Characterisation of epitope-specific B cells and the role of IgG Fc sialylation in murine arthritis models

Autoimmune diseases are a major burden for society and economy. One of the most common autoimmune diseases is rheumatoid arthritis (RA) characterized by joint inflammation, swelling and pain. If left untreated, it ultimately leads to disability. B cells play a major role in rheumatoid arthritis as shown by numerous studies and the success of anti-CD20 B cell depletion therapy in clinical use. In healthy individuals, B cells originate and develop in the bone marrow before they exit into the periphery where they mature and differentiate. B cells act in the body in a dual role, on the one hand as professional antigen-presenting cells (APCs), taking up antigen and presenting it to cognate T cells via MHC. On the other hand, B cells can generate and mature specific antibodies against almost any given antigenic target. This diversity is achieved by a process called V(D)J recombination. V, (D) and J segments are recombined during early B cell development, creating a vast diversity of unique sequences. Subsequently, the BCR diversity can be increased even further upon B cell activation by somatic hypermutation (SHM) and class switch recombination (CSR) in the germinal center (GC) reaction. However, the stochastic process of gene rearrangement and mutations also leads to autoreactive BCRs that upon encounter of self-antigen could initiate an autoreactive immune response. This fundamental dogma of autoimmunity has been postulated in many autoimmune diseases including RA. Therefore, it is important to understand the role and regulation of self-reactive B cells in arthritis. In study I, we investigated the role of Ncf4 dependent intracellular reactive oxygen species (ROS) in controlling the differentiation from B cells into antibody-producing plasma cells. By employing Ncf4 mutated (R58A) mice we could show that lower levels of intracellular ROS induce plasma cell formation, increased CXCR3 and decreased CXCR4 expression. Increased plasma cell formation led to higher self-reactive anti-Col2 antibody production and enhanced disease severity. We concluded that intrinsic ROS can substantially modulate self-reactive B cell differentiation and thereby the disease phenotype. In study II, we mapped the pathogenic B cell epitopes on glucose-6-phosphate isomerase (GPI), an autoantigen in human RA and mouse models of arthritis. We identified a single peptide (GPI293-307) as the most dominant epitope targeted both in human and mouse models. Following the observation of the early emergence of antibodies against these epitopes, we found that GPI293-307-specific B cells are not deleted during B cell development and activated in the pathogenesis of arthritis due to encounter of a structurally modified form of GPI protein on the articular cartilage surface exposing the GPI293-307 neoepitope. We concluded that this finding has important implications about the understanding of the role of naturally existing self-reactive B cells in GPI-mediated arthritis. In study III, we studied the B cell response to Collagen type II, another important autoantigen in human RA and mouse models of arthritis. The focus was on the C1 epitope, a triple-helical peptide sequence originally identified in collagen-dependent mouse models. Using both B cell receptor knock-in mouse models, healthy human donors, and RA patients, we could identify and characterise for the first time a population of physiologically occurring self-reactive B cells that exhibit an immune-suppressive phenotype. We conclude that B suppressor cells (Bsups) represent a new subpopulation of B cells tolerizing T cells against self-antigens. Finally, in study IV, we changed the focus from the specificity of self-reactive BCRs as conferred by the Fab fragment of immunoglobulins (Igs) to the importance of the Fc fragment. More specifically, we addressed the question of the interactions between the Immunoglobulin G (IgG) isotype, its Fc glycosylation, and the consequent effector functions in different murine arthritis models. To this end, we made use of available well- characterized pathogenic monoclonal antibodies (mAbs) causing arthritis in susceptible mouse strains. A glycoengineering method was applied on these antibodies to yield an array of different glycovariants to be tested in murine models. We showed that while the Fc glycan does not play a role in the collagen antibody-induced arthritis (CAIA) model, there seems to be an isotype -/and sialylation-dependent function in the regulation of arthritis severity in the collagen-induced arthritis (CIA) model. In conclusion, we contributed towards the understanding of naturally existing autoreactive B cells in arthritis autoimmunity

Threshold Resummation for Dark-Matter Production at the LHC

We derive precision predictions for the production of dark-matter particles recoiling against a jet with large transverse momentum at the LHC. The dark-matter fermions are described within a simplified model and couple to the Standard Model via a vector mediator. Our predictions for the mono-jet signature include the resummation of the leading and next-to-leading threshold logarithms. The corresponding matching coefficient is evaluated at NLO. The resummed result is matched to the fixed-order NLO cross section obtained from the MadGraph framework. We discuss numerical results for several benchmark scenarios at the LHC.Comment: 19 pages, 3 figure

First Results of the PixelGEM Central Tracking System for COMPASS

For its physics program with a high-intensity hadron beam of up to 2e7 particles/s, the COMPASS experiment at CERN requires tracking of charged particles scattered by very small angles with respect to the incident beam direction. While good resolution in time and space is mandatory, the challenge is imposed by the high beam intensity, requiring radiation-hard detectors which add very little material to the beam path in order to minimize secondary interactions. To this end, a set of triple-GEM detectors with a hybrid readout structure consisting of pixels in the beam region and 2-D strips in the periphery was designed and built. Successful prototype tests proved the performance of this new detector type, showing both extraordinary high rate capability and detection efficiency. The amplitude information allowed to achieve spatial resolutions about a factor of 10 smaller than the pitch and a time resolution close to the theoretical limit imposed by the layout. The PixelGEM central tracking system consisting of five detectors, slightly improved with respect to the prototype, was completely installed in the COMPASS spectrometer in spring 2008

