The circulating proteinase inhibitor α-1 antitrypsin regulates neutrophil degranulation and autoimmunity.

Pathological inflammation and autoimmune disease frequently involve elevated neutrophil activity in the absence of infectious agents. Tumor necrosis factor-α (TNF-α) contributes to many of the problems associated with autoimmune diseases. We investigated the ability of serum α-1 antitrypsin (AAT) to control TNF-α biosynthesis and signaling in neutrophils and assessed whether AAT deficiency (AATD) is a TNF-α-related disease. In vitro studies demonstrate that serum AAT coordinates TNF-α intracellular signaling and neutrophil degranulation of tertiary and secondary granules via modulation of ligand-receptor interactions. AATD patients homozygous for the Z allele were characterized by increased activation of the TNF-α system, as demonstrated by increased membrane TNF-α levels and increased plasma concentrations of TNF receptor 1 and neutrophil-released secondary and tertiary granule proteins. The incidence of autoantibodies directed against degranulated lactoferrin and surface protein accessible to these antibodies was increased in ZZ-AATD, leading to an enhanced rate of neutrophil reactive oxygen species production. Treatment of ZZ-AATD individuals with AAT augmentation therapy resulted in decreased membrane TNF-α expression and plasma levels of granule antigenic proteins and immunoglobulin G class autoantibodies. These results provide a mechanism by which AAT augmentation therapy affects TNF-α signaling in the circulating neutrophil, indicating promising potential of this therapy for other TNF-α-related diseases

A 21-year record of vertically migrating subepilimnetic populations of Cryptomonas spp.

The vertical distribution and diel migration of Cryptomonas spp. were monitored continuously for 21 years in mesotrophic Cross Reservoir, northeast Kansas, USA. The movements of these motile algae were tracked on multiple dates during July–October of each year using in situ fluorometry and optical microscopy of Lugol’s iodine-preserved samples. Episodes of subepilimnetic diel vertical migration by Cryptomonas were detected and recorded on 221 different days between 1994 and 2014, with just 2 of these years (1998 and 2013) lacking any sampling events with deep peaks sufficiently large enough to track. Whenever a subepilimnetic layer of Cryptomonas was detectable, it was generally observed to ascend toward the bottom of the epilimnion beginning approximately at sunrise; to descend toward the lake bottom during the late afternoon and evening; and to remain as a deep-dwelling population until dawn of the following day. Moreover, there was high day-to-day consistency in the absolute water column depths at which the migrating algal cells would cease their ascending or descending movement. We believe this unique and remarkable dataset comprises the most detailed record of diel migratory behavior for any planktonic freshwater alga reported for a single freshwater lake

A Spatially Resolved Inner Hole in the Disk around GM Aurigae

We present 0.3 arcsec resolution observations of the disk around GM Aurigae with the Submillimeter Array (SMA) at a wavelength of 860 um and with the Plateau de Bure Interferometer at a wavelength of 1.3 mm. These observations probe the distribution of disk material on spatial scales commensurate with the size of the inner hole predicted by models of the spectral energy distribution. The data clearly indicate a sharp decrease in millimeter optical depth at the disk center, consistent with a deficit of material at distances less than ~20 AU from the star. We refine the accretion disk model of Calvet et al. (2005) based on the unresolved spectral energy distribution (SED) and demonstrate that it reproduces well the spatially resolved millimeter continuum data at both available wavelengths. We also present complementary SMA observations of CO J=3-2 and J=2-1 emission from the disk at 2" resolution. The observed CO morphology is consistent with the continuum model prediction, with two significant deviations: (1) the emission displays a larger CO J=3-2/J=2-1 line ratio than predicted, which may indicate additional heating of gas in the upper disk layers; and (2) the position angle of the kinematic rotation pattern differs by 11 +/- 2 degrees from that measured at smaller scales from the dust continuum, which may indicate the presence of a warp. We note that photoevaporation, grain growth, and binarity are unlikely mechanisms for inducing the observed sharp decrease in opacity or surface density at the disk center. The inner hole plausibly results from the dynamical influence of a planet on the disk material. Warping induced by a planet could also potentially explain the difference in position angle between the continuum and CO data sets.Comment: 12 pages, 6 figures, accepted for publication in Ap

Finite-size scaling in silver nanowire films: design considerations for practical devices

We report the first application of finite-size scaling theory to nanostructured percolating networks, using silver nanowire (AgNW) films as a model system for experiment and simulation. AgNWs have been shown to be a prime candidate for replacing Indium Tin Oxide (ITO) in applications such as capacitive touch sensing. While their performance as large area films is well-studied, the production of working devices involves patterning of the films to produce isolated electrode structures, which exhibit finite-size scaling when these features are sufficiently small. We demonstrate a generalised method for understanding this behaviour in practical rod percolation systems, such as AgNW films, and study the effect of systematic variation of the length distribution of the percolating material. We derive a design rule for the minimum viable feature size in a device pattern, relating it to parameters which can be derived from a transmittance-sheet resistance data series for the material in question. This understanding has direct implications for the industrial adoption of silver nanowire electrodes in applications where small features are required including single-layer capacitive touch sensors, LCD and OLED display panels

