Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation

Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T > C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3+-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNɣ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/ɣ-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms

Pre-ALMA observations of GRBs in the mm/submm range

GRBs generate an afterglow emission that can be detected from radio to X-rays during days, or even weeks after the initial explosion. The peak of this emission crosses the mm/submm range during the first hours to days, making their study in this range crucial for constraining the models. Observations have been limited until now due to the low sensitivity of the observatories in this range. We present observations of 10 GRB afterglows obtained from APEX and SMA, as well as the first detection of a GRB with ALMA, and put them into context with all the observations that have been published until now in the spectral range that will be covered by ALMA. The catalogue of mm/submm observations collected here is the largest to date and is composed of 102 GRBs, of which 88 had afterglow observations, whereas the rest are host galaxy searches. With our programmes, we contributed with data of 11 GRBs and the discovery of 2 submm counterparts. In total, the full sample, including data from the literature, has 22 afterglow detections with redshift ranging from 0.168 to 8.2. GRBs have been detected in mm/submm wavelengths with peak luminosities spanning 2.5 orders of magnitude, the most luminous reaching 10^33erg s^-1 Hz^-1. We observe a correlation between the X-ray brightness at 0.5 days and the mm/submm peak brightness. Finally we give a rough estimate of the distribution of peak flux densities of GRB afterglows, based on the current mm/submm sample. Observations in the mm/submm bands have been shown to be crucial for our understanding of the physics of GRBs, but have until now been limited by the sensitivity of the observatories. With the start of the operations at ALMA, the sensitivity will be increased by more than an order of magnitude. Our estimates predict that, once completed, ALMA will detect up to 98% of the afterglows if observed during the passage of the peak synchrotron emission.Comment: 23 pages, 14 figures, 5 tables (one big one!), Accepted for publication in A&A. Includes the first observation of a GRB afterglow with ALM

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Is it really organic? - multi-isotopic analysis as a tool to discriminate between organic and conventional plants

Novel procedures for analytical authentication of organic plant products are urgently needed. Here we present the first study encompassing stable isotopes of hydrogen, carbon, nitrogen, oxygen, magnesium and sulphur as well as compound-specific nitrogen and oxygen isotope analysis of nitrate for discrimination of organically and conventionally grown plants. The study was based on wheat, barley, faba bean and potato produced in rigorously controlled long-term field trials comprising 144 experimental plots. Nitrogen isotope analysis revealed the use of animal manure, but was unable to discriminate between plants that were fertilized with synthetic nitrogen fertilizers or green manures from atmospheric nitrogen fixing legumes. This limitation was bypassed using oxygen isotope analysis of nitrate in potato tubers, while hydrogen isotope analysis allowed complete discrimination of organic and conventional wheat and barley grains. It is concluded, that multi-isotopic analysis has the potential to disclose fraudulent substitutions of organic with conventionally cultivated plants

Der Kampf um die Finanzierung der deutschen Einheit

Summary in EnglishAvailable from Bibliothek des Instituts fuer Weltwirtschaft, ZBW, Duesternbrook Weg 120, D-24105 Kiel W 281 (95.1) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman