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Creativity Motivation - What is motivation - Corey K Katir Advertising From http://www.creativitymotivation.com Describes motivation process for creativity with emphasis on intrinsic motivation by Corey K Katir Regulation of TH17 cell differentiation by innate immune signals From feeds.nature CD28 ligation increases macrophage suppression of T-cell proliferation From feeds.nature TLR3-dependent immune regulatory functions of human mesangial cells From feeds.nature Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy From feeds.nature Liver fibrosis: mechanisms of immune-mediated liver injury From feeds.nature PPAR-I3 is a major driver of the accumulation and phenotype of adipose tissue Treg cells From feeds.nature Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-I3, the amaster regulatora of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-I3 expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends. Compartmentalized calcium dynamics in a C. elegans interneuron encode head movement From feeds.nature The confinement of neuronal activity to specific subcellular regions is a mechanism for expanding the computational properties of neurons. Although the circuit organization underlying compartmentalized activity has been studied in several systems, its cellular basis is still unknown. Here we characterize compartmentalized activity in Caenorhabditis elegans RIA interneurons, which have multiple reciprocal connections to head motor neurons and receive input from sensory pathways. We show that RIA spatially encodes head movement on a subcellular scale through axonal compartmentalization. This subcellular axonal activity is dependent on acetylcholine release from head motor neurons and is simultaneously present and additive with glutamate-dependent globally synchronized activity evoked by sensory inputs. Postsynaptically, the muscarinic acetylcholine receptor GAR-3 acts in RIA to compartmentalize axonal activity through the mobilization of intracellular calcium stores. The compartmentalized activity functions independently of the synchronized activity to modulate locomotory behaviour. Brain-wide neuronal dynamics during motor adaptation in zebrafish From feeds.nature Neural activity is recorded at the cellular level, throughout the brain of larval zebrafish, while the animals interact with a virtual environment and adapt their motor output to changes in visual feedback; this is used to derive candidates of functional elements driving motor learning. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation From feeds.nature Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets and physiological functions have been unclear. Here we show that SIRT7 is an NAD+-dependent H3K18Ac (acetylated lysine 18 of histone H3) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by its interaction with the cancer-associated E26 transformed specific (ETS) transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has been linked to oncogenic transformation, and in patients is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells, including anchorage-independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by the viral oncoprotein E1A. Finally, SIRT7 depletion markedly reduces the tumorigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as a highly selective H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs and tumour formation in vivo. Sustained translational repression by eIF2I+--P mediates prion neurodegeneration From feeds.nature The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimeras, Parkinsonas and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the I+--subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2I+--P levels are seen in patients with Alzheimeras, Parkinsonas and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2I+--P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2I+--P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2I+--P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2I+--P dephosphorylation, increased eIF2I+--P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets From feeds.nature Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors. Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virusacomprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virusathat was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avianahuman reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production and distribution of effective countermeasures. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation From feeds.nature Transcription factors and chromatin modifiers are important in the programming and reprogramming of cellular states during development. Transcription factors bind to enhancer elements and recruit coactivators and chromatin-modifying enzymes to facilitate transcription initiation. During differentiation a subset of these enhancers must be silenced, but the mechanisms underlying enhancer silencing are poorly understood. Here we show that the histone demethylase lysine-specific demethylase 1 (LSD1; ref. 5), which demethylates histone H3 on Lysa4 or Lysa9 (H3K4/K9), is essential in decommissioning enhancers during the differentiation of mouse embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes that are critical for control of the state of ESCs. However, LSD1 is not essential for the maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to differentiate fully, and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At active enhancers, LSD1 is a component of the NuRD (nucleosome remodelling and histone deacetylase) complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1aNuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states. Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy From feeds.nature Aneuploidyathe state of having uneven numbers of chromosomesais a hallmark of cancer and a feature identified in yeast from diverse habitats. Recent studies have shown that aneuploidy is a form of large-effect mutation that is able to confer adaptive phenotypes under diverse stress conditions. Here we investigate whether pleiotropic stress could induce aneuploidy in budding yeast (Saccharomyces cerevisae). We show that whereas diverse stress conditions can induce an increase in chromosome instability, proteotoxic stress, caused by transient Hsp90 (also known as Hsp82 or Hsc82) inhibition or heat shock, markedly increased chromosome instability to produce a cell population with high karyotype diversity. The induced chromosome instability is linked to an evolutionarily conserved role for the Hsp90 chaperone complex in kinetochore assembly. Continued growth in the presence of an Hsp90 inhibitor resulted in the emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress potentiated fast adaptation to unrelated cytotoxic compounds by means of different aneuploid chromosome stoichiometries. These findings demonstrate that aneuploidy is a form of stress-inducible mutation in eukaryotes, capable of fuelling rapid phenotypic evolution and drug resistance, and reveal a new role for Hsp90 in regulating the emergence of adaptive traits under stress. G-protein-coupled receptor inactivation by an allosteric inverse-agonist antibody From feeds.nature G-protein-coupled receptors are the largest class of cell-surface receptors, and these membrane proteins exist in equilibrium between inactive and active states. Conformational changes induced by extracellular ligands binding to G-protein-coupled receptors result in a cellular response through the activation of G proteins. The A2A adenosine receptor (A2AAR) is responsible for regulating blood flow to the cardiac muscle and is important in the regulation of glutamate and dopamine release in the brain. Here we report the raising of a mouse monoclonal antibody against human A2AAR that prevents agonist but not antagonist binding to the extracellular ligand-binding pocket, and describe the structure of A2AAR in complex with the antibody Fab fragment (Fab2838). This structure reveals that Fab2838 recognizes the intracellular surface of A2AAR and that its complementarity-determining region, CDR-H3, penetrates into the receptor. CDR-H3 is located in a similar position to the G-protein carboxy-terminal fragment in the active opsin structure and to CDR-3 of the nanobody in the active I22-adrenergic receptor structure, but locks A2AAR in an inactive conformation. These results suggest a new strategy to modulate the activity of G-protein-coupled receptors. NATIONAL GEOGRAPHIC INTRODUCES DUET TRAVEL PHONE WITH DUAL SIM CAPABILITY From press.nationalgeographic WASHINGTON (June 17, 2009)—National Geographic has introduced the National Geographic Duet Travel Phone, designed specifically for the needs of the international traveler. The new handset supports two SIM cards and offers additional features useful for travelers, such as Bluetooth, a camera, FM radio, television and 1GB storage card. The Duet comes loaded with National Geographic content, including ringtones, wallpapers and travel-related videos from the National Geographic Channel. The Duet includes National Geographic's pay-as-you-go National Geographic Travel SIM card, allowing affordable calling in 185 countries, free incoming calls in more than 80 countries and 30 minutes of outgoing call credit (for most countries). Users have the option of inserting another SIM card in the phone and having a secondary number and service. This option is perfect for those who need to retain their current phone number while overseas or who want a secondary number dedicated for business or family. The service also offers 24/7 toll-free U.S.-based customer service directly from the handset via a three-digit access number. The National Geographic Travel SIM card can be purchased separately from the Duet phone for those travelers who already own a cell phone that is compatible for international use. "Our service offers comparable international coverage to carriers such as Verizon, T-Mobile and AT&T, but at a fraction of the cost. In today's economic environment, there is good reason to utilize National Geographic's international cellular service when traveling," said Sebastian Harrison, president of Cellular Abroad Inc. "The unique features of the new Duet handset perfectly complement the equally unique qualities of the service." The National Geographic Travel Phone is available online through CellularAbroad.com, Amazon.com, Expansys-usa.com and other select retailers. About National Geographic The National Geographic Society is one of the world's largest nonprofit scientific and educational organizations. Founded in 1888 to "increase and diffuse geographic knowledge," the Society works to inspire people to care about the planet. It reaches more than 360 million people worldwide each month through its official journal, National Geographic, and other magazines; National Geographic Channel; television documentaries; music; radio; films; books; DVDs; maps; exhibitions; live events; school publishing programs; interactive media; and merchandise. National