A new model of the deglaciation history of Antarctica over the past 25 kyr has been developed, which we refer to herein as ICE-6G_C (VM5a). This revision of its predecessor ICE-5G (VM2) has been ...constrained to fit all available geological and geodetic observations, consisting of: (1) the present day uplift rates at 42 sites estimated from GPS measurements, (2) ice thickness change at 62 locations estimated from exposure-age dating, (3) Holocene relative sea level histories from 12 locations estimated on the basis of radiocarbon dating and (4) age of the onset of marine sedimentation at nine locations along the Antarctic shelf also estimated on the basis of 14C dating. Our new model fits the totality of these data well. An additional nine GPS-determined site velocities are also estimated for locations known to be influenced by modern ice loss from the Pine Island Bay and Northern Antarctic Peninsula regions. At the 42 locations not influenced by modern ice loss, the quality of the fit of postglacial rebound model ICE-6G_C (VM5A) is characterized by a weighted root mean square residual of 0.9 mm yr–1. The Southern Antarctic Peninsula is inferred to be rising at 2 mm yr–1, requiring there to be less Holocene ice loss there than in the prior model ICE-5G (VM2). The East Antarctica coast is rising at approximately 1 mm yr–1, requiring ice loss from this region to have been small since Last Glacial Maximum. The Ellsworth Mountains, at the base of the Antarctic Peninsula, are inferred to be rising at 5–8 mm yr–1, indicating large ice loss from this area during deglaciation that is poorly sampled by geological data. Horizontal deformation of the Antarctic Plate is minor with two exceptions. First, O'Higgins, at the tip of the Antarctic Peninsula, is moving southeast at a significant 2 mm yr–1 relative to the Antarctic Plate. Secondly, the margins of the Ronne and Ross Ice Shelves are moving horizontally away from the shelf centres at an approximate rate of 0.8 mm yr–1, in viscous response to the early Holocene unloading of ice from the current locations of the ice shelf centers. ICE-6G_C (VM5A) fits the horizontal observations well (wrms residual speed of 0.7 mm yr–1), there being no need to invoke any influence of lateral variation in mantle viscosity. ICE-6G_C (VM5A) differs in several respects from the recently published W12A model of Whitehouse et al. First, the upper-mantle viscosity in VM5a is 5 × 1020 Pa s, half that in W12A. The VM5a profile, which is identical to that inferred on the basis of the Fennoscandian relaxation spectrum, North American relative sea level histories and Earth rotation constraints, when coupled with the revised ICE-6G_C deglaciation history, fits all of the available constraints. Secondly, the net contribution of Antarctica ice loss to global sea level rise is 13.6 m, 2/3 greater than the 8 m in W12A. Thirdly, ice loss occurs quickly from 12 to 5 ka, and the contribution to global sea level rise during Meltwater Pulse 1B (11.5 ka) is large (5 m), consistent with sedimentation constraints from cores from the Antarctica ice shelf. Fourthly, in ICE-6G_C there is no ice gain in the East Antarctica interior, as there is in W12A. Finally, the new model of Antarctic deglaciation reconciles the global constraint upon the global mass loss during deglaciation provided by the Barbados record of relative sea level history when coupled with the Northern Hemisphere counterpart of this new model.
It is now apparent that there are at least two heating mechanisms in the Sun's outer atmosphere, or corona. Wave heating may be the prevalent mechanism in quiet solar periods and may contribute to ...heating the corona to 1,500,000 K (refs 1-3). The active corona needs additional heating to reach 2,000,000-4,000,000 K; this heat has been theoretically proposed to come from the reconnection and unravelling of magnetic 'braids'. Evidence favouring that process has been inferred, but has not been generally accepted because observations are sparse and, in general, the braided magnetic strands that are thought to have an angular width of about 0.2 arc seconds have not been resolved. Fine-scale braiding has been seen in the chromosphere but not, until now, in the corona. Here we report observations, at a resolution of 0.2 arc seconds, of magnetic braids in a coronal active region that are reconnecting, relaxing and dissipating sufficient energy to heat the structures to about 4,000,000 K. Although our 5-minute observations cannot unambiguously identify the field reconnection and subsequent relaxation as the dominant heating mechanism throughout active regions, the energy available from the observed field relaxation in our example is ample for the observed heating.
The binding and cytochrome P45051 (CYP51) inhibition properties of a novel antifungal compound, VT-1161, against purified recombinant Candida albicans CYP51 (ERG11) and Homo sapiens CYP51 were ...compared with those of clotrimazole, fluconazole, itraconazole, and voriconazole. VT-1161 produced a type II binding spectrum with Candida albicans CYP51, characteristic of heme iron coordination. The binding affinity of VT-1161 for Candida albicans CYP51 was high (dissociation constant Kd, ≤ 39 nM) and similar to that of the pharmaceutical azole antifungals (Kd, ≤ 50 nM). In stark contrast, VT-1161 at concentrations up to 86 μM did not perturb the spectrum of recombinant human CYP51, whereas all the pharmaceutical azoles bound to human CYP51. In reconstitution assays, VT-1161 inhibited Candida albicans CYP51 activity in a tight-binding fashion with a potency similar to that of the pharmaceutical azoles but failed to inhibit the human enzyme at the highest concentration tested (50 μM). In addition, VT-1161 (MIC = 0.002 μg ml(-1)) had a more pronounced fungal sterol disruption profile (increased levels of methylated sterols and decreased levels of ergosterol) than the known CYP51 inhibitor voriconazole (MIC = 0.004 μg ml(-1)). Furthermore, VT-1161 weakly inhibited human CYP2C9, CYP2C19, and CYP3A4, suggesting a low drug-drug interaction potential. In summary, VT-1161 potently inhibited Candida albicans CYP51 and culture growth but did not inhibit human CYP51, demonstrating a >2,000-fold selectivity. This degree of potency and selectivity strongly supports the potential utility of VT-1161 in the treatment of Candida infections.
