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The NASA MESSENGER mission explored the innermost planet of the solar system and obtained a rich dataset of range measurements for the determination of Mercury's ephemeris. Here we use these precise data collected over seven years to estimate parameters related to General Relativity and the evolution of the Sun. These results confirm the validity of the Strong Equivalence Principle with a significantly refined uncertainty of the Nordtvedt parameter eta=(-6.6 plus or minus 7.2)x10(exp -5) By assuming a metric theory of gravitation, we retrieved the Post-Newtonian parameter beta = 1 + (-1.6 plus or minus 1.8)x10(exp -5) and the Sun's gravitational oblateness, J(sub 2 solar)=(2.246 plus or minus 0.022)x10(exp -7). Finally, we obtain an estimate of the time variation of the Sun gravitational parameter, G (raised dot)solar mass/G solar mass =(-6.13 plus or minus 1.47)x10(exp -14), which is consistent with the expected solar mass loss due to the solar wind and interior processes. This measurement allows us to constrain |G(raised dot)|/G to be less than 4 x 10(exp -14) yr(exp -1).

The epithelium serves as a highly selective barrier at mucosal surfaces. Upon injury, epithelial wound closure is orchestrated by a series of events that emanate from the epithelium itself as well as by the temporal recruitment of immune cells into the wound bed. Epithelial cells adjoining the wound flatten out, migrate, and proliferate to rapidly cover denuded surfaces and re-establish mucosal homeostasis. This process is highly regulated by proteins and lipids, proresolving mediators such as Annexin A1 protein and resolvins released into the epithelial milieu by the epithelium itself and infiltrating innate immune cells including neutrophils and macrophages. Failure to achieve these finely tuned processes is observed in chronic inflammatory diseases that are associated with non-healing wounds. An improved understanding of mechanisms that mediate repair is important in the development of therapeutics aimed to promote mucosal wound repair.

The physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form 1 . In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations 2 – 4 . Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1–2 kJ mol −1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control 5 . Accuracy of free-energy calculations can be improved by constructing an experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate and anhydrate crystal structures on the same energy landscape.

Background Perforations and anastomotic leakages of the upper gastrointestinal (GI) tract cause a high morbidity and mortality rate. Only limited data exist for endoscopic vacuum therapy (EVT) in the upper GI tract. Methods Fifty-two patients (37 men and 15 women, ages 41–94 years) were treated (12/2011–12/2015) with EVT for anastomotic insufficiency secondary to esophagectomy or gastrectomy ( n  = 39), iatrogenic esophageal perforation ( n  = 9) and Boerhaave syndrome ( n  = 4). After diagnosis, polyurethane sponges were endoscopically positioned with a total of 390 interventions and continuous negative pressure of 125 mm of mercury (mmHg) was applied to the EVT-system. Sponges were changed endoscopically twice per week. Clinical and therapy-related data and mortality were analyzed. Results After 1–25 changes of the sponge at intervals of 3–5 days with a mean of 6 sponge changes and a mean duration of therapy of 22 days, the defects were healed in 94.2 % of all patients without revision surgery. In three patients (6 %), EVT failed. Two of these patients died due to hemorrhage related to EVT. Four postinterventional strictures were observed during the follow-up of up to 4 years. Conclusion Esophageal wall defects of different etiology in the upper gastrointestinal tract can be treated successfully with EVT, considering that indication for EVT should be weighed carefully. EVT can be regarded as a novel life-saving therapeutic tool.

Fifteen-year-old adolescents (N = 109) in a longitudinal study of child development were recruited to examine differences in DNA methylation in relation to parent reports of adversity during the adolescents' infancy and preschool periods. Microarray technology applied to 28,000 cytosine—guanine dinucleotide sites within DNA derived from buccal epithelial cells showed differential methylation among adolescents whose parents reported high levels of stress during their children's early lives. Maternal stressors in infancy and paternal stressors in the preschool years were most strongly predictive of differential methylation, and the patterning of such epigenetic marks varied by children's gender. To the authors' knowledge, this is the first report of prospective associations between adversities in early childhood and the epigenetic conformation of adolescents' genomic DNA.

Significance Changes in the methylation status of cytosine nucleotides are a source of heritable epigenetic and phenotypic diversity in plants. Here we derive robust estimates of the rate at which cytosine methylation is spontaneously gained (forward epimutation) or lost (backward epimutation) in the genome of the model plant Arabidopsis thaliana . We show that the forward–backward dynamics of selectively neutral epimutations have a major impact on methylome evolution and shape genome-wide patterns of methylation diversity among natural populations in this species. The epimutation rates presented here can serve as reference values in future empirical and theoretical population epigenetic studies in plants. Stochastic changes in cytosine methylation are a source of heritable epigenetic and phenotypic diversity in plants. Using the model plant Arabidopsis thaliana , we derive robust estimates of the rate at which methylation is spontaneously gained (forward epimutation) or lost (backward epimutation) at individual cytosines and construct a comprehensive picture of the epimutation landscape in this species. We demonstrate that the dynamic interplay between forward and backward epimutations is modulated by genomic context and show that subtle contextual differences have profoundly shaped patterns of methylation diversity in A. thaliana natural populations over evolutionary timescales. Theoretical arguments indicate that the epimutation rates reported here are high enough to rapidly uncouple genetic from epigenetic variation, but low enough for new epialleles to sustain long-term selection responses. Our results provide new insights into methylome evolution and its population-level consequences.

