S110, a novel decitabine dinucleotide, increases fetal hemoglobin levels in baboons (P. anubis)

<p>Abstract</p> <p>Background</p> <p>S110 is a novel dinucleoside analog that could have advantages over existing DNA methyltransferase (DNMT) inhibitors such as decitabine. A potential therapeutic role for S110 is to increase fetal hemoglobin (HbF) levels to treat β-hemoglobinopathies. In these experiments the effect of S110 on HbF levels in baboons and its ability to reduce DNA methylation of the γ-globin gene promoter in vivo were evaluated.</p> <p>Methods</p> <p>The effect of S110 on HbF and γ-globin promoter DNA methylation was examined in cultured human erythroid progenitors and in vivo in the baboon pre-clinical model. S110 pharmacokinetics was also examined in the baboon model.</p> <p>Results</p> <p>S110 increased HbF and reduced DNA methylation of the γ-globin promoter in human erythroid progenitors and in baboons when administered subcutaneously. Pharmacokinetic analysis was consistent with rapid conversion of S110 into the deoxycytosine analog decitabine that binds and depletes DNA.</p> <p>Conclusion</p> <p>S110 is rapidly converted into decitabine, hypomethylates DNA, and induces HbF in cultured human erythroid progenitors and the baboon pre-clinical model.</p

Winter weather controls net influx of atmospheric CO2 on the north-west European shelf

Shelf seas play an important role in the global carbon cycle, absorbing atmospheric carbon dioxide (CO2) and exporting carbon (C) to the open ocean and sediments. The magnitude of these processes is poorly constrained, because observations are typically interpolated over multiple years. Here, we used 298500 observations of CO2 fugacity (fCO2) from a single year (2015), to estimate the net influx of atmospheric CO2 as 26.2 ± 4.7 Tg C yr-1 over the open NW European shelf. CO2 influx from the atmosphere was dominated by influx during winter as a consequence of high winds, despite a smaller, thermally-driven, air-sea fCO2 gradient compared to the larger, biologically-driven summer gradient. In order to understand this climate regulation service, we constructed a carbon-budget supplemented by data from the literature, where the NW European shelf is treated as a box with carbon entering and leaving the box. This budget showed that net C-burial was a small sink of 1.3 ± 3.1 Tg C yr-1, while CO2 efflux from estuaries to the atmosphere, removed the majority of river C-inputs. In contrast, the input from the Baltic Sea likely contributes to net export via the continental shelf pump and advection (34.4 ± 6.0 Tg C yr-1)

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Effect of AGM and Fetal Liver-Derived Stromal Cell Lines on Globin Expression in Adult Baboon (P. anubis) Bone Marrow-Derived Erythroid Progenitors

This study was performed to investigate the hypothesis that the erythroid micro-environment plays a role in regulation of globin gene expression during adult erythroid differentiation. Adult baboon bone marrow and human cord blood CD34+ progenitors were grown in methylcellulose, liquid media, and in co-culture with stromal cell lines derived from different developmental stages in identical media supporting erythroid differentiation to examine the effect of the micro-environment on globin gene expression. Adult progenitors express high levels of γ-globin in liquid and methylcellulose media but low, physiological levels in stromal cell co-cultures. In contrast, γ-globin expression remained high in cord blood progenitors in stromal cell line co-cultures. Differences in γ-globin gene expression between adult progenitors in stromal cell line co-cultures and liquid media required cell-cell contact and were associated with differences in rate of differentiation and γ-globin promoter DNA methylation. We conclude that γ-globin expression in adult-derived erythroid cells can be influenced by the micro-environment, suggesting new potential targets for HbF induction