Bromine atoms play a central role in atmospheric reactive halogen chemistry, depleting ozone and elemental mercury, thereby enhancing deposition of toxic mercury, particularly in the Arctic ...near-surface troposphere. However, direct bromine atom measurements have been missing to date, due to the lack of analytical capability with sufficient sensitivity for ambient measurements. Here we present direct atmospheric bromine atom measurements, conducted in the springtime Arctic. Measured bromine atom levels reached 14 parts per trillion (ppt, pmol mol−1; 4.2 × 10⁸ atoms per cm−3) and were up to 3–10 times higher than estimates using previous indirect measurements not considering the critical role of molecular bromine. Observed ozone and elemental mercury depletion rates are quantitatively explained by the measured bromine atoms, providing field validation of highly uncertain mercury chemistry. Following complete ozone depletion, elevated bromine concentrations are sustained by photochemical snowpack emissions of molecular bromine and nitrogen oxides, resulting in continued atmospheric mercury depletion. This study provides a breakthrough in quantitatively constraining bromine chemistry in the polar atmosphere, where this chemistry connects the rapidly changing surface to pollutant fate.
Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H (CFH, FH) and CFH related genes (CFHR1-5) are ...major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD (P-value = 7.1 × 10
), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch's membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels (P-value = 2.2 × 10
), independently of the AMD-protective CFHR1-3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD.
Studies of solar wind turbulence traditionally employ high-resolution magnetic field data, but high-resolution measurements of ion and electron moments have been possible only recently. We report the ...first turbulence studies of ion and electron velocity moments accumulated in pristine solar wind by the Fast Plasma Investigation (FPI) instrument on board the Magnetospheric Multiscale Mission. Use of these data is made possible by a novel implementation of a frequency domain Hampel filter, described herein. After presenting procedures for processing of the data, we discuss statistical properties of solar wind turbulence extending into the kinetic range. Magnetic field fluctuations dominate electron and ion-velocity fluctuation spectra throughout the energy-containing and inertial ranges. However, a multispacecraft analysis indicates that at scales shorter than the ion inertial length, electron velocity fluctuations become larger than ion-velocity and magnetic field fluctuations. The kurtosis of ion-velocity peaks around a few ion inertial lengths and returns to a near Gaussian value at sub-ion scales.
Human activities are transforming grassland biomass via changing climate, elemental nutrients, and herbivory. Theory predicts that food-limited herbivores will consume any additional biomass ...stimulated by nutrient inputs ('consumer-controlled'). Alternatively, nutrient supply is predicted to increase biomass where herbivores alter community composition or are limited by factors other than food ('resource-controlled'). Using an experiment replicated in 58 grasslands spanning six continents, we show that nutrient addition and vertebrate herbivore exclusion each caused sustained increases in aboveground live biomass over a decade, but consumer control was weak. However, at sites with high vertebrate grazing intensity or domestic livestock, herbivores consumed the additional fertilization-induced biomass, supporting the consumer-controlled prediction. Herbivores most effectively reduced the additional live biomass at sites with low precipitation or high ambient soil nitrogen. Overall, these experimental results suggest that grassland biomass will outstrip wild herbivore control as human activities increase elemental nutrient supply, with widespread consequences for grazing and fire risk.
Various magnetic resonance (MR) techniques are used to study the pathological evolution of demyelinating diseases, such as multiple sclerosis (MS). However, few studies have validated MR derived ...measurements with histopathology. Here, we determine the correlation of myelin water imaging, an MR measure of myelin content, with quantitative histopathologic measures of myelin density. The multi-component T2 distribution of water was determined from 25 formalin-fixed MS brain samples using a multi-echo T2 relaxation MR experiment. The myelin water fraction (MWF), defined as T2 signal below 30 milliseconds divided by the total signal, was determined for various regions of interest and compared to Luxol fast blue (myelin stain) mean optical density (OD) for each sample. MWF had a strong correlation with myelin stain mean (range) R2-/0.67 (0.45+ 0.92), validating MWF as a measure of myelin density. This quantitative technique has many practical applications for the in vivo monitoring of demyelination and remyelination in a variety of disorders of myelin.
Premature rupture of the fetal membranes is a major cause of preterm birth and its associated infant morbidity and mortality. Recently, it has become clear that rupture of the fetal membranes, term ...or preterm, is not merely the result of the stretch and shear forces of uterine contractions, but is, in significant part, the consequence of a programmed weakening process. Work in the rat model has demonstrated that collagen remodeling, with activation of matrix metalloproteinases (MMPs), and apoptosis increase markedly in the amnion at end-gestation, suggesting that these processes are involved in fetal membrane weakening. We have developed fetal membrane strength testing equipment and a systematic tissue sampling methodology that has allowed us to demonstrate that term, non-labored, fetal membranes have a zone of weakness overlying the cervix, which contains biochemical markers of both collagen remodeling and apoptosis. These findings provide strong support for the concept of programmed fetal membrane weakening prior to labor. Our model has also been used to establish the physical properties of individual fetal membrane components (amnion, chorion), determine the sequence of events during the fetal membrane rupture process, and demonstrate that treatment of fetal membranes with TNF or IL-1β, in vitro, induces weakness and the identical biochemical markers of collagen remodeling and apoptosis seen in the physiological weak zone. The ability to simultaneously correlate macroscopic physical properties with histological and biochemical fetal membrane characteristics, presents a unique perspective on the physiology of fetal membrane rupture.
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