1,522 research outputs found
Interleukin-1α Activity in Necrotic Endothelial Cells Is Controlled by Caspase-1 Cleavage of Interleukin-1 Receptor-2: IMPLICATIONS FOR ALLOGRAFT REJECTION.
Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection.This study was supported by British Heart Foundation Grants FS/09/005/26845, FS/13/3/30038 and FS/11/77/29327 (MCHC) & RG/13/14/30314 (MRB); the BHF Cambridge CRE; and the NIHR Cambridge BRC.This is the final version of the article. It first appeared from ASBMB via http://dx.doi.org/10.1074/jbc.M115.66791
Interatomic-Coulombic-decay-induced recapture of photoelectrons in helium dimers
We investigate the onset of photoionization shakeup induced interatomic
Coulombic decay (ICD) in He2 at the He+*(n = 2) threshold by detecting two He+
ions in coincidence. We find this threshold to be shifted towards higher
energies compared to the same threshold in the monomer. The shifted onset of
ion pairs created by ICD is attributed to a recapture of the threshold
photoelectron after the emission of the faster ICD electron.Comment: 5 Pages, 2 Figure
Vibrationally Resolved Decay Width of Interatomic Coulombic Decay in HeNe
We investigate the ionization of HeNe from below the He 1s3p excitation to
the He ionization threshold. We observe HeNe ions with an enhancement by
more than a factor of 60 when the He side couples resonantly to the radiation
field. These ions are an experimental proof of a two-center resonant
photoionization mechanism predicted by Najjari et al. [Phys. Rev. Lett. 105,
153002 (2010)]. Furthermore, our data provide electronic and vibrational state
resolved decay widths of interatomic Coulombic decay (ICD) in HeNe dimers. We
find that the ICD lifetime strongly increases with increasing vibrational
state.Comment: 7 pages, 5 figure
A measurement of the evolution of Interatomic Coulombic Decay in the time domain
During the last 15 years a novel decay mechanism of excited atoms has been
discovered and investigated. This so called ''Interatomic Coulombic Decay''
(ICD) involves the chemical environment of the electronically excited atom: the
excitation energy is transferred (in many cases over long distances) to a
neighbor of the initially excited particle usually ionizing that neighbor. It
turned out that ICD is a very common decay route in nature as it occurs across
van-der-Waals and hydrogen bonds. The time evolution of ICD is predicted to be
highly complex, as its efficiency strongly depends on the distance of the atoms
involved and this distance typically changes during the decay. Here we present
the first direct measurement of the temporal evolution of ICD using a novel
experimental approach.Comment: 6 pages, 4 figures, submitted to PR
Peripheral N Scattering: A Tool For Identifying The Two Pion Exchange Component Of The NN Potential
We study elastic N scattering and produce a quantitative correlation
between the range of the effective potential and the energy of the system. This
allows the identification of the waves and energies for which the scattering
may be said to be peripheral. We then show that the corresponding phase shifts
are sensitive to the tail of the NN potential, which is due to the exchange of
two pions. However, the present uncertainties in the experimental phase shifts
prevent the use of N scattering to discriminate the existing models
for the NN interaction.Comment: 19 pages, 6 PostScript figures, RevTeX, to be appear in Phys. Rev.
Alpha scattering and capture reactions in the A = 7 system at low energies
Differential cross sections for He- scattering were measured in
the energy range up to 3 MeV. These data together with other available
experimental results for He and H scattering were
analyzed in the framework of the optical model using double-folded potentials.
The optical potentials obtained were used to calculate the astrophysical
S-factors of the capture reactions HeBe and
HLi, and the branching ratios for the transitions into
the two final Be and Li bound states, respectively. For
HeBe excellent agreement between calculated and
experimental data is obtained. For HLi a value
has been found which is a factor of about 1.5 larger than the adopted value.
For both capture reactions a similar branching ratio of has been obtained.Comment: submitted to Phys.Rev.C, 34 pages, figures available from one of the
authors, LaTeX with RevTeX, IK-TUW-Preprint 930540
A Rare Myelin Protein Zero (MPZ) Variant Alters Enhancer Activity In Vitro and In Vivo
expression. variants. that resides within a previously described SOX10 binding site is associated with decreased enhancer activity, and alters binding of nuclear proteins. Additionally, the genomic segment harboring this variant directs tissue-relevant reporter gene expression in zebrafish. variant within a cis-acting transcriptional regulatory element. While we were unable to implicate this variant in disease onset, our data suggests that similar non-coding sequences should be screened for mutations in patients with neurological disease. Furthermore, our multi-faceted approach for examining the functional significance of non-coding variants can be readily generalized to study other loci important for myelin structure and function
Hirschsprung disease, associated syndromes and genetics: A review
Hirschsprung disease (HSCR, aganglionic megacolon) represents the main genetic cause of functional intestinal obstruction with an incidence of 1/5000 live births. This developmental disorder is a neurocristopathy and is characterised by the absence of the enteric ganglia along a variable length of the intestine. In the last decades, the development of surgical approaches has importantly decreased mortality and morbidity which allowed the emergence of familial cases. Isolated HSCR appears to be a non-Mendelian malformation with low, sex-dependent penetrance, and variable expression according to the length of the aganglionic segment. While all Mendelian modes of inheritance have been described in syndromic HSCR, isolated HSCR stands as a model for genetic disorders with complex patterns of inheritance. The tyrosine kinase receptor RET is the major gene with both rare coding sequence mutations and/or a frequent variant located in an enhancer element predisposing to the disease. Hitherto, 10 genes and five loci have been found to be involved in HSCR development.published_or_final_versio
Fine mapping of the 9q31 Hirschsprung’s disease locus
Hirschsprung’s disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 × 10−6 [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system
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
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