State of the Climate in 2010

Several large-scale climate patterns influenced climate conditions and weather patterns across the globe during 2010. The transition from a warm El Niño phase at the beginning of the year to a cool La Niña phase by July contributed to many notable events, ranging from record wetness across much of Australia to historically low Eastern Pacific basin and near-record high North Atlantic basin hurricane activity. The remaining five main hurricane basins experienced below- to well-below-normal tropical cyclone activity. The negative phase of the Arctic Oscillation was a major driver of Northern Hemisphere temperature patterns during 2009/10 winter and again in late 2010. It contributed to record snowfall and unusually low temperatures over much of northern Eurasia and parts of the United States, while bringing above-normal temperatures to the high northern latitudes. The February Arctic Oscillation Index value was the most negative since records began in 1950. The 2010 average global land and ocean surface temperature was among the two warmest years on record. The Arctic continued to warm at about twice the rate of lower latitudes. The eastern and tropical Pacific Ocean cooled about 1°C from 2009 to 2010, reflecting the transition from the 2009/10 El Niño to the 2010/11 La Niña. Ocean heat fluxes contributed to warm sea surface temperature anomalies in the North Atlantic and the tropical Indian and western Pacific Oceans. Global integrals of upper ocean heat content for the past several years have reached values consistently higher than for all prior times in the record, demonstrating the dominant role of the ocean in the Earth’s energy budget. Deep and abyssal waters of Antarctic origin have also trended warmer on average since the early 1990s. Lower tropospheric temperatures typically lag ENSO surface fluctuations by two to four months, thus the 2010 temperature was dominated by the warm phase El Niño conditions that occurred during the latter half of 2009 and early 2010 and was second warmest on record. The stratosphere continued to be anomalously cool. Annual global precipitation over land areas was about five percent above normal. Precipitation over the ocean was drier than normal after a wet year in 2009. Overall, saltier (higher evaporation) regions of the ocean surface continue to be anomalously salty, and fresher (higher precipitation) regions continue to be anomalously fresh. This salinity pattern, which has held since at least 2004, suggests an increase in the hydrological cycle. Sea ice conditions in the Arctic were significantly different than those in the Antarctic during the year. The annual minimum ice extent in the Arctic—reached in September—was the third lowest on record since 1979. In the Antarctic, zonally averaged sea ice extent reached an all-time record maximum from mid-June through late August and again from mid-November through early December. Corresponding record positive Southern Hemisphere Annular Mode Indices influenced the Antarctic sea ice extents. Greenland glaciers lost more mass than any other year in the decade-long record. The Greenland Ice Sheet lost a record amount of mass, as the melt rate was the highest since at least 1958, and the area and duration of the melting was greater than any year since at least 1978. High summer air temperatures and a longer melt season also caused a continued increase in the rate of ice mass loss from small glaciers and ice caps in the Canadian Arctic. Coastal sites in Alaska show continuous permafrost warming and sites in Alaska, Canada, and Russia indicate more significant warming in relatively cold permafrost than in warm permafrost in the same geographical area. With regional differences, permafrost temperatures are now up to 2°C warmer than they were 20 to 30 years ago. Preliminary data indicate there is a high probability that 2010 will be the 20th consecutive year that alpine glaciers have lost mass. Atmospheric greenhouse gas concentrations continued to rise and ozone depleting substances continued to decrease. Carbon dioxide increased by 2.60 ppm in 2010, a rate above both the 2009 and the 1980–2010 average rates. The global ocean carbon dioxide uptake for the 2009 transition period from La Niña to El Niño conditions, the most recent period for which analyzed data are available, is estimated to be similar to the long-term average. The 2010 Antarctic ozone hole was among the lowest 20% compared with other years since 1990, a result of warmer-than-average temperatures in the Antarctic stratosphere during austral winter between mid-July and early September. List of authors and affiliations... .3 Abstract 16 1. Introduction 17 2. Global Climate 27 a. Overview .. 27 b. Temperature 36; 1. Surface temperature .. 36; 2. Lower tropospheric temperatures 37; 3. Lower stratospheric temperatures .. 38; 4. Lake temperature 39 c. Hydrologic cycle .. 40; I. Surface humidity .. 40; 2. Total column water vapor .41; 3. Precipitation . 42; 4. Northern Hemisphere continental snow cover extent ... 44; 5. Global cloudiness 45; 6. River discharge . 46; 7. Permafrost thermal state . 48; 8. Groundwater and terrestrial water storage .. 49; 9. Soil moisture ..52; 10. Lake levels 53 d. Atmospheric circulation 55; 1. Mean sea level pressure . 55; 2. Ocean surface wind speed 56 e. Earth radiation budget at top-of-atmosphere ... 58 f. Atmosphere composition ...59; 1. Atmosphere chemical composition ...59; 2. Aerosols 65; 3. Stratospheric ozone 67 g. Land surface properties . 68; 1. Alpine glaciers and ice sheets .. 68; 2. Fraction of Absorbed Photosynthetically Active Radiation (FAPAR) ... 72; 3. Biomass burning ... 72; 4. Forest biomass and biomass change .74 3. Global Oceans 77 a. Overview .. 77 b. Sea surface temperatures .. 78 c. Ocean heat content .81 d. Global ocean heat fluxes ... 84 e. Sea surface salinity .. 86 f. Subsurface salinity ... 88 g. Surface currents ... 92; 1. Pacific Ocean 93; 2. Indian Ocean 94; 3. Atlantic Ocean . 95 h. Meridional overturning circulation observations in the subtropical North Atlantic . 95 i. Sea level variations ... 98 j. The global ocean carbon cycle 100; 1. Air-sea carbon dioxide fluxes 100; 2. Subsurface carbon inventory . 102; 3. Global ocean phytoplankton . 105 4. Tropics ... 109 a. Overview 109 b. ENSO and the tropical Pacific 109; 1. Oceanic conditions ... 109; 2. Atmospheric circulation: Tropics .110; 3. Atmospheric circulation: Extratropics ...112; 4. ENSO temperature and precipitation impacts .113 c. Tropical intraseasonal activity .113 d. Tropical cyclones 114; 1. Overview .114; 2. Atlantic basin ...115; 3. Eastern North Pacific basin .121; 4. Western North Pacific basin .. 123; 5. Indian Ocean basins .. 127; 6. Southwest Pacific basin 129; 7. Australian region basin 130 e. Tropical cyclone heat potential .. 132 f. Intertropical Convergence Zones . 134; 1. Pacific ... 134; 2. Atlantic 136 g. Atlantic multidecadal oscillation 137 h. Indian Ocean Dipole . 138 5. The arctic ... 143 a. Overview 143 b. Atmosphere 143 c. Ocean .. 145; 1. Wind-driven circulation . 145; 2. Ocean temperature and salinity 145; 3. Biology and geochemistry .. 146; 4. Sea level .. 148 d. Sea ice cover ... 148; 1. Sea ice extent . 148; 2. Sea ice age ... 149; 3. Sea ice thickness 150 e. Land .. 150; 1. Vegetation ... 150; 2. Permafrost ... 152; 3. River discharge ... 153; 4. Terrestrial snow 154; 5. Glaciers outside Greenland 155 f. Greenland ... 156; 1. Coastal surface air temperature . 156; 2. Upper air temperatures . 158; 3. Atmospheric circulation . 158; 4. Surface melt extent and duration and albedo . 159; 5. Surface mass balance along the K-Transect .. 159; 6. Total Greenland mass loss from GRACE . 160; 7. Marine-terminating glacier area changes .. 160 6. ANTARCTICA ..161 a. Overview .161 b. Circulation ...161 c. Surface manned and automatic weather station observations 163 d. Net precipitation ... 164 e. 2009/10 Seasonal melt extent and duration . 167 f. Sea ice extent and concentration .. 167 g. Ozone depletion 170 7. Regional climates ... 173 a. Overview 173 b. North America ... 173; 1. Canada 173; 2. United States .. 175; 3. México . 179 c. Central America and the Caribbean .. 182; 1. Central America 182; 2. The Caribbean ... 183 d. South America .. 186; 1. Northern South America and the Tropical Andes . 186; 2. Tropical South America east of the Andes .. 187; 3. Southern South America 190 e. Africa 192; 1. Northern Africa 192; 2. Western Africa .. 193; 3. Eastern Africa . 194; 4. Southern Africa .. 196; 5. Western Indian Ocean countries 198 f. Europe . 199; 1. Overview 199; 2. Central and Western Europe 202; 3. The Nordic and Baltic countries . 203; 4. Iberia 205; 5. Mediterranean, Italian, and Balkan Peninsulas .206; 6. Eastern Europe .. 207; 7. Middle East ..208 g. Asia ... 210; 1. Russia ... 210; 2. East Asia ..215; 3. South Asia 217; 4. Southwest Asia ...219 h. Oceania ...222; 1. Southwest Pacific ..222; 2. Northwest Pacific, Micronesia .. 224; 3. Australia .. 227; 4. New Zealand .. 229 8. SEASONAL SUMMARIES ... 233 Acknowledgments 237 Appendix: Acronyms and Abbreviations 238 References . 24

