Search for photonic signatures of gauge-mediated supersymmetry in 13 TeV pp collisions with the ATLAS detector

A search is presented for photonic signatures, motivated by generalized models of gauge-mediated supersymmetry breaking. This search makes use of proton-proton collision data at √s = 13 TeV corresponding to an integrated luminosity of 36.1 fb −1 recorded by the ATLAS detector at the LHC, and it explores models dominated by both strong and electroweak production of supersymmetric partner states. Experimental signatures incorporating an isolated photon and significant missing transverse momentum are explored. These signatures include events with an additional photon or additional jet activity not associated with any specific underlying quark flavor. No significant excess of events is observed above the Standard Model prediction, and 95% confidence-level upper limits of between 0.083 fb and 0.32 fb are set on the visible cross section of contributions from physics beyond the Standard Model. These results are interpreted in terms of lower limits on the masses of gluinos, squarks, and gauginos in the context of generalized models of gauge-mediated supersymmetry, which reach as high as 2.3 TeV for strongly produced and 1.3 TeV for weakly produced supersymmetric partner pairs

Search for High-Mass Resonances Decaying to τν in pp Collisions at √s=13 TeV with the ATLAS Detector

A search for high-mass resonances decaying to τν using proton-proton collisions at √s=13 TeV produced by the Large Hadron Collider is presented. Only τ-lepton decays with hadrons in the final state are considered. The data were recorded with the ATLAS detector and correspond to an integrated luminosity of 36.1 fb−1. No statistically significant excess above the standard model expectation is observed; model-independent upper limits are set on the visible τν production cross section. Heavy W′ bosons with masses less than 3.7 TeV in the sequential standard model and masses less than 2.2–3.8 TeV depending on the coupling in the nonuniversal G(221) model are excluded at the 95% credibility level

Influence of clouds on the spectral actinic flux density in the lower troposphere (INSPECTRO): overview of the field campaigns

Ultraviolet radiation is the key factor driving tropospheric photochemistry. It is strongly modulated by clouds and aerosols. A quantitative understanding of the radiation field and its effect on photochemistry is thus only possible with a detailed knowledge of the interaction between clouds and radiation. The overall objective of the project INSPECTRO was the characterization of the three-dimensional actinic radiation field under cloudy conditions. This was achieved during two measurement campaigns in Norfolk (East Anglia, UK) and Lower Bavaria (Germany) combining space-based, aircraft and ground-based measurements as well as simulations with the one-dimensional radiation transfer model UVSPEC and the three-dimensional radiation transfer model MYSTIC. During both campaigns the spectral actinic flux density was measured at several locations at ground level and in the air by up to four different aircraft. This allows the comparison of measured and simulated actinic radiation profiles. In addition satellite data were used to complete the information of the three dimensional input data set for the simulation. A three-dimensional simulation of actinic flux density data under cloudy sky conditions requires a realistic simulation of the cloud field to be used as an input for the 3-D radiation transfer model calculations. Two different approaches were applied, to derive high- and low-resolution data sets, with a grid resolution of about 100 m and 1 km, respectively. The results of the measured and simulated radiation profiles as well as the results of the ground based measurements are presented in terms of photolysis rate profiles for ozone and nitrogen dioxide. During both campaigns all spectroradiometer systems agreed within ±10% if mandatory corrections e.g. stray light correction were applied. Stability changes of the systems were below 5% over the 4 week campaign periods and negligible over a few days. The J(O1D) data of the single monochromator systems can be evaluated for zenith angles less than 70°, which was satisfied by nearly all airborne measurements during both campaigns. The comparison of the airborne measurements with corresponding simulations is presented for the total, downward and upward flux during selected clear sky periods of both campaigns. The compliance between the measured (from three aircraft) and simulated downward and total flux profiles lies in the range of ±15%.© Author(s) 2008. This work is distributed under the Creative Commons Attribution 3.0 License

Human-like PB2 627K Influenza Virus Polymerase Activity Is Regulated by Importin-α1 and -α7

Influenza A viruses may cross species barriers and transmit to humans with the potential to cause pandemics. Interplay of human- (PB2 627K) and avian-like (PB2 627E) influenza polymerase complexes with unknown host factors have been postulated to play a key role in interspecies transmission. Here, we have identified human importin-α isoforms (α1 and α7) as positive regulators of human- but not avian-like polymerase activity. Human-like polymerase activity correlated with efficient recruitment of α1 and α7 to viral ribonucleoprotein complexes (vRNPs) without affecting subcellular localization. We also observed that human-like influenza virus growth was impaired in α1 and α7 downregulated human lung cells. Mice lacking α7 were less susceptible to human- but not avian-like influenza virus infection. Thus, α1 and α7 are positive regulators of human-like polymerase activity and pathogenicity beyond their role in nuclear transport

