumann, Johannes,Feytout, Amelie,Dharmalingam, Gopuraja,Carroll, Thomas,Amado, Inê,s F.,Bruno, Ludovica,Lee, Keunwook,Walzer, Thierry,Mann, Matthias,Freitas, Anto The Rockefeller University Press 2014 The Journal of experimental medicine Vol.211 No.11

<P>T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in <I>Il2</I>-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the <I>Mtor</I> and <I>Rictor</I> mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of <I>Mtor</I> and one allele of <I>Rictor</I> was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation–independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.</P>

Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice

Gerrit Wolters-Eisfeld,Baris Mercanoglu,Bianca T. Hofmann,Thomas Wolpers,Claudia Schnabel,Sönke Harder,Pascal Steffen,Kai Bachmann,Babett Steglich,Jörg Schrader,Nicola Gagliani,Hartmut Schlüter,Cenap 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-

Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially Oglycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O-glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant Oglycans might be relevant for pathogenic mechanisms of the pancreas.

Cancer Cytogenetics: Methodology Revisited

Thomas S. K. Wan 대한진단검사의학회 2014 Annals of Laboratory Medicine Vol.34 No.6

The Philadelphia chromosome was the first genetic abnormality discovered in cancer (in 1960), and it was found to be consistently associated with CML. The description of the Philadelphia chromosome ushered in a new era in the field of cancer cytogenetics. Accu- mulating genetic data have been shown to be intimately associated with the diagnosis and prognosis of neoplasms; thus, karyotyping is now considered a mandatory investigation for all newly diagnosed leukemias. The development of FISH in the 1980s overcame many of the drawbacks of assessing the genetic alterations in cancer cells by karyotyping. Karyo- typing of cancer cells remains the gold standard since it provides a global analysis of the abnormalities in the entire genome of a single cell. However, subsequent methodological advances in molecular cytogenetics based on the principle of FISH that were initiated in the early 1990s have greatly enhanced the efficiency and accuracy of karyotype analysis by marrying conventional cytogenetics with molecular technologies. In this review, the de- velopment, current utilization, and technical pitfalls of both the conventional and molecu- lar cytogenetics approaches used for cancer diagnosis over the past five decades will be discussed.

An experimental and simulation study of novel channel designs for open-cathode high-temperature polymer electrolyte membrane fuel cells

Thomas, S.,Bates, A.,Park, S.,Sahu, A.K.,Lee, S.C.,Son, B.R.,Kim, J.G.,Lee, D.H. Applied Science Publishers 2016 APPLIED ENERGY Vol.165 No.-

<P>A minimum balance of plant (BOP) is desired for an open-cathode high temperature polymer electrolyte membrane (HTPEM) fuel cell to ensure low parasitic losses and a compact design. The advantage of an open-cathode system is the elimination of the coolant plate and incorporation of a blower for oxidant and coolant supply, which reduces the overall size of the stack, power losses, and results in a lower system volume. In the present study, we present unique designs for an open-cathode system which offers uniform temperature distribution with a minimum temperature gradient and a uniform flow distribution through each cell. Design studies were carried out to increase power density. An experimental and simulation approach was carried out to design the novel open-cathode system. Two unique parallel serpentine flow designs were developed to yield a low pressure drop and uniform flow distribution, one without pins and another with pins. A five-cell stack was fabricated in the lab based on the new design. Performance and flow distribution studies revealed better performance, uniform flow distribution, and a reduced temperature gradient across the stack; improving overall system efficiency. (C) 2015 Elsevier Ltd. All rights reserved.</P>

Organization of the Mammalian Metabolome according to Organ Function, Lineage Specialization, and Longevity

Ma, S.,Yim, S.,Lee, S.G.,Kim, E.,Lee, S.R.,Chang, K.T.,Buffenstein, R.,Lewis, Kaitlyn N.,Park, Thomas J.,Miller, Richard A.,Clish, Clary B.,Gladyshev, Vadim N. Cell Press 2015 Cell metabolism Vol.22 No.2

Biological diversity among mammals is remarkable. Mammalian body weights range seven orders of magnitude and lifespans differ more than 100-fold among species. While genetic, dietary, and pharmacological interventions can be used to modulate these traits in model organisms, it is unknown how they are determined by natural selection. By profiling metabolites in brain, heart, kidney, and liver tissues of 26 mammalian species representing ten taxonomical orders, we report metabolite patterns characteristic of organs, lineages, and species longevity. Our data suggest different rates of metabolite divergence across organs and reveal patterns representing organ-specific functions and lineage-specific physiologies. We identified metabolites that correlated with species lifespan, some of which were previously implicated in longevity control. We also compared the results with metabolite changes in five long-lived mouse models and observed some similar patterns. Overall, this study describes adjustments of the mammalian metabolome according to lifespan, phylogeny, and organ and lineage specialization.

Empirical Analysis of OPEC Pricing Behavior Under Wealth Maximization and Rule of Thumb Models

Lowinger, Thomas C.,Wihlborg, Clas,Willman, Elliott S. 세종대학교 국제경제연구소 1988 Journal of Economic Integration Vol.3 No.1

This paper presents, empirically tests and contrasts two models of OPEC oil price determination over the period 1974-1985. First, we test a structural model that assumes that in order to maximize wealtn OPEC adjusts prices and production within each period, as a result of change in underlying demand and cost conditions. Subsequently, we present and test a rule of thumb model to explain OPEC's short run pricing behavior. A central consideration in such models relates to the determination of OPEC's target capacity utilization. Herein two formulations are proposed. First, OPEC is assumed to have an exogenously determined long run target for capacity. Second, it is assumed that OPEC sets the long run price of oil based on a revenue objective. The models were tested with quarterly data using ordinary least squares corrected for serial autocorrelation by means of the Cochrane-Orcutt technique. The rule of thumb model turns out to be comparable in terms of its explanatory power to a structural model of OPEC's pricing behavior. The results lend support to the notion that OPEC apparently sets prices and output within a longer term framework while using a rule of thum by mechanism to react to short term fluctuations in demand. Furthermore, the results reported in this paper are more consistent with a target for capacity utilization, while being strongly inconsistent with a target for revenues objective.