CNTF Mediates Neurotrophic Factor Secretion and Fluid Absorption in Human Retinal Pigment Epithelium

Ciliary neurotrophic factor (CNTF) protects photoreceptors and regulates their phototransduction machinery, but little is known about CNTF's effects on retinal pigment epithelial (RPE) physiology. Therefore, we determined the expression and localization of CNTF receptors and the physiological consequence of their activation in primary cultures of human fetal RPE (hfRPE). Cultured hfRPE express CNTF, CT1, and OsM and their receptors, including CNTFRα, LIFRβ, gp130, and OsMRβ, all localized mainly at the apical membrane. Exogenous CNTF, CT1, or OsM induces STAT3 phosphorylation, and OsM also induces the phosphorylation of ERK1/2 (p44/42 MAP kinase). CNTF increases RPE survivability, but not rates of phagocytosis. CNTF increases secretion of NT3 to the apical bath and decreases that of VEGF, IL8, and TGFβ2. It also significantly increases fluid absorption (JV) across intact monolayers of hfRPE by activating CFTR chloride channels at the basolateral membrane. CNTF induces profound changes in RPE cell biology, biochemistry, and physiology, including the increase in cell survival, polarized secretion of cytokines/neurotrophic factors, and the increase in steady-state fluid absorption mediated by JAK/STAT3 signaling. In vivo, these changes, taken together, could serve to regulate the microenvironment around the distal retinal/RPE/Bruch's membrane complex and provide protection against neurodegenerative disease