Geographic has funded more than 9,000 scientific research, conservation and exploration projects and supports an education program promoting geographic literacy. For more information, visit nationalgeographic.com. About Cellular Abroad Cellular Abroad has been operating since 2001 and has become the most popular choice among international travelers for cellular service. With offices in Playa del Rey, Calif., and in Italy, Cellular Abroad has helped tens of thousands of travelers obtain affordable and reliable cellular service while traveling abroad. Cellular Abroad has an outstanding record of customer service and is committed to making international cellular service available to everyone. Visit Cellular Abroad at www.cellularabroad.com or call (800) 287-5072. NEW NATIONAL GEOGRAPHIC WIRELESS SERVICE CONNECTS FAMILIES AND FRIENDS ABROAD FOR LESS From press.nationalgeographic WASHINGTON (May 14, 2009)--Building on its Talk Abroad™ international calling plan, National Geographic, together with Cellular Abroad, has introduced a new, affordable cell phone service that allows U.S. residents to make and receive international calls using the strength of the country's largest digital wireless network. This new subscription-free cell phone service provides users with a viable alternative to high monthly charges and long-term contracts and is now available online at CellularAbroad.com and in stores at J&R, Expansys, Fry's and other select retailers. Whereas the Talk Abroad Travel Phone is geared toward those traveling overseas, the new National Geographic phone service is the ideal solution for those calling from within the United States. The domestic service provides competitive rates when calling locations across the globe, with the convenience of using a U.S.-based phone number. Direct-dial calls from the United States to many international destinations, including Mexico, Canada, China and the United Kingdom, start at $0.17 per minute, while domestic calls are just $0.15 per minute. Users can choose from the Motorola V3 Razr Explorer Quad Band phone for $199 and the Motorola C139 Dual Band phone for $69. Both handsets using this service include 133 minutes of free domestic talk time. With 24/7, toll-free, U.S.-based customer support, and no bills, activation fees, service contracts or other hidden fees, the National Geographic phone service offers full flexibility. Each phone is preloaded with iconic images, wallpapers and ring tones from National Geographic's award-winning archives and comes with a battery, wall charger, SIM card and user manual. "The new National Geographic phone service is perfect for people who need dependable wireless service but don't want to pay for minutes they won't use," said John Dumbacher, senior vice president, licensing, for National Geographic. "Both plans offer customers easy, reliable and budget-conscious solutions to keep in touch with friends and family here at home and overseas." For more information, visit natgeophone.com. About National Geographic The National Geographic Society is one of the world's largest nonprofit scientific and educational organizations. Founded in 1888 to "increase and diffuse geographic knowledge," the Society works to inspire people to care about the planet. It reaches more than 360 million people worldwide each month through its official journal, National Geographic, and other magazines; National Geographic Channel; television documentaries; music; radio; films; books; DVDs; maps; exhibitions; live events; school publishing programs; interactive media; and merchandise. National Geographic has funded more than 9,000 scientific research, conservation and exploration projects and supports an education program combating geographic illiteracy. For more information, visit nationalgeographic.com. About Cellular Abroad Cellular Abroad has been operating since 2001 and has become the most popular choice among international travelers for cellular service. Cellular Abroad has an outstanding record of customer service and is committed to making international cellular service available to everyone. Visit Cellular Abroad at cellularabroad.com or call (800) 287-5072. The dual PH domain protein Opy1 functions as a sensor and modulator of PtdIns(4,5)P2 synthesis From feeds.nature The lipid PtdIns(4,5)P2 regulates many cellular processes including exo- and endocytosis. Localized PtdIns(4,5)P2 synthesis is regulated by assembly of the PtdIns(4)P 5-kinase Mss4 in plasma membrane patches and by feedback inhibition by Opy1. Notch and Mef2 synergize to promote proliferation and metastasis through JNK signal activation in Drosophila From feeds.nature Based on a modifier screen in Drosophila, Mef2 and Notch are shown to functionally cooperate in the control of cellular proliferation and metastasis with further reaching implications for breast cancer. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions From feeds.nature Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesionsThis study offers a novel view on the role of telomere attrition in human tumours, providing evidence for tumour suppressor activity resulting from telomere dysfunction-induced DNA damage responses. NURDs are required for diversity From feeds.nature NURD was recently shown to functionally recruit PRC2 to a set of common target genes. A new study in Cell Stem Cell reveals a crucial role for NURD in embryonic stem cell lineage commitment by regulating the transcriptional heterogeneity of pluripotency factors. 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