The phenomenon of thermal diffusion (mass diffusion driven by a temperature gradient, known as the Ludwig-Soret effect) has been investigated for over 150 years, but an understanding of its ...underlying physical basis remains elusive. A significant hurdle in studying thermal diffusion has been the difficulty of characterizing it. Extensive experiments over the past century have established that the Soret coefficient, S(T) (a single parameter that describes the steady-state result of thermal diffusion), is highly sensitive to many factors. This sensitivity makes it very difficult to obtain a robust characterization of thermal diffusion, even for a single material. Here we show that for thermal diffusion experiments that span a wide range in composition and temperature, the difference in S(T) between isotopes of diffusing elements that are network modifiers (iron, calcium and magnesium) is independent of the composition and temperature. On the basis of this finding, we propose an additive decomposition for the functional form of S(T) and argue that a theoretical approach based on local thermodynamic equilibrium holds promise for describing thermal diffusion in silicate melts and other complex solutions. Our results lead to a simple and robust framework for characterizing isotope fractionation by thermal diffusion in natural and synthetic systems.
Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on ...the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.
Shallow-water carbonate sediments constitute the bulk of sedimentary carbonates in the geologic record and are widely used archives of Earth’s chemical and climatic history. One of the main ...limitations in interpreting the geochemistry of ancient carbonate sediments is the potential for post-depositional diagenetic alteration. In this study, we use paired measurements of calcium (44Ca/40Ca or δ44Ca) and magnesium (26Mg/24Mg or δ26Mg) isotope ratios in sedimentary carbonates and associated pore-fluids as a tool to understand the mineralogical and diagenetic history of Neogene shallow-water carbonate sediments from the Bahamas and southwest Australia. We find that the Ca and Mg isotopic composition of bulk carbonate sediments at these sites exhibits systematic stratigraphic variability that is related to both mineralogy and early marine diagenesis. The observed variability in bulk sediment Ca isotopes is best explained by changes in the extent and style of early marine diagenesis from one where the composition of the diagenetic carbonate mineral is determined by the chemistry of the fluid (fluid-buffered) to one where the composition of the diagenetic carbonate mineral is determined by the chemistry of the precursor sediment (sediment-buffered). Our results indicate that this process, together with variations in carbonate mineralogy (aragonite, calcite, and dolomite), plays a fundamental and underappreciated role in determining the regional and global stratigraphic expressions of geochemical tracers (δ13C, δ18O, major, minor, and trace elements) in shallow-water carbonate sediments in the geologic record. Our results also provide evidence that a large shallow-water carbonate sink that is enriched in 44Ca can explain the mismatch between the δ44/40Ca value of rivers and deep-sea carbonate sediments and call into question the hypothesis that the δ44/40Ca value of seawater depends on the mineralogy of primary carbonate precipitations (e.g. ‘aragonite seas’ and ‘calcite seas’). Finally, our results for sedimentary dolomites suggest that paired measurements of Ca and Mg isotopes may provide a unique geochemical fingerprint of mass transfer during dolomitization to better understand the paleo-environmental information preserved in these enigmatic but widespread carbonate minerals.
OBJECTIVETo prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.
METHODSAdults treated with ...brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.
RESULTSOf 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04–9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ).
CONCLUSIONSAdjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.
CLINICALTRIALS.GOV IDENTIFIERNCT00572195.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
Uranium groundwater contamination due to U mining and processing affects numerous sites globally. Bioreduction of soluble, mobile U(VI) to U(IV)-bearing solids is potentially a very effective ...remediation strategy. Uranium isotopes (238U/235U) have been utilized to track the progress of microbial reduction, with laboratory and field studies finding a ∼1‰ isotopic fractionation, with the U(IV) product enriched in 238U. However, the isotopic fractionation produced by adsorption may complicate the use of 238U/235U to trace microbial reduction. A previous study found that adsorption of U(VI) onto Mn oxides produced a −0.2‰ fractionation with the adsorbed U(VI) depleted in 238U. In this study, adsorption to quartz, goethite, birnessite, illite, and aquifer sediments induced an average isotopic fractionation of −0.15‰ with the adsorbed U(VI) isotopically lighter than coexisting aqueous U(VI). In bicarbonate-bearing matrices, the fractionation depended little on the nature of the sorbent, with only birnessite producing an atypically large fractionation. In the case of solutions with ionic strengths much lower than those of typical groundwater, less isotopic fractionation was produced than U(VI) solutions with greater ionic strength. Studies using U isotope data to assess U(VI) reduction must consider adsorption as a lesser, but significant isotope fractionation process.
