Marine biogeochemical responses to the North Atlantic Oscillation in a coupled climate model

In this study a coupled ocean-atmosphere model containing interactive marine biogeochemistry is used to analyze interannual, lagged, and decadal marine biogeochemical responses to the North Atlantic Oscillation (NAO), the dominant mode of North Atlantic atmospheric variability. The coupled model adequately reproduces present-day climatologies and NAO atmospheric variability. It is shown that marine biogeochemical responses to the NAO are governed by different mechanisms according to the time scale considered. On interannual time scales, local changes in vertical mixing, caused by modifications in air-sea heat, freshwater, and momentum fluxes, are most relevant in influencing phytoplankton growth through light and nutrient limitation mechanisms. At subpolar latitudes, deeper mixing occurring during positive NAO winters causes a slight decrease in late winter chlorophyll concentration due to light limitation and a 10%–20% increase in spring chlorophyll concentration due to higher nutrient availability. The lagged response of physical and biogeochemical properties to a high NAO winter shows some memory in the following 2 years. In particular, subsurface nutrient anomalies generated by local changes in mixing near the American coast are advected along the North Atlantic Current, where they are suggested to affect downstream chlorophyll concentration with 1 year lag. On decadal time scales, local and remote mechanisms act contemporaneously in shaping the decadal biogeochemical response to the NAO. The slow circulation adjustment, in response to NAO wind stress curl anomalies, causes a basin redistribution of heat, freshwater, and biogeochemical properties which, in turn, modifies the spatial structure of the subpolar chlorophyll bloom

Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues

Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy approximate to 4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter

The Spatial Expansion and Ecological Footprint of Fisheries (1950 to Present)

Using estimates of the primary production required (PPR) to support fisheries catches (a measure of the footprint of fishing), we analyzed the geographical expansion of the global marine fisheries from 1950 to 2005. We used multiple threshold levels of PPR as percentage of local primary production to define ‘fisheries exploitation’ and applied them to the global dataset of spatially-explicit marine fisheries catches. This approach enabled us to assign exploitation status across a 0.5° latitude/longitude ocean grid system and trace the change in their status over the 56-year time period. This result highlights the global scale expansion in marine fisheries, from the coastal waters off North Atlantic and West Pacific to the waters in the Southern Hemisphere and into the high seas. The southward expansion of fisheries occurred at a rate of almost one degree latitude per year, with the greatest period of expansion occurring in the 1980s and early 1990s. By the mid 1990s, a third of the world's ocean, and two-thirds of continental shelves, were exploited at a level where PPR of fisheries exceed 10% of PP, leaving only unproductive waters of high seas, and relatively inaccessible waters in the Arctic and Antarctic as the last remaining ‘frontiers.’ The growth in marine fisheries catches for more than half a century was only made possible through exploitation of new fishing grounds. Their rapidly diminishing number indicates a global limit to growth and highlights the urgent need for a transition to sustainable fishing through reduction of PPR

Unique reporter-based sensor platforms to monitor signalling in cells

Introduction: In recent years much progress has been made in the development of tools for systems biology to study the levels of mRNA and protein, and their interactions within cells. However, few multiplexed methodologies are available to study cell signalling directly at the transcription factor level. <p/>Methods: Here we describe a sensitive, plasmid-based RNA reporter methodology to study transcription factor activation in mammalian cells, and apply this technology to profiling 60 transcription factors in parallel. The methodology uses two robust and easily accessible detection platforms; quantitative real-time PCR for quantitative analysis and DNA microarrays for parallel, higher throughput analysis. <p/>Findings: We test the specificity of the detection platforms with ten inducers and independently validate the transcription factor activation. <p/>Conclusions: We report a methodology for the multiplexed study of transcription factor activation in mammalian cells that is direct and not theoretically limited by the number of available reporters

Conserved and Distinct Modes of CREB/ATF Transcription Factor Regulation by PP2A/B56γ and Genotoxic Stress

Activating transcription factor 1 (ATF1) and the closely related proteins CREB (cyclic AMP resonse element binding protein) and CREM (cyclic AMP response element modulator) constitute a subfamily of bZIP transcription factors that play critical roles in the regulation of cellular growth, metabolism, and survival. Previous studies demonstrated that CREB is phosphorylated on a cluster of conserved Ser residues, including Ser-111 and Ser-121, in response to DNA damage through the coordinated actions of the ataxia-telangiectasia-mutated (ATM) protein kinase and casein kinases 1 and 2 (CK1/2). Here, we show that DNA damage-induced phosphorylation by ATM is a general feature of CREB and ATF1. ATF1 harbors a conserved ATM/CK cluster that is constitutively and stoichiometrically phosphorylated by CK1 and CK2 in asynchronously growing cells. Exposure to DNA damage further induced ATF1 phosphorylation on Ser-51 by ATM in a manner that required prior phosphorylation of the upstream CK residues. Hyperphosphorylated ATF1 showed a 4-fold reduced affinity for CREB-binding protein. We further show that PP2A, in conjunction with its targeting subunit B56γ, antagonized ATM and CK1/2-dependent phosphorylation of CREB and ATF1 in cellulo. Finally, we show that CK sites in CREB are phosphorylated during cellular growth and that phosphorylation of these residues reduces the threshold of DNA damage required for ATM-dependent phosphorylation of the inhibitory Ser-121 residue. These studies define overlapping and distinct modes of CREB and ATF1 regulation by phosphorylation that may ensure concerted changes in gene expression mediated by these factors

