Background Allergy vaccines should be easily applicable, safe, and efficacious. For Bet v 1–mediated birch pollen and associated food allergies, a single wild-type allergen does not provide a ...complete solution. Objective We aimed to combine immunologically relevant epitopes of Bet v 1 and the 2 clinically most important related food allergens from apple and hazelnut to a single hybrid protein, termed MBC4. Methods After identification of T cell epitope–containing parts on each of the 3 parental allergens, the hybrid molecule was designed to cover relevant epitopes and evaluated in silico . Thereby a mutation was introduced into the hybrid sequence, which should alter the secondary structure without compromising the immunogenic properties of the molecule. Results MBC4 and the parental allergens were purified to homogeneity. Analyses of secondary structure elements revealed substantial changes rendering the hybrid de facto nonreactive with patients' serum IgE. Nevertheless, the protein was monomeric in solution. MBC4 was able to activate T-cell lines from donors with birch pollen allergy and from mice immunized with the parental allergens. Moreover, on immunization of mice and rabbits, MBC4 induced cross-reactive IgG antibodies, which were able to block the binding of human serum IgE. Conclusion Directed epitope rearrangements combined with a knowledge-based structural modification resulted in a protein unable to bind IgE from allergic patients. Still, properties to activate specific T cells or induce blocking antibodies were conserved. This suggests that MBC4 is a suitable vaccine candidate for the simultaneous treatment of Bet v 1 and associated food allergies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
Objective
To evaluate tender joints (TJ) and swollen joints (SJ) for the assessment of ultrasound (US) defined inflammation in PsA.
Methods
Eighty-three PsA patients underwent clinical and ...US examinations at two scheduled study visits 12 months apart. Tenderness and swelling were assessed at 68 and 66 joints, respectively, and US examinations were conducted at all 68 joints. At patient level, associations with clinical composites and US scores were performed using correlations and by analysing patients with predominantly tender (pTender) or swollen joints (pSwollen). At joint level, a Power Doppler (PD) value ≥ 1 was defined as active synovitis. A generalized linear mixed model was created to assess the predictive value of TJ and SJ for active synovitis after 12 months.
Results
SJC showed better correlations with GS/PD scores (r = 0.37/0.47) than with TJC (PD: r = 0.33), while TJC correlated better with patient reported outcomes (PROMs) like patient global assessment (TJC: r = 0.57; SJC r = 0.39). Patients with pTender showed poorer results for PROMs and disease activity scores than patients with pSwollen, but not for laboratory or US markers of inflammation. Swollen joints showed active synovitis in 35% of cases, while only 16% of tender joints were active according to US. Swelling at baseline better predicted active synovitis at the same joint after 12 months odds ratio (OR) 6.33, P <0.001 as compared with tenderness (OR 3.58, P <0.001).
Conclusions
SJ are more closely linked with US signs of inflammation as compared with TJ in PsA. Joint swelling is a better predictor for signs of US inflammation than tenderness after one year of follow-up.
Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail ...in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA.
The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1–6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA).
We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations.
Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.
•Analysis of active STAT signaling in peripheral leucocytes identifies distinct clusters of RA patients.•In a subset of RA patients JAK/STAT signaling in leucocytes is inactive despite active disease.•In patients with recent-onset RA JAK/STAT signaling is reduced irrespective of up-stream cytokines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
44.
HE-LHC: The High-Energy Large Hadron Collider Altmannshofer, W.; Arsenyev, S. A.; Azatov, A. ...
The European physical journal. ST, Special topics,
2019, Volume:
228, Issue:
5
Journal Article
Peer reviewed
Open access
In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. ...The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Publikationsberatung an Universitäten Karin Lackner, Lisa Schilhan, Christian Kaier / Karin Lackner, Lisa Schilhan, Christian Kaier
2020, 202005
eBook, Book
Open access
Die Publikationsberatung ist ein stetig wichtiger werdendes Feld für Universitäten und ihre Bibliotheken. Sie stellt eine erfolgreiche Verbreitung von Forschungsergebnissen sicher und unterstützt vor ...allem junge Forschende. Die Autor*innen des Bandes liefern sowohl für Mitarbeiter*innen aus der Verwaltung als auch aus der Wissenschaft grundlegende Informationen zu zahlreichen Aspekten des wissenschaftlichen Publikationsprozesses sowie zu relevanten Themen der Publikationsberatung. Dabei vermitteln sie praktische Erfahrungen aus unterschiedlichen Einrichtungen und bieten Anregungen und Empfehlungen für Angebote zur Publikationsunterstützung: grundlegendes Know-how für den Auf- und Ausbau eines bedarfsgerechten Publikationsservices.
Managing the tension between efficiency and flexibility is one of the core challenges that organizations must tackle in order to survive in the global competitive environment. Ambidexterity has been ...identified in the literature as a key way of managing this tension. Despite the enormous popularity of the concept of ambidexterity, the questions of how HR practices influence exploration and exploitation and support organizational ambidexterity remain underexplored. Drawing on our empirical case studies of three mid-sized 'hidden champions' in different high-tech manufacturing industries, we show how an ambidextrous human resource management (HRM) system works. We demonstrate that ambidextrous HRM systems can be regarded as a special type of high-performance work system (HPWS) that facilitates the continuous integration of exploration and exploitation in the pursuit of flexibility and efficiency. In particular, we elucidate how firms apply integrative employment practices and integrative work practices to facilitate collaboration and to create and strengthen a common frame of reference that fosters knowledge integration. Finally, setting up an ambidextrous HRM system supports the complementary interplay between a common frame of reference and a firm's ability to integrate knowledge in order to manage the conflicting demands of exploration and exploitation.