State of the climate in 2013

In 2013, the vast majority of the monitored climate variables reported here maintained trends established in recent decades. ENSO was in a neutral state during the entire year, remaining mostly on the cool side of neutral with modest impacts on regional weather patterns around the world. This follows several years dominated by the effects of either La Niña or El Niño events. According to several independent analyses, 2013 was again among the 10 warmest years on record at the global scale, both at the Earths surface and through the troposphere. Some regions in the Southern Hemisphere had record or near-record high temperatures for the year. Australia observed its hottest year on record, while Argentina and New Zealand reported their second and third hottest years, respectively. In Antarctica, Amundsen-Scott South Pole Station reported its highest annual temperature since records began in 1957. At the opposite pole, the Arctic observed its seventh warmest year since records began in the early 20th century. At 20-m depth, record high temperatures were measured at some permafrost stations on the North Slope of Alaska and in the Brooks Range. In the Northern Hemisphere extratropics, anomalous meridional atmospheric circulation occurred throughout much of the year, leading to marked regional extremes of both temperature and precipitation. Cold temperature anomalies during winter across Eurasia were followed by warm spring temperature anomalies, which were linked to a new record low Eurasian snow cover extent in May. Minimum sea ice extent in the Arctic was the sixth lowest since satellite observations began in 1979. Including 2013, all seven lowest extents on record have occurred in the past seven years. Antarctica, on the other hand, had above-average sea ice extent throughout 2013, with 116 days of new daily high extent records, including a new daily maximum sea ice area of 19.57 million km2 reached on 1 October. ENSO-neutral conditions in the eastern central Pacific Ocean and a negative Pacific decadal oscillation pattern in the North Pacific had the largest impacts on the global sea surface temperature in 2013. The North Pacific reached a historic high temperature in 2013 and on balance the globally-averaged sea surface temperature was among the 10 highest on record. Overall, the salt content in nearsurface ocean waters increased while in intermediate waters it decreased. Global mean sea level continued to rise during 2013, on pace with a trend of 3.2 mm yr-1 over the past two decades. A portion of this trend (0.5 mm yr-1) has been attributed to natural variability associated with the Pacific decadal oscillation as well as to ongoing contributions from the melting of glaciers and ice sheets and ocean warming. Global tropical cyclone frequency during 2013 was slightly above average with a total of 94 storms, although the North Atlantic Basin had its quietest hurricane season since 1994. In the Western North Pacific Basin, Super Typhoon Haiyan, the deadliest tropical cyclone of 2013, had 1-minute sustained winds estimated to be 170 kt (87.5 m s-1) on 7 November, the highest wind speed ever assigned to a tropical cyclone. High storm surge was also associated with Haiyan as it made landfall over the central Philippines, an area where sea level is currently at historic highs, increasing by 200 mm since 1970. In the atmosphere, carbon dioxide, methane, and nitrous oxide all continued to increase in 2013. As in previous years, each of these major greenhouse gases once again reached historic high concentrations. In the Arctic, carbon dioxide and methane increased at the same rate as the global increase. These increases are likely due to export from lower latitudes rather than a consequence of increases in Arctic sources, such as thawing permafrost. At Mauna Loa, Hawaii, for the first time since measurements began in 1958, the daily average mixing ratio of carbon dioxide exceeded 400 ppm on 9 May. The state of these variables, along with dozens of others, and the 2013 climate conditions of regions around the world are discussed in further detail in this 24th edition of the State of the Climate series. © 2014, American Meteorological Society. All rights reserved

Bridging ocean color observations of the 1980s and 2000s in search of long-term trends

[1] A comprehensive revision of the Coastal Zone Color Scanner (CZCS) data-processing algorithms has been undertaken to generate a revised level 2 data set from the near-8-year archive (1979–1986) collected during this ‘‘proof-of-concept’ ’ mission. The final goal of this work is to establish a baseline for a global, multiyear, multisensor ocean color record, to be built from observations of past (i.e., CZCS), present, and future missions. To produce an internally consistent time series, the same revised algorithms also have been applied to the first 5 years of the Sea-viewing Wide Field-of-view Sensor (SeaWiFS) ocean color observations (1998–2002). Such a database is necessary in order to determine whether or not the ocean biogeochemistry has evolved in the past years and, if so, to be able to detect near future trends. Algorithmic and calibration aspects, along with validation results presented in this paper, are tailored toward the identification of long-term trends, which mandated this reprocessing effort. The analysis of decadal changes from the CZCS to the SeaWiFS era shows an overall increase of the world ocean average chlorophyll concentration by about 22%, mainly due to large increases in the intertropical areas, where the seasonal cycles also substantially changed over the past 2 decades. Increases in higher latitudes, where seasonal cycles did not change, contribute to a lesser extent to the general trend. In contrast, oligotrophic gyres display declining concentrations