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Non-invasive delivery of hyaluronan into the stratum corneum (SC) is extremely difficult because of its high molecular weight and the strong barrier of the SC. We developed a safe method of administering hyaluronan into the human SC and determined its penetration route. The amount of hyaluronan that penetrated into the SC was 1.5–3 times higher in the presence of magnesium chloride hexahydrate (MgCl 2 ) than other metal chlorides. The root-mean-square radius of hyaluronan in water decreased with the addition of MgCl 2 . Moreover, MgCl 2 solutions maintained their dissolved state on a plastic plate for a long time, suggesting that size compaction and inhibition of hyaluronan precipitation on the skin enhanced hyaluronan into the SC. Our results also strongly suggest that an intercellular route contributes to the penetration of hyaluronan from the upper to the middle layer of the SC. No disruption to the SC barrier was observed after continuous use once a day for 1 month, demonstrating the potential of our method for the safe, topical application of hyaluronan.

Accurate knowledge of the location and magnitude of ocean heat content (OHC) variability and change is essential for understanding the processes that govern decadal variations in surface temperature, quantifying changes in the planetary energy budget, and developing constraints on the transient climate response to external forcings. We present an overview of the temporal and spatial characteristics of OHC variability and change as represented by an ensemble of dynamical and statistical ocean reanalyses (ORAs). Spatial maps of the 0–300 m layer show large regions of the Pacific and Indian Oceans where the interannual variability of the ensemble mean exceeds ensemble spread, indicating that OHC variations are well-constrained by the available observations over the period 1993–2009. At deeper levels, the ORAs are less well-constrained by observations with the largest differences across the ensemble mostly associated with areas of high eddy kinetic energy, such as the Southern Ocean and boundary current regions. Spatial patterns of OHC change for the period 1997–2009 show good agreement in the upper 300 m and are characterized by a strong dipole pattern in the Pacific Ocean. There is less agreement in the patterns of change at deeper levels, potentially linked to differences in the representation of ocean dynamics, such as water mass formation processes. However, the Atlantic and Southern Oceans are regions in which many ORAs show widespread warming below 700 m over the period 1997–2009. Annual time series of global and hemispheric OHC change for 0–700 m show the largest spread for the data sparse Southern Hemisphere and a number of ORAs seem to be subject to large initialization ‘shock’ over the first few years. In agreement with previous studies, a number of ORAs exhibit enhanced ocean heat uptake below 300 and 700 m during the mid-1990s or early 2000s. The ORA ensemble mean (±1 standard deviation) of rolling 5-year trends in full-depth OHC shows a relatively steady heat uptake of approximately 0.9 ± 0.8 W m −2 (expressed relative to Earth’s surface area) between 1995 and 2002, which reduces to about 0.2 ± 0.6 W m −2 between 2004 and 2006, in qualitative agreement with recent analysis of Earth’s energy imbalance. There is a marked reduction in the ensemble spread of OHC trends below 300 m as the Argo profiling float observations become available in the early 2000s. In general, we suggest that ORAs should be treated with caution when employed to understand past ocean warming trends—especially when considering the deeper ocean where there is little in the way of observational constraints. The current work emphasizes the need to better observe the deep ocean, both for providing observational constraints for future ocean state estimation efforts and also to develop improved models and data assimilation methods.

The mean and variability of the Atlantic meridional overturning circulation (AMOC), as represented in six ocean reanalysis products, are analyzed over the period 1960–2007. Particular focus is on multi-decadal trends and interannual variability at 26.5°N and 45°N. For four of the six reanalysis products, corresponding reference simulations obtained from the same models and forcing datasets but without the imposition of subsurface data constraints are included for comparison. An emphasis is placed on identifying general characteristics of the reanalysis representation of AMOC relative to their reference simulations without subsurface data constraints. The AMOC as simulated in these two sets are presented in the context of results from the Coordinated Ocean-ice Reference Experiments phase II (CORE-II) effort, wherein a common interannually varying atmospheric forcing data set was used to force a large and diverse set of global ocean-ice models. Relative to the reference simulations and CORE-II forced model simulations it is shown that (1) the reanalysis products tend to have greater AMOC mean strength and enhanced variance and (2) the reanalysis products are less consistent in their year-to-year AMOC changes. We also find that relative to the reference simulations (but not the CORE-II forced model simulations) the reanalysis products tend to have enhanced multi-decadal trends (from 1975–1995 to 1995–2007) in the mid to high latitudes of the northern hemisphere.