Efficient Nuclear Transport of Structurally Disturbed Cargo: Mutations in a Cargo Protein Switch Its Cognate Karyopherin

The Karyopherin (Kap) family of nuclear transport receptors enables trafficking of proteins to and from the nucleus in a precise, regulated manner. Individual members function in overlapping pathways, while simultaneously being very specific for their main cargoes. The details of this apparent contradiction and rules governing pathway preference remain to be further elucidated. S. cerevisiae Lhp1 is an abundant protein that functions as an RNA chaperone in a variety of biologically important processes. It localizes almost exclusively to the nucleus and is imported by Kap108. We show that mutation of 3 of the 275 residues in Lhp1 alters its import pathway to a Kap121-dependent process. This mutant does not retain wild-type function and is bound by several chaperones. We propose that Kap121 also acts as a chaperone, one that can act as a genetic buffer by transporting mutated proteins to the nucleus

Exportin 4 Interacts with Sox9 through the HMG Box and Inhibits the DNA Binding of Sox9

Sox9 is a transcription factor that is required for tissue development in mammals. In general, such transcription factors require co-regulators for precise temporal and spatial control of the activation and inactivation of the numerous genes necessary for precise development during embryogenesis. Here we identify a new Sox9 co-regulator: Using affinity chromatography with immobilized Sox9 protein, we identified exportin 4 (Exp4) as an interacting protein of Sox9 in human cultured cells. Interaction between endogenous Exp4 and Sox9 proteins was confirmed in the human osteosarcoma U2OS cells by immunoprecipitation experiments using anti-Sox9 antibody. siRNA depletion of Exp4 enhanced transcription of Sox9 target genes in U2OS cells, but did not affect nuclear localization of Sox9. These results suggest that Exp4 regulates Sox9 activity in the nucleus. Furthermore we found that the HMG box of Sox9 was responsible for binding to Exp4, and the HMG box was required for suppression of Sox9-mediated transcription. This contrasts with the known Sox9 co-regulators which bind to its transcriptional activation domain. Chromatin immunoprecipitation analyses revealed that Exp4 prevents Sox9 binding to the enhancers of its target genes. These results demonstrate that Exp4 acts as a Sox9 co-regulator that directly regulates binding of Sox9 to its target genes

Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis

Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu

The role of the proteasome in the generation of MHC class I ligands and immune responses

The ubiquitin–proteasome system (UPS) degrades intracellular proteins into peptide fragments that can be presented by major histocompatibility complex (MHC) class I molecules. While the UPS is functional in all mammalian cells, its subunit composition differs depending on cell type and stimuli received. Thus, cells of the hematopoietic lineage and cells exposed to (pro)inflammatory cytokines express three proteasome immunosubunits, which form the catalytic centers of immunoproteasomes, and the proteasome activator PA28. Cortical thymic epithelial cells express a thymus-specific proteasome subunit that induces the assembly of thymoproteasomes. We here review new developments regarding the role of these different proteasome components in MHC class I antigen processing, T cell repertoire selection and CD8 T cell responses. We further discuss recently discovered functions of proteasomes in peptide splicing, lymphocyte survival and the regulation of cytokine production and inflammatory responses

Additive effects of LPL, APOA5 and APOE variant combinations on triglyceride levels and hypertriglyceridemia: results of the ICARIA genetic sub-study