Conversion of altimetry-derived ice-sheet volume change to mass requires an understanding of the evolution of the combined ice and air content within the firn column. In the absence of suitable techniques to observe the changes to the firn column across the entirety of an ice sheet, the firn column processes are typically modeled. Here, we present new simulations of firn processes over the Greenland and Antarctic ice sheets (GrIS and AIS) using the Community Firn Model and atmospheric reanalysis variables for more than four decades. A data set of more than 250 measured depth–density profiles from both ice sheets provides the basis of the calibration of the dry-snow densification scheme. The resulting scheme results in a reduction in the rate of densification, relative to a commonly used semi-empirical model, through a decreased dependence on the accumulation rate, a proxy for overburden stress. The 1980–2020 modeled firn column runoff, when combined with atmospheric variables from MERRA-2, generates realistic mean integrated surface mass balance values for the Greenland (+390 Gt yr(exp −1)) and Antarctic (+2612 Gt yr(exp −1)) ice sheets when compared to published model-ensemble means. We find that seasonal volume changes associated with firn air content are on average approximately 2.5 times larger than those associated with mass fluxes from surface processes for the AIS and 1.5 times larger for the GrIS; however, when averaged over multiple years, ice and air-volume fluctuations within the firn column are of comparable magnitudes. Between 1996 and 2019, the Greenland Ice Sheet lost nearly 5% of its firn air content, indicating a reduction in the total meltwater retention capability. Nearly all (94 %) of the meltwater produced over the Antarctic Ice Sheet is retained within the firn column through infiltration and refreezing.

Background Anastomotic leakage represents a major complication following resections in colorectal surgery. Among others, intestinal inflammation such as in inflammatory bowel disease is a significant risk factor for disturbed anastomotic healing. Despite technical advancements and several decades of focused research, the underlying mechanisms remain incompletely understood. Animal experiments will remain the backbone of this research in the near future. Here, instructions on a standardized and reproducible murine model of preoperative colitis and colorectal anastomosis formation are provided to amplify research on anastomotic healing during inflammatory disease. Methods We demonstrate the combination of experimental colitis and colorectal anastomosis formation in a mouse model. The model allows for monitoring of anastomotic healing during inflammatory disease through functional outcomes, clinical scores, and endoscopy and histopathological examination, as well as molecular analysis. Discussion Postoperative weight loss is used as a parameter to monitor general recovery. Functional stability can be measured by recording bursting pressure and location. Anastomotic healing can be evaluated macroscopically from the luminal side by endoscopic scoring and from the extraluminal side by assessing adhesion and abscess formation or presence of dehiscence. Histologic examination allows for detailed evaluation of the healing process. Conclusion The murine model presented in this paper combines adjustable levels of experimental colitis with a standardized method for colorectal anastomosis formation. Extensive options for sample analysis and evaluation of clinical outcomes allow for detailed research of the mechanisms behind defective anastomotic healing.

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib. Crystal polymorphism can lead to substances with vastly differing physicochemical properties, which has serious implications in the pharmaceutical industry. Here, the authors use in silico polymorph screening to accurately predict the resulting structures under set crystallisation environments.

Simultaneous observations of moulins and boreholes in western Greenland show that water delivery to the base of the ice sheet via moulins affects short-term ice velocity fluctuations, but not late-season ice velocity decelerations. Ice velocity response to subglacial pressure variation Increased meltwater delivery to the base of the Greenland Ice Sheet will increase the ice sheet velocity, accelerating its inevitable rush towards the ocean and subsequent sea level rise. Or will it? Debate on this topic is at the forefront of cryospheric research, but has been hampered by the lack of simultaneous observations of hydraulic head in moulins, vertical shafts that deliver water to the base of the ice sheet, and boreholes, which monitor basal water pressure. Lauren Andrews and colleagues now provide these observations from a small region in western Greenland and reveal that water delivery by moulins into channelized basal flow is indeed linked to short-term fluctuations in ice velocity. Late season decelerations in ice velocity, however, seem to be controlled by changes in unchannelized flow, rather than any shifts in the moulin system. Seasonal acceleration of the Greenland Ice Sheet is influenced by the dynamic response of the subglacial hydrologic system to variability in meltwater delivery to the bed 1 , 2 via crevasses and moulins (vertical conduits connecting supraglacial water to the bed of the ice sheet). As the melt season progresses, the subglacial hydrologic system drains supraglacial meltwater more efficiently 1 , 2 , 3 , 4 , decreasing basal water pressure 4 and moderating the ice velocity response to surface melting 1 , 2 . However, limited direct observations of subglacial water pressure 4 , 5 , 6 , 7 mean that the spatiotemporal evolution of the subglacial hydrologic system remains poorly understood. Here we show that ice velocity is well correlated with moulin hydraulic head but is out of phase with that of nearby (0.3–2 kilometres away) boreholes, indicating that moulins connect to an efficient, channelized component of the subglacial hydrologic system, which exerts the primary control on diurnal and multi-day changes in ice velocity. Our simultaneous measurements of moulin and borehole hydraulic head and ice velocity in the Paakitsoq region of western Greenland show that decreasing trends in ice velocity during the latter part of the melt season cannot be explained by changes in the ability of moulin-connected channels to convey supraglacial melt. Instead, these observations suggest that decreasing late-season ice velocity may be caused by changes in connectivity in unchannelized regions of the subglacial hydrologic system. Understanding this spatiotemporal variability in subglacial pressures is increasingly important because melt-season dynamics affect ice velocity beyond the conclusion of the melt season 8 , 9 , 10 .