A model of the Arctic Ocean carbon cycle

Author Posting. © American Geophysical Union, 2011. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 116 (2011): C12020, doi:10.1029/2011JC006998.A three dimensional model of Arctic Ocean circulation and mixing, with a horizontal resolution of 18 km, is overlain by a biogeochemical model resolving the physical, chemical and biological transport and transformations of phosphorus, alkalinity, oxygen and carbon, including the air-sea exchange of dissolved gases and the riverine delivery of dissolved organic carbon. The model qualitatively captures the observed regional and seasonal trends in surface ocean PO4, dissolved inorganic carbon, total alkalinity, and pCO2. Integrated annually, over the basin, the model suggests a net annual uptake of 59 Tg C a−1, within the range of published estimates based on the extrapolation of local observations (20–199 Tg C a−1). This flux is attributable to the cooling (increasing solubility) of waters moving into the basin, mainly from the subpolar North Atlantic. The air-sea flux is regulated seasonally and regionally by sea-ice cover, which modulates both air-sea gas transfer and the photosynthetic production of organic matter, and by the delivery of riverine dissolved organic carbon (RDOC), which drive the regional contrasts in pCO2 between Eurasian and North American coastal waters. Integrated over the basin, the delivery and remineralization of RDOC reduces the net oceanic CO2 uptake by ~10%.This study has been carried out as part of ECCO2 and SASS (Synthesis of the Arctic System Science) projects funded by NASA and NSF, respectively. MM and MJF are grateful for support from the National Science Foundation (ARC-0531119 and ARC-0806229) for financial support. MM also acknowledges NASA for providing computer time, the use of the computing facilities at NAS center and also the Scripps post-doctoral program for further financial support that helped to complete the manuscript. RMK also acknowledges NOAA for support (NA08OAR4310820 and NA08OAR4320752).2012-06-1

Respiratory distress and perinatal lethality in Nedd4-2-deficient mice

The epithelial sodium channel (ENaC) is essential for sodium homoeostasis in many epithelia. ENaC activity is required for lung fluid clearance in newborn animals and for maintenance of blood volume and blood pressure in adults. In vitro studies show that the ubiquitin ligase Nedd4-2 ubiquitinates ENaC to regulate its cell surface expression. Here we show that knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung. This increased ENaC activity is the likely reason for premature fetal lung fluid clearance in Nedd4-2−/− animals, resulting in a failure to inflate lungs and perinatal lethality. A small percentage of Nedd4-2−/− animals survive up to 22 days, and these animals also show increased ENaC expression and develop lethal sterile inflammation of the lung. Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival

Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation

Aims Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes. Methods/results In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKαThr172, and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)Ser133 phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKαThr172 phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression. Conclusions These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against cardiovascular events seen in patients with RA treated with MTX

Direct targets of Klf5 transcription factor contribute to the maintenance of mouse embryonic stem cell undifferentiated state

<p>Abstract</p> <p>Background</p> <p>A growing body of evidence has shown that Krüppel-like transcription factors play a crucial role in maintaining embryonic stem cell (ESC) pluripotency and in governing ESC fate decisions. Krüppel-like factor 5 (Klf5) appears to play a critical role in these processes, but detailed knowledge of the molecular mechanisms of this function is still not completely addressed.</p> <p>Results</p> <p>By combining genome-wide chromatin immunoprecipitation and microarray analysis, we have identified 161 putative primary targets of Klf5 in ESCs. We address three main points: (1) the relevance of the pathways governed by Klf5, demonstrating that suppression or constitutive expression of single Klf5 targets robustly affect the ESC undifferentiated phenotype; (2) the specificity of Klf5 compared to factors belonging to the same family, demonstrating that many Klf5 targets are not regulated by Klf2 and Klf4; and (3) the specificity of Klf5 function in ESCs, demonstrated by the significant differences between Klf5 targets in ESCs compared to adult cells, such as keratinocytes.</p> <p>Conclusions</p> <p>Taken together, these results, through the definition of a detailed list of Klf5 transcriptional targets in mouse ESCs, support the important and specific functional role of Klf5 in the maintenance of the undifferentiated ESC phenotype.</p> <p>See: <url>http://www.biomedcental.com/1741-7007/8/125</url></p

Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation

CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431-650 of TORC1. As a physiological activator of CREB, interleukin 1α triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling. © 2008 by The American Society for Cell Biology.published_or_final_versio