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We quantify the interannual-to-decadal variability of the heat content (mean temperature) of the world ocean from the surface through 3000-meter depth for the period 1948 to 1998. The heat content of the world ocean increased by ∼ 2× 1023joules between the mid-1950s and mid-1990s, representing a volume mean warming of 0.06°C. This corresponds to a warming rate of 0.3 watt per meter squared (per unit area of Earth's surface). Substantial changes in heat content occurred in the 300- to 1000-meter layers of each ocean and in depths greater than 1000 meters of the North Atlantic. The global volume mean temperature increase for the 0- to 300-meter layer was 0.31°C, corresponding to an increase in heat content for this layer of ∼ 1023joules between the mid-1950s and mid-1990s. The Atlantic and Pacific Oceans have undergone a net warming since the 1950s and the Indian Ocean has warmed since the mid-1960s, although the warming is not monotonic.

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.

The Earth system is accumulating energy due to human-induced activities. More than 90% of this energy has been stored in the ocean as heat since 1970, with ∼60% of that in the upper 700 m. Differences in upper-ocean heat content anomaly (OHCA) estimates, however, exist. Here, we use a dataset protocol for 1970–2008—with six instrumental bias adjustments applied to expendable bathythermograph (XBT) data, and mapped by six research groups—to evaluate the spatiotemporal spread in upper OHCA estimates arising from two choices: 1) those arising from instrumental bias adjustments and 2) those arising from mathematical (i.e., mapping) techniques to interpolate and extrapolate data in space and time. We also examined the effect of a common ocean mask, which reveals that exclusion of shallow seas can reduce global OHCA estimates up to 13%. Spread due to mapping method is largest in the Indian Ocean and in the eddy-rich and frontal regions of all basins. Spread due to XBT bias adjustment is largest in the Pacific Ocean within 30°N–30°S. In both mapping and XBT cases, spread is higher for 1990–2004. Statistically different trends among mapping methods are found not only in the poorly observed Southern Ocean but also in the well-observed northwest Atlantic. Our results cannot determine the best mapping or bias adjustment schemes, but they identify where important sensitivities exist, and thus where further understanding will help to refine OHCA estimates. These results highlight the need for further coordinated OHCA studies to evaluate the performance of existing mapping methods along with comprehensive assessment of uncertainty estimates.

Analyses of historical ocean temperature data at a depth of 125 meters in the North Atlantic Ocean indicate that from 1950 to 1990 the subtropical and subarctic gyres exhibited linear trends that were opposite in phase. In addition, multivariate analyses of yearly mean temperature anomaly fields between 20°N and 70°N in the North Atlantic show a characteristic space-time temperature oscillation from 1947 to 1990. A quasidecadal oscillation, first identified at Ocean Weather Station C, is part of a basin-wide feature. Gyre and basin-scale variations such as these provide the observational basis for climate diagnostic and modeling studies.

Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 [95% CI 1·4–36·6]; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 [95% CI 1·3–34·4]; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 [95% CI 5·3–37·8]; p=0·007). VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Inovio Pharmaceuticals.

Microphysiological systems (MPSs) are in vitro models that capture facets of in vivo organ function through use of specialized culture microenvironments, including 3D matrices and microperfusion. Here, we report an approach to co-culture multiple different MPSs linked together physiologically on re-useable, open-system microfluidic platforms that are compatible with the quantitative study of a range of compounds, including lipophilic drugs. We describe three different platform designs – “4-way”, “7-way”, and “10-way” – each accommodating a mixing chamber and up to 4, 7, or 10 MPSs. Platforms accommodate multiple different MPS flow configurations, each with internal re-circulation to enhance molecular exchange, and feature on-board pneumatically-driven pumps with independently programmable flow rates to provide precise control over both intra- and inter-MPS flow partitioning and drug distribution. We first developed a 4-MPS system, showing accurate prediction of secreted liver protein distribution and 2-week maintenance of phenotypic markers. We then developed 7-MPS and 10-MPS platforms, demonstrating reliable, robust operation and maintenance of MPS phenotypic function for 3 weeks (7-way) and 4 weeks (10-way) of continuous interaction, as well as PK analysis of diclofenac metabolism. This study illustrates several generalizable design and operational principles for implementing multi-MPS “physiome-on-a-chip” approaches in drug discovery.

The Maumee River is the primary source for nutrients fueling seasonal Microcystis-dominated blooms in western Lake Erie’s open waters though such blooms in the river are infrequent. The river also serves as source water for multiple public water systems and a large food services facility in northwest Ohio. On 20 September 2017, an unprecedented bloom was reported in the Maumee River estuary within the Toledo metropolitan area, which triggered a recreational water advisory. Here we (1) explore physical drivers likely contributing to the bloom’s occurrence, and (2) describe the toxin concentration and bacterioplankton taxonomic composition. A historical analysis using 10-years of seasonal river discharge, water level, and local wind data identified two instances when high-retention conditions occurred over ≥ 10 d in the Maumee River estuary: in 2016 and during the 2017 bloom. Observation by remote sensing imagery supported the advection of cyanobacterial cells into the estuary from the lake during 2017 and the lack of an estuary bloom in 2016 due to a weak cyanobacterial bloom in the lake. A rapid-response survey during the 2017 bloom determined levels of the cyanotoxins, specifically microcystins, in excess of recreational contact limits at sites within the lower 20 km of the river while amplicon sequencing found these sites were dominated by Microcystis. These results highlight the need to broaden our understanding of physical drivers of cyanobacterial blooms within the interface between riverine and lacustrine systems, particularly as such blooms are expected to become more prominent in response to a changing climate.

Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysis of RNA sequencing data from 1641 samples across 43 tissues from 175 individuals, generated as part of the pilot phase of the Genotype-Tissue Expression (GTEx) project. We describe the landscape of gene expression across tissues, catalog thousands of tissue-specific and shared regulatory expression quantitative trait loci (eQTL) variants, describe complex network relationships, and identify signals from genome-wide association studies explained by eQTLs. These findings provide a systematic understanding of the cellular and biological consequences of human genetic variation and of the heterogeneity of such effects among a diverse set of human tissues.