174 research outputs found
Thermal (n, γ) cross section and resonance integral of 171Tm
Background: About 50% of the heavy elements are produced in stars during the slow neutron capture process.
The analysis of branching points allows us to set constraints on the temperature and the neutron density in the
interior of stars.
Purpose: The temperature dependence of the branch point 171Tm is weak. Hence, the 171Tm neutron capture
cross section can be used to constrain the neutron density during the main component of the s process in thermally
pulsing asymptotic giant branch (TP-AGB) stars.
Methods: A 171Tm sample produced at the ILL was activated with thermal and epithermal neutrons at the
TRIGA research reactor at the Johannes Gutenberg-Universität Mainz.
Results: The thermal neutron capture cross section and the resonance integral have been measured for the first
time to be σth = 9.9 ± 0.9 b and σRI = 193 ± 14 b.
Conclusions: Based on our results, new estimations of the direct capture components’ impact on the
Maxwellian-nAveraged cross sections (MACS) are possible.European Unions’s Seventh Framework Programme (FP/2007-2013
Characterization of the QUartz Photon Intensifying Detector (QUPID) for Noble Liquid Detectors
Dark Matter and Double Beta Decay experiments require extremely low
radioactivity within the detector materials. For this purpose, the University
of California, Los Angeles and Hamamatsu Photonics have developed the QUartz
Photon Intensifying Detector (QUPID), an ultra-low background photodetector
based on the Hybrid Avalanche Photo Diode (HAPD) and entirely made of
ultraclean synthetic fused silica. In this work we present the basic concept of
the QUPID and the testing measurements on QUPIDs from the first production
line. Screening of radioactivity at the Gator facility in the Laboratori
Nazionali del Gran Sasso has shown that the QUPIDs safely fulfill the low
radioactive contamination requirements for the next generation zero background
experiments set by Monte Carlo simulations. The quantum efficiency of the QUPID
at room temperature is > 30% at the xenon scintillation wavelength. At low
temperatures, the QUPID shows a leakage current less than 1 nA and a global
gain of 10^5. In these conditions, the photocathode and the anode show > 95%
linearity up to 1 uA for the cathode and 3 mA for the anode. The photocathode
and collection efficiency are uniform to 80% over the entire surface. In
parallel with single photon counting capabilities, the QUPIDs have a good
timing response: 1.8 +/- 0.1 ns rise time, 2.5 +/- 0.2 ns fall time, 4.20 +/-
0.05 ns pulse width, and 160 +/- 30 ps transit time spread. The QUPIDs have
also been tested in a liquid xenon environment, and scintillation light from
57Co and 210Po radioactive sources were observed.Comment: 15 pages, 22 figure
A Soluble Form of the High Affinity IgE Receptor, Fc-Epsilon-RI, Circulates in Human Serum
Soluble IgE receptors are potential in vivo modulators of
IgE-mediated immune responses and are thus important for our basic understanding
of allergic responses. We here characterize a novel soluble version of the
IgE-binding alpha-chain of Fc-epsilon-RI (sFcεRI), the high affinity
receptor for IgE. sFcεRI immunoprecipitates as a protein of ∼40 kDa and
contains an intact IgE-binding site. In human serum, sFcεRI is found as a
soluble free IgE receptor as well as a complex with IgE. Using a newly
established ELISA, we show that serum sFcεRI levels correlate with serum IgE
in patients with elevated IgE. We also show that serum of individuals with
normal IgE levels can be found to contain high levels of sFcεRI. After
IgE-antigen-mediated crosslinking of surface FcεRI, we detect sFcεRI in
the exosome-depleted, soluble fraction of cell culture supernatants. We further
show that sFcεRI can block binding of IgE to FcεRI expressed at the cell
surface. In summary, we here describe the alpha-chain of FcεRI as a
circulating soluble IgE receptor isoform in human serum
Remodeling the Proteostasis Network to Rescue Glucocerebrosidase Variants by Inhibiting ER-Associated Degradation and Enhancing ER Folding
Gaucher’s disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize the protein’s native folding leading to ER-associated degradation (ERAD) of the misfolded enzyme. Enhancing the cellular folding capacity by remodeling the proteostasis network promotes native folding and lysosomal activity of mutated GC variants. However, proteostasis modulators reported so far, including ERAD inhibitors, trigger cellular stress and lead to induction of apoptosis. We show herein that lacidipine, an L-type Ca2+ channel blocker that also inhibits ryanodine receptors on the ER membrane, enhances folding, trafficking and lysosomal activity of the most severely destabilized GC variant achieved via ERAD inhibition in fibroblasts derived from patients with GD. Interestingly, reprogramming the proteostasis network by combining modulation of Ca2+ homeostasis and ERAD inhibition remodels the unfolded protein response and dramatically lowers apoptosis induction typically associated with ERAD inhibition
IgE Mediated Autoallergy against Thyroid Peroxidase – A Novel Pathomechanism of Chronic Spontaneous Urticaria?
Chronic spontaneous urticaria (csU), which is characterized by recurrent episodes
of mast cell-driven wheal and flare-type skin reactions, is often associated with
elevated total IgE levels and thyroid autoimmunity. We speculate that some csU
patients express IgE autoantibodies against thyroid antigens such as thyroid
peroxidase (TPO), which could bind to skin mast cells and induce their
activation.We developed and used a site-directed human IgE capture ELISA to quantify
IgE-anti-TPO. We used this assay and investigated csU patients
(n = 478) and healthy control subjects
(n = 127) for IgE-anti-TPO and then assessed
IgE-anti-TPO-positive and -negative csU patients for clinical and serological
differences. ( = 61%, IgE-anti-TPO:
median 6.67, interquartile range 5.39–8.24). IgE-anti-TPO-positive and
-negative csU patients had very similar distributions of age and gender as well as
disease activity and duration. IgE-anti-TPO-positive csU patients exhibited
significantly higher IgG-anti-TPO levels and lymphocyte counts as well as
decreased C4 complement levels.Our findings show that a sizeable subgroup of csU patients expresses IgE
antibodies against thyroid peroxidase. These autoantibodies could cause
“autoallergic” mast cell activation, a novel pathomechanism of chronic
spontaneous urticaria
Intestinal, extra-intestinal and systemic sequelae of Toxoplasma gondii induced acute ileitis in mice harboring a human gut microbiota
Background Within seven days following peroral high dose infection with
Toxoplasma gondii susceptible conventionally colonized mice develop acute
ileitis due to an underlying T helper cell (Th) -1 type immunopathology. We
here addressed whether mice harboring a human intestinal microbiota developed
intestinal, extra-intestinal and systemic sequelae upon ileitis induction.
Methodology/Principal findings Secondary abiotic mice were generated by broad-
spectrum antibiotic treatment and associated with a complex human intestinal
microbiota following peroral fecal microbiota transplantation. Within three
weeks the human microbiota had stably established in the murine intestinal
tract as assessed by quantitative cultural and culture-independent (i.e.
molecular 16S rRNA based) methods. At day 7 post infection (p.i.) with 50
cysts of T. gondii strain ME49 by gavage human microbiota associated (hma)
mice displayed severe clinical, macroscopic and microscopic sequelae
indicating acute ileitis. In diseased hma mice increased numbers of innate and
adaptive immune cells within the ileal mucosa and lamina propria and elevated
intestinal secretion of pro-inflammatory mediators including IFN-γ, IL-12 and
nitric oxide could be observed at day 7 p.i. Ileitis development was
accompanied by substantial shifts in intestinal microbiota composition of hma
mice characterized by elevated total bacterial loads and increased numbers of
intestinal Gram-negative commensals such as enterobacteria and Bacteroides /
Prevotella species overgrowing the small and large intestinal lumen.
Furthermore, viable bacteria translocated from the inflamed ileum to extra-
intestinal including systemic compartments. Notably, pro-inflammatory immune
responses were not restricted to the intestinal tract as indicated by
increased pro-inflammatory cytokine secretion in extra-intestinal (i.e. liver
and kidney) and systemic compartments including spleen and serum.
Conclusion/Significance With respect to the intestinal microbiota composition
“humanized” mice display acute ileitis following peroral high dose T. gondii
infection. Thus, hma mice constitute a suitable model to further dissect the
interactions between pathogens, human microbiota and vertebrate host immunity
during acute intestinal inflammation
Ubiquitylation in ERAD: Reversing to Go Forward?
Proteins are co-translationally inserted into the endoplasmic reticulum (ER) where they undergo maturation. Homeostasis in the ER requires a highly sensitive and selective means of quality control. This occurs through ER-associated degradation (ERAD).This complex ubiquitin-proteasome–mediated process involves ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3),lumenal and cytosolic chaperones, and other proteins, including the AAA ATPase p97 (VCP; Cdc48 in yeast). Probing of processes involving proteasomal degradation has generally depended on proteasome inhibitors or knockdown of specific E2s or E3s. In this issue of PLoS Biology, Ernst et al. demonstrate the utility of expressing the catalytic domain of a viral deubiquitylating enzyme to probe the ubiquitin system. Convincing evidence is provided that deubiquitylation is integral to dislocation of ERAD substrates from the ER membrane. The implications of this work for understanding ERAD and the potential of expressing deubiquitylating enzyme domains for studying ubiquitin-mediated processes are discussed
Enzymatic Blockade of the Ubiquitin-Proteasome Pathway
Ubiquitin-dependent processes control much of cellular physiology. We show that expression of a highly active, Epstein-Barr virus-derived deubiquitylating enzyme (EBV-DUB) blocks proteasomal degradation of cytosolic and ER-derived proteins by preemptive removal of ubiquitin from proteasome substrates, a treatment less toxic than the use of proteasome inhibitors. Recognition of misfolded proteins in the ER lumen, their dislocation to the cytosol, and degradation are usually tightly coupled but can be uncoupled by the EBV-DUB: a misfolded glycoprotein that originates in the ER accumulates in association with cytosolic chaperones as a deglycosylated intermediate. Our data underscore the necessity of a DUB activity for completion of the dislocation reaction and provide a new means of inhibition of proteasomal proteolysis with reduced cytotoxicity.National Institutes of Health (U.S.)EMBO (long term Fellowship 2008-379)Boehringer Ingelheim Fond
Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila
The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration
- …