Earth's mantle nitrogen (N) content is comparable to that found in its N‐rich atmosphere. Mantle N has been proposed to be primordial or sourced by later subduction, yet its origin has not been elucidated. Here we model N partitioning during the magma ocean stage following planet formation and the subsequent cycling between the surface and mantle over Earth history using argon (Ar) and N isotopes as tracers. The partitioning model, constrained by Ar, shows that only about 10% of the total N content can be trapped in the solidified mantle due to N's low solubility in magma and low partitioning coefficients in minerals in oxidized conditions supported from geophysical and geochemical studies. A possible solution for the primordial origin is that Earth had about 10 times more N at the time of magma ocean solidification. We show that the excess N could be removed by impact erosion during late accretion. The cycling model, constrained by N isotopes, shows that mantle N can originate from efficient N subduction, if the sedimentary N burial rate on early Earth is comparable to that of modern Earth. Such a high N burial rate requires biotic processing. Finally, our model provides a methodology to distinguish the two possible origins with future analysis of the surface and mantle N isotope record. Plain Language Summary Nitrogen (N) is the main component of Earth's atmosphere, and essential for life. The atmospheric N content influences Earth's climate and capability to retain its surface water. Primary biological production is limited by bio‐available N as well as phosphorous on modern Earth. It has been recently recognized that Earth's interior contains N comparable to that found in its atmosphere, and thus its origin is important for our understanding of Earth‐life co‐evolution. We modeled N partitioning in Earth's molten stage and long‐term cycling after Earth's solidification. Two scenarios are proposed from our modeling. One is that Earth's mantle acquired its modern N content in the earlier stage due to an excess amount of N Earth accreted, which was later lost to space following asteroid impacts. Another is that Earth's mantle acquired N via subduction of N‐rich sediments, which requires the sedimentary N burial rate on early Earth comparable to the modern value sustained by biological activity. The two scenarios can be tested with future analysis of the geochemical record of surface and mantle N. Key Points We studied two possible origins for mantle nitrogen: the primordial and recycling scenarios The primordial scenario requires accretion of excess nitrogen and impact erosion during late accretion The recycling scenario needs efficient N fixation and biotic processing on early Earth

Marine biogenic sulphur affects Earth’s radiation budget and may be an indicator of primary productivity in the Southern Ocean, which is closely related to atmospheric CO 2 variability through the biological pump. Previous ice-core studies in Antarctica show little climate dependence of marine biogenic sulphur emissions and hence primary productivity, contradictory to marine sediment records. Here we present new 720,000-year ice core records from Dome Fuji in East Antarctica and show that a large portion of non-sea-salt sulphate, which was traditionally used as a proxy for marine biogenic sulphate, likely originates from terrestrial dust during glacials. By correcting for this, we make a revised calculation of biogenic sulphate and find that its flux is reduced in glacial periods. Our results suggest reduced dimethylsulphide emissions in the Antarctic Zone of the Southern Ocean during glacials and provide new evidence for the coupling between climate and the Southern Ocean sulphur cycle. Ice core derived marine biogenic sulphate does not agree with marine sediment records. Here based on new ice core records spanning the past 720,000 years obtained from Dome Fuji the authors propose that dust contributed a higher percentage of sulphate aerosols than previously thought.

Abstract Background Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown. Hypothesis/Objectives Administration of pimobendan (0.4–0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia. Animals 360 client-owned dogs with MMVD with left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5. Methods Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia. Results Median time to primary endpoint was 1228 days (95% CI: 856–NA) in the pimobendan group and 766 days (95% CI: 667–875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47–0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952–NA) in the pimobendan group and 902 days (95% CI: 747–1061) in the placebo group) (P = .012). Conclusions and Clinical Importance Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.

An ensemble of nine operational ocean reanalyses (ORAs) is now routinely collected, and is used to monitor the consistency across the tropical Pacific temperature analyses in real-time in support of ENSO monitoring, diagnostics, and prediction. The ensemble approach allows a more reliable estimate of the signal as well as an estimation of the noise among analyses. The real-time estimation of signal-to-noise ratio assists the prediction of ENSO. The ensemble approach also enables us to estimate the impact of the Tropical Pacific Observing System (TPOS) on the estimation of ENSO-related oceanic indicators. The ensemble mean is shown to have a better accuracy than individual ORAs, suggesting the ensemble approach is an effective tool to reduce uncertainties in temperature analysis for ENSO. The ensemble spread, as a measure of uncertainties in ORAs, is shown to be partially linked to the data counts of in situ observations. Despite the constraints by TPOS data, uncertainties in ORAs are still large in the northwestern tropical Pacific, in the SPCZ region, as well as in the central and northeastern tropical Pacific. The uncertainties in total temperature reduced significantly in 2015 due to the recovery of the TAO/TRITON array to approach the value before the TAO crisis in 2012. However, the uncertainties in anomalous temperature remained much higher than the pre-2012 value, probably due to uncertainties in the reference climatology. This highlights the importance of the long-term stability of the observing system for anomaly monitoring. The current data assimilation systems tend to constrain the solution very locally near the buoy sites, potentially damaging the larger-scale dynamical consistency. So there is an urgent need to improve data assimilation systems so that they can optimize the observation information from TPOS and contribute to improved ENSO prediction.

