Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy

Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications

Serum RANKL, osteoprotegerin (OPG), and RANKL/OPG ratio in nephrotic children

Receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG) play key roles in the pathogenesis of glucocorticoid-induced osteoporosis (GIO). The aim of our study was to determine whether the cumulative glucocorticoid dose (CGCS) in children with idiopathic nephrotic syndrome (INS) has any effect on the concentration of serum RANKL and OPG and the RANKL/OPG ratio. The study population consisted of 90 children with INS, aged 3–20 years, who were treated with GCS. These children were divided into two groups according to the CGCS: low (L) <1 g/kg body weight (BW) and high (H) ≥1 g/kg BW, respectively. The control group (C) consisted of 70 healthy children. RANKL concentration was observed to be significantly higher and OPG significantly lower in INS children than in the reference group: 0.21 (range 0.01–1.36) versus 0.15 (0–1.42) pmol/l (p < 0.05), respectively, and 3.76 (1.01–7.25) versus 3.92 (2.39–10.23) pmol/l (p < 0.05), respectively. The RANKL/OPG ratio was significantly higher in INS children (p < 0.01). The concentration of RANKL, similar to the RANKL/OPG ratio, was significantly higher in Group H children than in Group L children: 0.46 (0.02–1.36 ) versus 0.19 (0.01–1.25) (p < 0.01) and 0.14 (0.01–0.71) versus 0.05 (0.002–0.37) (p < 0.01), respectively. The concentration of OPG was similar in both groups. There was a positive correlation between CGCS and the concentration of sRANKL as well as the RANKL/OPG ratio (in both cases r = 0.33, p < 0.05). Based on these results, we suggest that long-term exposure to GCS results in a dose-dependent increase in serum RANKL concentration and the RANKL/OPG ratio, but not in the level of serum OPG

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides

The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

The field surrounding NGC 7603: cosmological or non-cosmological redshifts?

We present new observations of the field surrounding the Seyfert galaxy NGC 7603, where four galaxies with different redshifts--NGC 7603 (z=0.029), NGC 7603B (z=0.057) and two fainter emission line galaxies (z=0.245 and z=0.394)--are apparently connected by a narrow filament, leading to a possible case of anomalous redshift. The observations comprise broad and narrow band imaging and intermediate resolution spectroscopy of some of the objects in the field. The new data confirm the redshift of the two emission-line objects found within the filament connecting NGC 7603 and NGC 7603B, and settles their type with better accuracy. Although both objects are point-like in ground based images, using HST archive images we show that the objects have structure with a FWHM=0.3-0.4 arcsec. This and the relative strength and width of the main spectral lines allow us to classify these as HII galaxies with very vigorous star formation, while the rest of the filament and NGC 7603B lack star formation. We delineate the halo of NGC 7603 out to 26.2 mag/square arcsec in the Sloan r band filter and find evidence for strong internal distortions. New narrow emission line galaxies at z=0.246, 0.117 and 0.401 are also found at respectively 0.8, 1.5 and 1.7 arcmin to the West of the filament within the fainter contour of this halo. The probability of three background galaxies of any type with apparent B-magnitudes up to 16.6, 21.1 and 22.1 (the observed magnitudes, extinction correction included) being randomly projected on the filament of the fourth galaxy (NGC 7603) is computed resulting ~ 3 x 10^(-9).Comment: 34 pages, 9 figures, Astronomy & Astrophysics accepte

SKA Science Data Challenge 2: analysis and results

The Square Kilometre Array Observatory (SKAO) will explore the radio sky to new depths in order to conduct transformational science. SKAO data products made available to astronomers will be correspondingly large and complex, requiring the application of advanced analysis techniques to extract key science findings. To this end, SKAO is conducting a series of Science Data Challenges, each designed to familiarise the scientific community with SKAO data and to drive the development of new analysis techniques. We present the results from Science Data Challenge 2 (SDC2), which invited participants to find and characterise 233245 neutral hydrogen (Hi) sources in a simulated data product representing a 2000~h SKA MID spectral line observation from redshifts 0.25 to 0.5. Through the generous support of eight international supercomputing facilities, participants were able to undertake the Challenge using dedicated computational resources. Alongside the main challenge, `reproducibility awards' were made in recognition of those pipelines which demonstrated Open Science best practice. The Challenge saw over 100 participants develop a range of new and existing techniques, with results that highlight the strengths of multidisciplinary and collaborative effort. The winning strategy -- which combined predictions from two independent machine learning techniques to yield a 20 percent improvement in overall performance -- underscores one of the main Challenge outcomes: that of method complementarity. It is likely that the combination of methods in a so-called ensemble approach will be key to exploiting very large astronomical datasets.Comment: Under review by MNRAS; 28 pages, 16 figure

Correlated long-range mixed-harmonic fluctuations measured in pp, p+Pb and low-multiplicity Pb+Pb collisions with the ATLAS detector

For abstract see published article