An evolutionary study of volatile chemistry in protoplanetary disks

The volatile composition of a planet is determined by the inventory of gas and ice in the parent disk. The volatile chemistry in the disk is expected to evolve over time, though this evolution is poorly constrained observationally. We present ALMA observations of C18O, C2H, and the isotopologues H13CN, HC15N, and DCN towards five Class 0/I disk candidates. Combined with a sample of fourteen Class II disks presented in Bergner et al. (2019b), this data set offers a view of volatile chemical evolution over the disk lifetime. Our estimates of C18O abundances are consistent with a rapid depletion of CO in the first ~0.5-1 Myr of the disk lifetime. We do not see evidence that C2H and HCN formation are enhanced by CO depletion, possibly because the gas is already quite under-abundant in CO. Further CO depletion may actually hinder their production by limiting the gas-phase carbon supply. The embedded sources show several chemical differences compared to the Class II stage, which seem to arise from shielding of radiation by the envelope (impacting C2H formation and HC15N fractionation) and sublimation of ices from infalling material (impacting HCN and C18O abundances). Such chemical differences between Class 0/I and Class II sources may affect the volatile composition of planet-forming material at different stages in the disk lifetime.Comment: Accepted to Ap

An unbiased ALMA spectral survey of the LkCa 15 and MWC 480 protoplanetary disks

Funding: R.A.L. gratefully acknowledges funding from ALMA Student Observing Support and a Jansky Fellowship. K.I.O. acknowledges funding from the David and Lucile Packard Foundation and from the Simons Foundation (SCOL #321183). J.H. acknowledges support from the National Science Foundation Graduate Research Fellowship under grant No. DGE-1144152. E.A.B. acknowledges funding through NSF grant AST-1514670 and NASA NNX16AB48G. C.W. acknowledges financial support from STFC (grant reference ST/R000549/1) and the University of Leeds.The volatile contents of protoplanetary disks both set the potential for planetary chemistry and provide valuable probes of defining disk system characteristics such as stellar mass, gas mass, ionization, and temperature structure. Current disk molecular inventories are fragmented, however, giving an incomplete picture: unbiased spectral line surveys are needed to assess the volatile content. We present here an overview of such a survey of the protoplanetary disks around the Herbig Ae star MWC 480 and the T Tauri star LkCa 15 in ALMA Band 7, spanning ∼36 GHz from 275 to 317 GHz and representing an order of magnitude increase in sensitivity over previous single-dish surveys. We detect 14 molecular species (including isotopologues), with five species (C34S, 13CS, H2CS, DNC, and C2D) detected for the first time in protoplanetary disks. Significant differences are observed in the molecular inventories of MWC 480 and LkCa 15, and we discuss how these results may be interpreted in light of the different physical conditions of these two disk systems.PostprintPeer reviewe

The cometary composition of a protoplanetary disk as revealed by complex cyanides

Observations of comets and asteroids show that the Solar Nebula that spawned our planetary system was rich in water and organic molecules. Bombardment brought these organics to the young Earth's surface, seeding its early chemistry. Unlike asteroids, comets preserve a nearly pristine record of the Solar Nebula composition. The presence of cyanides in comets, including 0.01% of methyl cyanide (CH3CN) with respect to water, is of special interest because of the importance of C-N bonds for abiotic amino acid synthesis. Comet-like compositions of simple and complex volatiles are found in protostars, and can be readily explained by a combination of gas-phase chemistry to form e.g. HCN and an active ice-phase chemistry on grain surfaces that advances complexity[3]. Simple volatiles, including water and HCN, have been detected previously in Solar Nebula analogues - protoplanetary disks around young stars - indicating that they survive disk formation or are reformed in situ. It has been hitherto unclear whether the same holds for more complex organic molecules outside of the Solar Nebula, since recent observations show a dramatic change in the chemistry at the boundary between nascent envelopes and young disks due to accretion shocks[8]. Here we report the detection of CH3CN (and HCN and HC3N) in the protoplanetary disk around the young star MWC 480. We find abundance ratios of these N-bearing organics in the gas-phase similar to comets, which suggests an even higher relative abundance of complex cyanides in the disk ice. This implies that complex organics accompany simpler volatiles in protoplanetary disks, and that the rich organic chemistry of the Solar Nebula was not unique.Comment: Definitive version of the manuscript is published in Nature, 520, 7546, 198, 2015. This is the author's versio

Systematic Analysis of Copy Number Variations in the Pathogenic Yeast Candida parapsilosis Identifies a Gene Amplification in RTA3 That is Associated with Drug Resistance

We analyzed the genomes of 170 C. parapsilosis isolates and identified multiple copy number variations (CNVs). We identified two genes, RTA3 (CPAR2_104610) and ARR3 (CPAR2_601050), each of which was the target of multiple independent amplification events. Phylogenetic analysis shows that most of these amplifications originated only once. For ARR3, which encodes a putative arsenate transporter, 8 distinct CNVs were identified, ranging in size from 2.3 kb to 10.5 kb with 3 to 23 copies. For RTA3, 16 distinct CNVs were identified, ranging in size from 0.3 kb to 4.5 kb with 2 to ~50 copies. One unusual amplification resulted in a DUP-TRP/INV-DUP structure similar to some human CNVs. RTA3 encodes a putative phosphatidylcholine (PC) floppase which is known to regulate the inward translocation of PC in Candida albicans. We found that an increased copy number of RTA3 correlated with resistance to miltefosine, an alkylphosphocholine drug that affects PC metabolism. Additionally, we conducted an adaptive laboratory evolution experiment in which two C. parapsilosis isolates were cultured in increasing concentrations of miltefosine. Two genes, CPAR2_303950 and CPAR2_102700, coding for putative PC flippases homologous to S. cerevisiae DNF1 gained homozygous protein-disrupting mutations in the evolved strains. Overall, our results show that C. parapsilosis can gain resistance to miltefosine, a drug that has recently been granted orphan drug designation approval by the United States Food and Drug Administration for the treatment of invasive candidiasis, through both CNVs or loss-of-function alleles in one of the flippase genes