In this study, we quantified carbonaceous PM2.5 in Malaysia through annual observations of PM2.5, focusing on organic compounds derived from biomass burning. We determined organic carbon (OC), elemental carbon and concentrations of solvent-extractable organic compounds (biomarkers derived from biomass burning sources and n-alkanes). We observed seasonal variations in the concentrations of pyrolyzed OC (OP), levoglucosan (LG), mannosan (MN), galactosan, syringaldehyde, vanillic acid (VA) and cholesterol. The average concentrations of OP, LG, MN, galactosan, VA and cholesterol were higher during the southwestern monsoon season (June-September) than during the northeastern monsoon season (December-March), and these differences were statistically significant. Conversely, the syringaldehyde concentration during the southwestern monsoon season was lower. The PM2.5 OP / OC4 mass ratio allowed distinguishing the seven samples, which have been affected by the Indonesian peatland fires (IPFs). In addition, we observed significant differences in the concentrations between the Indonesian peatland fire (IPF) and other samples of many chemical species. Thus, the chemical characteristics of PM2.5 in Malaysia appeared to be significantly influenced by IPFs during the southwestern monsoon season. Furthermore, we evaluated two indicators, the vanillic acid / syringic acid (VA / SA) and LG / MN mass ratios, which have been suggested as indicators of IPFs. The LG / MN mass ratio ranged from 14 to 22 in the IPF samples and from 11 to 31 in the other samples. Thus, the respective variation ranges partially overlapped. Consequently, this ratio did not satisfactorily reflect the effects of IPFs in Malaysia. In contrast, the VA / SA mass ratio may serve as a good indicator, since it significantly differed between the IPF and other samples. However, the OP / OC4 mass ratio provided more remarkable differences than the VA / SA mass ratio, offering an even better indicator. Finally, we extracted biomass burning emissions' sources such as IPF, softwood/hardwood burning and meat cooking through varimax-rotated principal component analysis.

Sea surface temperature (SST) fronts in mid- to high-latitude oceans have significant impacts on extratropical atmospheric circulations and climate. In the western subarctic Pacific, sharp SST fronts form between the cold subarctic water and the recently found quasi-stationary jets that advect warm waters originating in the Kuroshio northeastward. Here we present a new mechanism of the jet formation paying attention to the propagation of baroclinic Rossby waves that is deflected by eddy-driven barotropic flows over bottom rises, although their height is low (~500 m) compared with the depth of the North Pacific Ocean (~6000 m). Steered by the barotropic flows, Rossby waves bring a thicker upper layer from the subtropical gyre and a thinner upper layer from the subarctic gyre, thereby creating a thickness jump, hence a surface jet, where they converge. This study reveals an overlooked role of low-rise bottom topography in regulating SST anomalies in subpolar oceans. Sea surface temperature fronts in mid-and-high latitudes give significant impacts on atmospheric circulations and climate. Here, the authors uncover a new mechanism on the sea surface front genesis in the subpolar oceans in which small-amplitude bottom topography is surprisingly effective.

Although laterality assessed by computed tomography (CT) in primary aldosteronism (PA) is not always concordant with that assessed by adrenal vein sampling (AVS), it is unclear whether all patients diagnosed with PA should undergo AVS for subtype classification. The aim of the current study was to investigate the accuracy of CT in subtype classification and to develop a prediction score for bilateral subtype in patients without adrenal tumour. As part of the WAVES-J study, 393 patients with PA were analysed. Subtyping using CT was concordant with that using AVS in 68% (269/393) of patients in the total sample, and in 38% (68/156) of patients with unilateral tumours, 56% (5/9) of patients with bilateral tumours and 89% (204/228) of patients without tumour. In patients without tumour, female gender, plasma aldosterone concentration (pg ml −1 ) to plasma renin activity ratio ⩽550 and serum potassium ⩾3.8 mEq l −1 were shown to be independent predictors for bilateral subtype. A prediction score based on these three variables was constructed with one point attributed to each variable. A score of three points had 29% sensitivity and 96% specificity in a receiver operating characteristic curve analysis. The results suggest that although CT is not sufficiently accurate for subtype classification in patients with adrenal tumours, it is sufficient to determine bilateral subtype in patients without tumour. Moreover, using our clinical prediction score in patients without tumour could be useful in determining the necessity of AVS for subtype classification.