Prospective assessment of pre-existing and de novo anti-HLA IgE in kidney, liver, lung and heart transplantation

IntroductionAntibody mediated rejection (ABMR) is a major factor limiting outcome after organ transplantation. Anti-HLA donor-specific antibodies (DSA) of the IgG isotype are mainly responsible for ABMR. Recently DSA of the IgE isotype were demonstrated in murine models as well as in a small cohort of sensitized transplant recipients. In the present study, we aimed to determine the frequency of pre-existing and de novo anti-HLA IgE antibodies in a cohort of 105 solid organ transplant recipients.MethodsWe prospectively measured anti-HLA IgE antibodies in a cohort of kidney (n=60), liver, heart and lung (n=15 each) transplant recipients before and within one-year after transplantation, employing a single-antigen bead assay for HLA class I and class II antigens. Functional activity of anti-HLA IgE antibodies was assessed by an in vitro mediator release assay. Antibodies of the IgG1-4 subclasses and Th1 and Th2 cytokines were measured in anti-HLA IgE positive patients.ResultsPre-existing anti-HLA IgE antibodies were detected in 10% of renal recipients (including 3.3% IgE-DSA) and in 4.4% of non-renal solid organ transplant recipients (heart, liver and lung cohort). Anti-HLA IgE occurred only in patients that were positive for anti-HLA IgG, and most IgE positive patients had had a previous transplant. Only a small fraction of patients developed de novo anti-HLA IgE antibodies (1.7% of kidney recipients and 4.4% of non-renal recipients), whereas no de novo IgE-DSA was detected. IgG subclass antibodies showed a distinct pattern in patients who were positive for anti-HLA IgE. Moreover, patients with anti-HLA IgE showed elevated Th2 and also Th1 cytokine levels. Serum from IgE positive recipients led to degranulation of basophils in vitro, demonstrating functionality of anti-HLA IgE.DiscussionThese data demonstrate that anti-HLA IgE antibodies occur at low frequency in kidney, liver, heart and lung transplant recipients. Anti-HLA IgE development is associated with sensitization at the IgG level, in particular through previous transplants and distinct IgG subclasses. Taken together, HLA specific IgE sensitization is a new phenomenon in solid organ transplant recipients whose potential relevance for allograft injury requires further investigation

Investigations of the Mars Upper Atmosphere with ExoMars Trace Gas Orbiter

The Martian mesosphere and thermosphere, the region above about 60 km, is not the primary target of the ExoMars 2016 mission but its Trace Gas Orbiter (TGO) can explore it and address many interesting issues, either in-situ during the aerobraking period or remotely during the regular mission. In the aerobraking phase TGO peeks into thermospheric densities and temperatures, in a broad range of latitudes and during a long continuous period. TGO carries two instruments designed for the detection of trace species, NOMAD and ACS, which will use the solar occultation technique. Their regular sounding at the terminator up to very high altitudes in many different molecular bands will represent the first time that an extensive and precise dataset of densities and hopefully temperatures are obtained at those altitudes and local times on Mars. But there are additional capabilities in TGO for studying the upper atmosphere of Mars, and we review them briefly. Our simulations suggest that airglow emissions from the UV to the IR might be observed outside the terminator. If eventually confirmed from orbit, they would supply new information about atmospheric dynamics and variability. However, their optimal exploitation requires a special spacecraft pointing, currently not considered in the regular operations but feasible in our opinion. We discuss the synergy between the TGO instruments, specially the wide spectral range achieved by combining them. We also encourage coordinated operations with other Mars-observing missions capable of supplying simultaneous measurements of its upper atmosphere

Literary heritage of Panteleymon Romanov, 1883-1938

The purpose of this thesis is to establish the importance of Panteleymon Romanov in Soviet literature. Even though Romanov began writing many years before the Revolution, he became known as an author only after the Revolution when he published "Childhood", his first work, in 1920. Little success attended this effort. However, like any true artist he was not interested in writing merely to gain fame, but more to express his philosophy of life. He adopted the realistic style of the classical writers of the 19th Century and applied it to the conditions created by the Revolution and post-Revolutionary period. Thus he mirrored the life around him. At the time of War-Communism, 1917-1921, when most of the writers were engaged in political and internal struggle to define the path that the new literature was to take, Romanov wrote several volumes of humorous short stories on how the peasants greeted the political changes. By rewriting these humorous stories in a serious vein, he incorporated them into his greatest work under the title "Rus". His stories about the younger members of society and their attitudes toward love were also very popular. In these stories on love Romanov described the new attitude towards sex relationships between young people, the position of the unmarried mother, and the new family life without the sacrament of the church. His best stories on this theme are: "Without Cherry Blossom", "The Big Family", "The Right to Love" and the novel "The New Commandment". These were all widely read and discussed among the Komsomols and npn-Komsomols alike. Towards the end of the N.E.P. period, Romanov became more interested in the social conduct of the old intelligentsia as applied to its relationship with the new government. One of his best known stories of this period is "The Right to Live" which deals with a non-Party writer who tried unsuccessfully to conform to the demands of the Party. Romanov has developed this theme further in his novel "Comrade Kislyakov". In these two novels, Romanov expressed his regret that intellectuals did not have heroic qualities, energy, and will power to fight for their political and human rights. Romanov has often been regarded as a controversial writer both by the Soviet and the emigreé critics. The latter accused Romanov of slandering the morals of the old intelligentsia, while most of the former accused him of being blind to the growth of the Soviet masses because he had not accepted the Revolution. In studying literary life in the first decade of the Soviet government, one can say that Romanov and his works occupied a singular position of importance in Soviet literature. Romanov's style being easy and old-fashioned appealed to the masses. The humorous incidents in his stories, unlike those of Zoshchenko or O'Henry, follow one another continuously. Romanov also differs from Zoshchenko in the description of his heroes. Whereas Zoshchenko emphasises the individual characters, Romanov, on the contrary, develops the importance of the people, as a whole. He can truly be regarded as a popular sociological writer. After the Revolution, Romanov took the position of an independent creative writer and he maintained it as such until 1936. He insisted on his freedom to write what his conscience dictated and he never changed his position. For this reason a conflict between himself and the Soviet government was inevitable. After the confiscation of his work, "Comrade Kislyakov" in 1930, the doors to the publishing houses were closed for Romanov. However, through the intervention of Bukharin, the ban was lifted in 1936 when some of his short sketches about his excursion to the Molotov automobile factory in Nizhni-Novgorod were published. When Romanov died in 1938 of heart disease, there was no obituary notice from the Writers1 Union. Thus a bright star faded from the galaxy of Soviet literature, without any literary astronomer noticing it. Even today none of his works is published in the U.S.S.R. and he is not counted among those who have made a worthy contribution to Soviet letters.Arts, Faculty ofCentral, Eastern, and Northern European Studies, Department ofGraduat

Die Pflegeinitiative aus pflegewissenschaftlicher Perspektive: Wie pflegewissenschaftliche Erkenntnisse für die Umsetzung der Pflegeinitiative genutzt werden können

Der Pflegeberuf steht angesichts des Bevölkerungswachstums und der Alterung der Gesellschaft, aber auch der gesellschaftlichen Veränderungen vor grossen Herausforderungen. Um die Qualität der Pflege erhalten zu können, müssen zwingend mehr Pflegefachkräfte ausgebildet und die Arbeitsbedingungen verbessert werden. Beides waren Forderungen der Schweizer Volksinitiative „Für eine starke Pflege” (siehe: Artikel 117b Bundesverfassung1), die am 28. November 2021 mit einem historischen Abstimmungserfolg an der Urne angenommen wurde

Sensitization to grass pollen allergen molecules in a birth cohort—natural Phl p 4 as an early indicator of grass pollen allergy

International audienceBackground: Grass pollen allergy is one of the most common allergies worldwide.Objective: The aim of this study was to evaluate the usefulness of grass pollen allergen molecules for prediction of grass pollen allergy during childhood and up to adolescence.Method: Questionnaire data and sera obtained from the study subjects at the ages of 4, 8, and 16 years from the population-based Barn/Children Allergy Milieu Stockholm Epidemiology birth cohort were used. Sera from 763 representative subjects with serum samples available at all 3 ages were analyzed for IgE reactivity to 8 Phleum pratense (Phl p) allergens (MeDALL [Mechanisms for the Development of Allergies] chip) and to timothy grass extract (ImmunoCAP). Allergic rhinitis to grass pollen (ARg) was defined as upper airway symptoms during grass pollen exposure.Results: The prevalence of sensitization to any Phl p molecule was higher compared with that to timothy extract at all 3 ages: at the age of 4 years, 9.7% versus 6.8%; at the age of 8 years, 28.4% versus 15.3%; and at the age of 16 years, 37.1% versus 27.1%. General estimating equations analyses revealed that among children sensitized at the age of 4 years, the overall odds ratio (OR) of later ARg (up to 16 years) was increased only for IgE reactivity to Phl p 1 (OR = 4.9) and natural Phl p 4 (OR = 6.9). The likelihood of later symptoms increased with the number of allergen molecules; at the age of 4 years, 2 or more molecules predicted ARg to 78% and 3 or more molecules predicted ARg to 95%. A positive test result for timothy extract predicted ARg to 70%.Conclusions: Natural Phl p 4 is a hitherto unrecognized early indicator of grass pollen allergy, in addition to Phl p 1. To identify grass pollen sensitization and predict later ARg, allergen molecules are of added value to timothy extract alone and may help clinicians improve prediction of grass pollen allergy

Transite: A Computational Motif-Based Analysis Platform That Identifies RNA-Binding Proteins Modulating Changes in Gene Expression

© 2020 The Author(s) Krismer et al. present a computational approach to identify RNA-binding proteins (RBPs) that modulate post-transcriptional control of gene expression using RNA expression data as inputs. By applying this approach to publicly available patient datasets, they identify and experimentally confirm that the RBP hnRNPC contributes to chemotherapy resistance in lung cancer

Vaccine Based on Recombinant Fusion Protein Combining Hepatitis B Virus PreS with SARS-CoV-2 Wild-Type- and Omicron-Derived Receptor Binding Domain Strongly Induces Omicron-Neutralizing Antibodies in a Murine Model

Background: COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a recurrent endemic disease affecting the whole world. Since November 2021, Omicron and its subvariants have dominated in the spread of the disease. In order to prevent severe courses of disease, vaccines are needed to boost and maintain antibody levels capable of neutralizing Omicron. Recently, we produced and characterized a SARS-CoV-2 vaccine based on a recombinant fusion protein consisting of hepatitis B virus (HBV)-derived PreS and two SARS-CoV-2 wild-type RBDs. Objectives: To develop a PreS-RBD vaccine which induces high levels of Omicron-specific neutralizing antibodies. Methods: We designed, produced, characterized and compared strain-specific (wild-type: W-PreS-W; Omicron: O-PreS-O), bivalent (mix of W-PreS-W and O-PreS-O) and chimeric (i.e., W-PreS-O) SARS-CoV-2 protein subunit vaccines. Immunogens were characterized in vitro using protein chemical methods, mass spectrometry, and circular dichroism in combination with thermal denaturation and immunological methods. In addition, BALB/c mice were immunized with aluminum–hydroxide-adsorbed proteins and aluminum hydroxide alone (i.e., placebo) to study the specific antibody and cytokine responses, safety and Omicron neutralization. Results: Defined and pure immunogens could be produced in significant quantities as secreted and folded proteins in mammalian cells. The antibodies induced after vaccination with different doses of strain-specific, bivalent and chimeric PreS-RBD fusion proteins reacted with wild-type and Omicron RBD in a dose-dependent manner and resulted in a mixed Th1/Th2 immune response. Interestingly, the RBD-specific IgG levels induced with the different vaccines were comparable, but the W-PreS-O-induced virus neutralization titers against Omicron (median VNT50: 5000) were seven- and twofold higher than the W-PreS-W- and O-PreS-O-specific ones, respectively, and they were six-fold higher than those of the bivalent vaccine. Conclusion: Among the tested immunogens, the chimeric PreS-RBD subunit vaccine, W-PreS-O, induced the highest neutralizing antibody titers against Omicron. Thus, W-PreS-O seems to be a highly promising COVID-19 vaccine candidate for further preclinical and clinical evaluation

Response of methanogenic archaea to Late Pleistocene and Holocene climate changes in the Siberian Arctic

In order to investigate the link between the methane dynamics in permafrost deposits and climate changes in the past, we studied the abundance,composition and methane production of methanogenic communities in Late Pleistocene and Holocene sediments of the Siberian Arctic. We detected intervals of increased methane concentrations in Late Pleistocene and Holocene deposits along a 42 ka old permafrost sequence from Kurungnakh Island in the Lena Delta (northeast Siberia). Increased amounts of archaeal life markers (intact phospholipid ethers) and a high variety in genetic fingerprints detected by 16S ribosomal ribonucleic acid (rRNA) gene analyses of methanogenic archaea suggest presently living and presumably active methanogenic archaea in distinct layers predominantly in Holocene deposits but also in deep frozen ground at 17 m depth. Potential methanogenic activity was confirmed by incubation experiments. By comparing methane concentrations, microbial incubation experiments, gene analysis of methanogens and microbial life markers (intact phospholipid esters and ethers) to already partly degraded membrane lipids such as archaeol and isoprenoid glycerol dialkyl glycerol tetraethers (GDGT), we demonstrated that archaeol likely represents a signal of past methanogenic archaea. The archaeol signal was used to reconstruct the response of methanogenic communities to past temperature changes in the Siberian Arctic and the data suggest higher methane emissions occurred during warm periods, particularly during an interval in the Late Pleistocene. This new data on present and past methanogenic communities in the Siberian terrestrial permafrost imply that these microorganisms will respond to the predicted future temperature rise in the Arctic with increasing methane production as demonstrated in previous warmer periods

Lower magnitude and faster waning of antibody responses to SARS-CoV-2 vaccination in anti-TNF-α-treated IBD patients are linked to lack of activation and expansion of cTfh1 cells and impaired B memory cell formationResearch in context

Summary: Background: Patients with inflammatory bowel disease (IBD) and healthy controls received primary SARS-CoV-2-mRNA vaccination and a booster after six months. Anti-TNF-α-treated patients showed significantly lower antibody (Ab) levels and faster waning than α4β7-integrin-antagonist recipients and controls. This prospective cohort study aimed to elucidate the underlying mechanisms on the basis of circulating T-follicular helper cells (cTfh) and B memory cells. Methods: We measured SARS-CoV-2- Wuhan and Omicron specific Abs, B- and T-cell subsets at baseline and kinetics of Spike (S)-specific B memory cells along with distributions of activated cTfh subsets before and after primary and booster vaccination. Findings: Lower and faster waning of Ab levels in anti-TNF-α treated IBD patients was associated with low numbers of total and naïve B cells vs. expanded plasmablasts prior to vaccination. Along with their low Ab levels against Wuhan and Omicron VOCs, reduced S-specific B memory cells were identified after the 2nd dose which declined to non-detectable after 6 months. In contrast, IBD patients with α4β7-integrin-antagonists and controls mounted and retained high Ab levels after the 2nd dose, which was associated with a pronounced increase in S-specific B memory cells that were maintained or expanded up to 6 months. Booster vaccination led to a strong increase of Abs with neutralizing capacity and S-specific B memory cells in these groups, which was not the case in anti-TNF-α treated IBD patients. Of note, Ab levels and S-specific B memory cells in particular post-booster correlated with the activation of cTfh1 cells after primary vaccination. Interpretations: The reduced magnitude, persistence and neutralization capacity of SARS-CoV-2 specific Abs after vaccination in anti-TNF-α-treated IBD patients were associated with impaired formation and maintenance of S-specific B memory cells, likely due to absent cTfh1 activation leading to extra-follicular immune responses and diminished B memory cell diversification. These observations have implications for patient-tailored vaccination schedules/vaccines in anti-TNF-α-treated patients, irrespective of their underlying disease. Funding: The study was funded by third party funding of the Institute of Specific Prophylaxis and Tropical Medicine at the Medical University Vienna. The funders had no role in study design, data collection, data analyses, interpretation, or writing of report