Structure of Development or Development and Topology of Biological Shapeexemplified on the early embryology in the egg of the nematode C. elegans

The pre-morpho-genetic development of nematode Caenorhabditis elegans in the egg is studied to formulate a base system, in which rules that govern the formation of shape and functions in biological organisms can be defined. The spatial cell positions and the cell movements are subject of analysis by mathematical means, with respect to the determination of biological form and function . The mathematical concepts of Vector space chains, Matrix and Boundary operations are made available for the analysis. The development of one organism can be described in a unique matrix form. The structure of the development of two different organisms can be compared

Plasma dynamic synthesis of iron oxides in the «frequency operation» mode of coaxial magnetoplasma accelerator

It is known that the epsilon phase of iron oxide e-Fe2O3 has the highest value of coercive force among all known simple metal oxides (~24 kOe) and is characterized by ferromagnetic resonance in the frequency range from 100 to 200 GHz. The noted features determine the possibility of its wide application. However, there is the problem of synthesis and stabilization this crystal structure at room temperature. In this paper, we consider the possibility to obtain e-Fe2O3 by the plasma dynamic method when the system is operating in the frequency (multi-pulse) regime. The influence of the number power supply impulses on the phase composition of the synthesized products was studied using X-ray diffractometry

Health-related locus of control and health behaviour among university students in North Rhine Westphalia, Germany

Helmer SM, Krämer A, Mikolajczyk RT. Health-related locus of control and health behaviour among university students in North Rhine Westphalia, Germany. BMC Research Notes. 2012;5(1): 703

Learning the language of QCD jets with transformers

Transformers have become the primary architecture for natural language processing. In this study, we explore their use for auto-regressive density estimation in high-energy jet physics, which involves working with a high-dimensional space. We draw an analogy between sentences and words in natural language and jets and their constituents in high-energy physics. Specifically, we investigate density estimation for light QCD jets and hadronically decaying boosted top jets. Since transformers allow easy sampling from learned densities, we exploit their generative capability to assess the quality of the density estimate. Our results indicate that the generated data samples closely resemble the original data, as evidenced by the excellent agreement of distributions such as particle multiplicity or jet mass. Furthermore, the generated samples are difficult to distinguish from the original data, even by a powerful supervised classifier. Given their exceptional data processing capabilities, transformers could potentially be trained directly on the massive LHC data sets to learn the probability densities in high-energy jet physics.Comment: Few references added; Version accepted for publication by JHE

Association between Infant and Young Child Feeding (IYCF) Indicators and the Nutritional Status of Children (6–23 Months) in Northern Ghana

Anin SK, Saaka M, Fischer F, Krämer A. Association between Infant and Young Child Feeding (IYCF) Indicators and the Nutritional Status of Children (6–23 Months) in Northern Ghana. Nutrients. 2020;12(9): 2565.Although recommended infant and young child feeding (IYCF) practices have been found to be protective against undernutrition in some settings, there is no finality yet due to inconsistencies in the literature. A cross-sectional survey of 581 mother-child pairs was conducted in northern Ghana in June 2018. The association between IYCF indicators and child undernutrition (stunting and wasting) were assessed. The descriptive analysis showed that 66.4% of the children (6–23 months) were introduced to complementary feeding in a timely manner, 69.4% met the minimum meal frequency, and 38.9% met the minimum acceptable diet daily. The prevalence of stunting, wasting, underweight and overweight was 33.2%, 14.1%, 27% and 2.6%, respectively. From the multivariable binary logistic regression, child gender, child age group and source of power for lighting the household were significantly associated with wasting. Intake of iron-rich foods, child age group, and maternal height were significantly associated with stunting after adjusting for confounders. The prevalence of the compliance with IYCF indicators was relatively high. None of the individual IYCF indicators showed significant association with undernutrition, except intake of iron-rich foods for stunting. Nutrition-specific interventions targeted at improving IYCF practices, dietary diversification and intake of nutrient-rich meals, should be adopted and scaled up to address undernutrition in northern Ghana

Prevalence of hepatitis and HIV infections and vaccination rates in patients entering the heroin-assisted treatment in Switzerland between 1994 and 2002

Background::  Hepatitis C virus (HCV) remains very prevalent in injection drug users (IDUs). In spite of recommended vaccinations against hepatitis A virus (HAV) and hepatitis B virus (HBV), many IDUs remain susceptible to HAV and HBV. Study population and methods::  Patients entering heroin-assisted treatment between 2000 and 2002 (N=210) were compared for infectious disease status with patients entering this treatment in 1998 (N=243) and between 1994 and 1996 (N=1035). Infection status was determined with the aid of questionnaires and blood tests for antibodies against HAV, HBV core antigen, HCV and HIV. Results::  In the cohort 2000-2002 78.3% of the patients were HCV positive, 53.3% were HBV positive, 41.2% were HAV positive and 12.6% were HIV positive. In comparison to the cohorts entering the heroin- assisted treatment at an earlier time, there was a significant reduction of HBV and HAV infections, but not of HCV and HIV infections. 15.6% of the patients entering between 2000 and 2002 were vaccinated against HBV and 10.3% against HAV. 31.1% of patients at entrance were susceptible for HBV and 48.5% for HAV. In comparison to patients entering treatment in 1998 there was no significant increase in patients who were vaccinated against HBV. Conclusions:: This data illustrates the need for improving HCV prevention and more consequent vaccination against HBV and HAV in IDU