We present high-precision measurements of Mg and Fe isotopic compositions of olivine, orthopyroxene (opx), and clinopyroxene (cpx) for 18 lherzolite xenoliths from east central China and provide the ...first combined Fe and Mg isotopic study of the upper mantle. δ
56Fe in olivines varies from 0.18‰ to −0.22‰ with an average of −0.01
±
0.18‰ (2SD,
n
=
18), opx from 0.24‰ to −0.22‰ with an average of 0.04
±
0.20‰, and cpx from 0.24‰ to −0.16‰ with an average of 0.10
±
0.19‰. δ
26Mg of olivines varies from −0.25‰ to −0.42‰ with an average of −0.34
±
0.10‰ (2SD,
n
=
18), opx from −0.19‰ to −0.34‰ with an average of −0.25
±
0.10‰, and cpx from −0.09‰ to −0.43‰ with an average of −0.24
±
0.18‰. Although current precision (∼±0.06‰ for δ
56Fe; ±0.10‰ for δ
26Mg, 2SD) limits the ability to analytically distinguish inter-mineral isotopic fractionations, systematic behavior of inter-mineral fractionation for both Fe and Mg is statistically observed: Δ
56Fe
ol–cpx
=
−0.10
±
0.12‰ (2SD,
n
=
18); Δ
56Fe
ol–opx
=
−0.05
±
0.11‰; Δ
26Mg
ol–opx
=
−0.09
±
0.12‰; Δ
26Mg
ol–cpx
=
−0.10
±
0.15‰. Fe and Mg isotopic composition of bulk rocks were calculated based on the modes of olivine, opx, and cpx. The average δ
56Fe of peridotites in this study is 0.01
±
0.17‰ (2SD,
n
=
18), similar to the values of chondrites but slightly lower than mid-ocean ridge basalts (MORB) and oceanic island basalts (OIB). The average δ
26Mg is −0.30
±
0.09‰, indistinguishable from chondrites, MORB, and OIB. Our data support the conclusion that the bulk silicate Earth (BSE) has chondritic δ
56Fe and δ
26Mg.
The origin of inter-mineral fractionations of Fe and Mg isotopic ratios remains debated. δ
56Fe between the main peridotite minerals shows positive linear correlations with slopes within error of unity, strongly suggesting intra-sample mineral–mineral Fe and Mg isotopic equilibrium. Because inter-mineral isotopic equilibrium should be reached earlier than major element equilibrium via chemical diffusion at mantle temperatures, Fe and Mg isotope ratios of coexisting minerals could be useful tools for justifying mineral thermometry and barometry on the basis of chemical equilibrium between minerals. Although most peridotites in this study exhibit a narrow range in δ
56Fe, the larger deviations from average δ
56Fe for three samples likely indicate changes due to metasomatic processes. Two samples show heavy δ
56Fe relative to the average and they also have high La/Yb and total Fe content, consistent with metasomatic reaction between peridotite and Fe-rich and isotopically heavy melt. The other sample has light δ
56Fe and slightly heavy δ
26Mg, which may reflect Fe–Mg inter-diffusion between peridotite and percolating melt.
In principle, optical phase-sensitive amplifiers are known to be capable of realizing noiseless amplification, as well as improving the signal-to-noise-ratio of optical links by 3 dB compared to ...conventional, phase-insensitively amplified links. However, current state-of-the-art phase-sensitive amplifiers are still far from being practical, lacking, for example, significant noise performance improvement, broadband gain and modulation-format transparency. Here, we demonstrate experimentally, for the first time, an optical-fibre-based non-degenerate phase-sensitive amplifier link consisting of a phase-insensitive parametric copier followed by a phase-sensitive amplifier that provides broadband amplification, signal modulation-format independence, and nearly 6 dB link noise-figure improvement over conventional, erbium-doped fibre amplifier-based links. The PSA has a record-low 1.1 dB noise figure, and can be extended to work with multiple wavelength channels with modest system complexity. This concept can also be realized in other materials with third-order nonlinearities, and is useful in any attenuation-limited optical link.
Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of ...DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.
We conducted laboratory experiments to investigate isotopic fractionations during oxidation of tetravalent uranium, U(IV), by dissolved oxygen. In hydrochloric acid media with the U(IV) dissolved, ...the δ238U value of the remaining U(IV) increased as the extent of oxidation increased. The δ238U value of the product U(VI) paralleled, but was offset to 1.1±0.2‰ lower than the remaining U(IV). In contrast, oxidation of solid U(IV) by dissolved oxygen in 20mM NaHCO3 solution at pH=9.4 caused only a weak fractionation (∼0.1‰ to 0.3‰), with δ238U being higher in the dissolved U(VI) relative to the solid U(IV). We suggest that isotope fractionation during oxidation of solid U(IV) is inhibited by a “rind effect”, where the surface layer of the solid U(IV) must be completely oxidized before the next layer is exposed to oxidant. The necessity of complete conversion of each layer results in minimal isotopic effect. The weak shift in δ238U of U(VI) is attributed to adsorption of part of the product U(VI) to the solid U(IV) surfaces.
Objective To compare the annual prevalence of the autism symptom phenotype and of registered diagnoses for autism spectrum disorder during a 10 year period in children.Design Population based ...study.Setting Child and Adolescent Twin Study and national patient register, Sweden.Participants 19 993 twins (190 with autism spectrum disorder) and all children (n=1 078 975; 4620 with autism spectrum disorder) born in Sweden over a 10 year period from 1993 to 2002.Main outcome measures Annual prevalence of the autism symptom phenotype (that is, symptoms on which the diagnostic criteria are based) assessed by a validated parental telephone interview (the Autism-Tics, ADHD and other Comorbidities inventory), and annual prevalence of reported diagnoses of autism spectrum disorder in the national patient register.Results The annual prevalence of the autism symptom phenotype was stable during the 10 year period (P=0.87 for linear time trend). In contrast, there was a monotonic significant increase in prevalence of registered diagnoses of autism spectrum disorder in the national patient register (P<0.001 for linear trend).Conclusions The prevalence of the autism symptom phenotype has remained stable in children in Sweden while the official prevalence for registered, clinically diagnosed, autism spectrum disorder has increased substantially. This suggests that administrative changes, affecting the registered prevalence, rather than secular factors affecting the pathogenesis, are important for the increase in reported prevalence of autism spectrum disorder.
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