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BFBNIB, IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
Nitration of pollen derived allergens can occur by NO(2) and ozone in polluted air and it has already been shown that nitrated major birch (Betula verrucosa) pollen allergen Bet v 1.0101 (Bet v 1) ...exhibits an increased potency to trigger an immune response. However, the mechanisms by which nitration might contribute to the induction of allergy are still unknown. In this study, we assessed the effect of chemically induced nitration of Bet v 1 on the generation of HLA-DR associated peptides. Human dendritic cells were loaded with unmodified Bet v 1 or nitrated Bet v 1, and the naturally processed HLA-DR associated peptides were subsequently identified by liquid chromatography-mass spectrometry. Nitration of Bet v 1 resulted in enhanced presentation of allergen-derived HLA-DR-associated peptides. Both the copy number of Bet v 1 derived peptides as well as the number of nested clusters was increased. Our study shows that nitration of Bet v 1 alters antigen processing and presentation via HLA-DR, by enhancing both the quality and the quantity of the Bet v 1-specific peptide repertoire. These findings indicate that air pollution can contribute to allergic diseases and might also shed light on the analogous events concerning the nitration of self-proteins.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pollen is one of the most common causes of allergy worldwide, making the study of their molecular composition crucial for the advancement of allergy research. Despite substantial efforts in this ...field, it is not yet clear why some plant pollens strongly provoke allergies while others do not. However, proteases and protease inhibitors from allergen sources are known to play an important role in the development of pollen allergies. In this study, we aim to uncover differences in the transcriptional pattern of proteases and protease inhibitors in
and
pollen as models for high and low allergenic potential, respectively. We applied RNA sequencing to
and
pollen. After de-novo assembly we derived general functional profiles of the protein coding transcripts. By utilization of domain based functional annotation we identified potential proteases and protease inhibitors and compared their expression in the two types of pollen. Functional profiles are highly similar between
and
pollen. Both pollen contain proteases and inhibitors from 53 and 7 Pfam families, respectively. Some of the members comprised within those families are implicated in facilitating allergen entry, while others are known allergens themselves. Our work revealed several candidate proteins which, with further investigation, represent exciting new leads in elucidating the process behind allergic sensitization.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
B-cell depleting therapies result in diminished humoral immunity following vaccination against COVID-19, but our understanding on the impact on cellular immune responses is limited. Here, we ...performed a detailed analysis of cellular immunity following mRNA vaccination in patients receiving B-cell depleting therapy using ELISpot assay and flow cytometry. Anti-SARS-CoV-2 spike receptor-binding domain antibody assays were performed to elucidate B-cell responses. To complement our cellular analysis, we performed immunophenotyping for T- and B-cell subsets. We show that SARS-CoV-2 vaccination using mRNA vaccines elicits cellular T-cell responses in patients under B-cell depleting therapy. Some facets of this immune response including TNFα production of CD4+ T-cells and granzyme B production of CD8+ T-cells, however, are distinctly diminished in these patients. Consequently, it appears that the finely coordinated process of T-cell activation with a uniform involvement of CD4+ and CD8+ T-cells as seen in HCs is disturbed in autoimmune patients. In addition, we observed that immune cell composition does impact cellular immunity as well as sustainability of anti-spike antibody titers. Our data suggest disturbed cellular immunity following mRNA vaccination in patients treated with B-cell depleting therapy. Immune cell composition may be an important determinant for vaccination efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The sampling error of Global Positioning System (GPS) radio occultation (RO) derived temperature climatologies is computed over a representative time span of 2 years and compared for Sun‐synchronous ...and non‐Sun‐synchronous Low Earth Orbit (LEO) satellites. The main focus lies on the sampling error's local time component, which is caused by incomplete sampling of the diurnal cycle and which depends on the geometry of the satellite orbits. The Sun‐synchronous satellite MetOp (Meteorological Operational European weather satellite) and the non‐Sun‐synchronous satellite CHAMP (Challenging Minisatellite Payload), both carrying GPS RO instruments on board, serve as representative cases. For the Sun‐synchronous satellite MetOp the local time component remains constant during the whole observation period such that the magnitude of the local time errors in monthly mean or longer‐term mean RO climatologies is generally lower than ±0.1 K. Except for potential long‐term effects of global warming on the diurnal cycle, which might require calibration, this small local time component is stable on decadal timescales and is mainly positive in the Northern Hemisphere and at low latitudes, whereas it is mainly negative in the Southern Hemisphere. These features are attributable to a slight orbit‐determined asymmetry in local time sampling. The typical (temporally stable) local time error of an annual mean MetOp climatology resolved into 18 zonal bands amounts to ∼0.04 K. For the non‐Sun‐synchronous satellite CHAMP the local time error component in monthly mean RO climatologies is also small (up to about ±0.15 K) but more variable (about zero mean) at middle and high latitudes. At low latitudes it results in sinusoidally varying positive and negative deviations with a several‐months period, resulting from the local time drift of the satellite. The magnitude of local time errors is slightly larger compared to MetOp since the monthly averaging period is too short for CHAMP to entirely sample a diurnal cycle; a longer averaging period further decreases CHAMP's local time component. An annual mean climatology resolved into 18 zonal bands shows for CHAMP a typical local time residual error component of ∼0.03 K. The overall evidence is that even with single RO satellites, monthly climatologies of high accuracy (sampling error <0.3 K) with the local time component being a minor part (<0.1 K to 0.15 K) can be obtained.
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