<p>Abstract</p> <p>Background</p> <p>Hypertriglyceridemia (HTG) is a well-established independent risk factor for cardiovascular disease and the influence of several genetic variants in genes related with triglyceride (TG) metabolism has been described, including <it>LPL</it>, <it>APOA5 </it>and <it>APOE</it>. The combined analysis of these polymorphisms could produce clinically meaningful complementary information.</p> <p>Methods</p> <p>A subgroup of the ICARIA study comprising 1825 Spanish subjects (80% men, mean age 36 years) was genotyped for the <it>LPL</it>-HindIII (rs320), S447X (rs328), D9N (rs1801177) and N291S (rs268) polymorphisms, the <it>APOA5</it>-S19W (rs3135506) and -1131T/C (rs662799) variants, and the <it>APOE </it>polymorphism (rs429358; rs7412) using PCR and restriction analysis and TaqMan assays. We used regression analyses to examine their combined effects on TG levels (with the log-transformed variable) and the association of variant combinations with TG levels and hypertriglyceridemia (TG ≥ 1.69 mmol/L), including the covariates: gender, age, waist circumference, blood glucose, blood pressure, smoking and alcohol consumption.</p> <p>Results</p> <p>We found a significant lowering effect of the <it>LPL</it>-HindIII and S447X polymorphisms (<it>p </it>< 0.0001). In addition, the D9N, N291S, S19W and -1131T/C variants and the <it>APOE</it>-ε4 allele were significantly associated with an independent additive TG-raising effect (<it>p </it>< 0.05, <it>p </it>< 0.01, <it>p </it>< 0.001, <it>p </it>< 0.0001 and <it>p </it>< 0.001, respectively). Grouping individuals according to the presence of TG-lowering or TG-raising polymorphisms showed significant differences in TG levels (<it>p </it>< 0.0001), with the lowest levels exhibited by carriers of two lowering variants (10.2% reduction in TG geometric mean with respect to individuals who were homozygous for the frequent alleles of all the variants), and the highest levels in carriers of raising combinations (25.1% mean TG increase). Thus, carrying two lowering variants was protective against HTG (OR = 0.62; 95% CI, 0.39-0.98; <it>p </it>= 0.042) and having one single raising polymorphism (OR = 1.20; 95% CI, 1.39-2.87; <it>p </it>< 0.001) or more (2 or 3 raising variants; OR = 2.90; 95% CI, 1.56-5.41; <it>p </it>< 0.001) were associated with HTG.</p> <p>Conclusion</p> <p>Our results showed a significant independent additive effect on TG levels of the <it>LPL </it>polymorphisms HindIII, S447X, D9N and N291S; the S19W and -1131T/C variants of <it>APOA5</it>, and the ε4 allele of <it>APOE </it>in our study population. Moreover, some of the variant combinations studied were significantly associated with the absence or the presence of hypertriglyceridemia.</p

Chromosome 7 and 19 Trisomy in Cultured Human Neural Progenitor Cells

BACKGROUND:Stem cell expansion and differentiation is the foundation of emerging cell therapy technologies. The potential applications of human neural progenitor cells (hNPCs) are wide ranging, but a normal cytogenetic profile is important to avoid the risk of tumor formation in clinical trials. FDA approved clinical trials are being planned and conducted for hNPC transplantation into the brain or spinal cord for various neurodegenerative disorders. Although human embryonic stem cells (hESCs) are known to show recurrent chromosomal abnormalities involving 12 and 17, no studies have revealed chromosomal abnormalities in cultured hNPCs. Therefore, we investigated frequently occurring chromosomal abnormalities in 21 independent fetal-derived hNPC lines and the possible mechanisms triggering such aberrations. METHODS AND FINDINGS:While most hNPC lines were karyotypically normal, G-band karyotyping and fluorescent in situ hybridization (FISH) analyses revealed the emergence of trisomy 7 (hNPC(+7)) and trisomy 19 (hNPC(+19)), in 24% and 5% of the lines, respectively. Once detected, subsequent passaging revealed emerging dominance of trisomy hNPCs. DNA microarray and immunoblotting analyses demonstrate epidermal growth factor receptor (EGFR) overexpression in hNPC(+7) and hNPC(+19) cells. We observed greater levels of telomerase (hTERT), increased proliferation (Ki67), survival (TUNEL), and neurogenesis (beta(III)-tubulin) in hNPC(+7) and hNPC(+19), using respective immunocytochemical markers. However, the trisomy lines underwent replicative senescence after 50-60 population doublings and never showed neoplastic changes. Although hNPC(+7) and hNPC(+19) survived better after xenotransplantation into the rat striatum, they did not form malignant tumors. Finally, EGF deprivation triggered a selection of trisomy 7 cells in a diploid hNPC line. CONCLUSIONS:We report that hNPCs are susceptible to accumulation of chromosome 7 and 19 trisomy in long-term cell culture. These results suggest that micro-environmental cues are powerful factors in the selection of specific hNPC aneuploidies, with trisomy of chromosome 7 being the most common. Given that a number of stem cell based clinical trials are being conducted or planned in USA and a recent report in PLoS Medicine showing the dangers of grafting an inordinate number of cells, these data substantiate the need for careful cytogenetic evaluation of hNPCs (fetal or hESC-derived) before their use in clinical or basic science applications