Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease: the salivary glands of patients with Sjögren's syndrome

Structures resembling germinal centers are seen in the salivary glands of patients with Sjögren's syndrome, but it is not known whether the microenvironment of these cell clusters is sufficient for the induction of a germinal center response. Therefore, we cloned and sequenced rearranged Ig V genes expressed by B cells isolated from sections of labial salivary gland biopsies from two Sjögren's syndrome patients. Rearranged V genes from B cells within one cell cluster were polyclonal and most had few somatic mutations. Two adjacent clusters from another patient each contained one dominant B cell clone expressing hypermutated V genes. None of the rearranged V genes was found in both clusters, suggesting that cells are unable to migrate out into the surrounding tissue and seed new clusters. The ratios of replacement to silent mutations in the framework and complementarity determining regions suggest antigen selection of high-affinity mutants. These results show that an antigen-driven, germinal center-type B cell response is taking place within the salivary glands of Sjögren's syndrome patients. In view of the recent demonstration of a germinal center response within the rheumatoid synovial membrane and the existence of similar structures in the target tissues of other autoimmune. diseases, we propose that germinal center- type responses can be induced in the nonlymphoid target tissues of a variety of autoimmune diseases

GPCSIM : an instrument simulator of polymer analysis by size exclusion chromatography for demonstration and training purposes

A computer simulation has been developed with the purpose of demonstrating and visualizing a multitude of effects in the molecular characterization of synthetic polymer mixtures by size exclusion (gel permeation) chromatography. The chromatographic results and their interpretation are influenced by numerous parameters originating from sample, column and instrumentation used (injection, detection etc). The target audience for the software tool consists of polymers scientists, teachers of separation science and students. Especially for the latter audience it is important to stress that the software enables intentional creation of mistakes and learning from these mistakes. What the user can do ranges from visualization (quantitatively) all retention and dispersion effects, validation of experimental setup, checking sensitivity for certain operating conditions, extrapolation current instrument specifications, and in general performing hypothetical experiments. Several examples, such as column choice, band broadening, detection comparison and possible artifacts in the calculation of distributions are presented. This simulator is part of a family of similar tools for gas chromatography, high performance liquid chromatography, micellar electrokinetic chromatography and capillary electrophoresis. They have proved their effectiveness in education of separation science topics at several European universities

The role of the Union Health and Safety Committee in evaluating the health hazards of hospital workers: A case study

The Union Health and Safety Committee is an important tool for evaluating and reducing job-related health risks among hospital workers. The experience of one such committee which effectively performed this duty at New York University Medical Center has led to a city-wide survey by District 1199 of working conditions and health status among hospital laboratory workers. Results showed a possible association of hepatitis with some job practices and led to constructive suggestions for improving working conditions and reducing disease risk among hospital workers

Co-Evolution of quasispecies: B-cell mutation rates maximize viral error catastrophes

Co-evolution of two coupled quasispecies is studied, motivated by the competition between viral evolution and adapting immune response. In this co-adaptive model, besides the classical error catastrophe for high virus mutation rates, a second ``adaptation-'' catastrophe occurs, when virus mutation rates are too small to escape immune attack. Maximizing both regimes of viral error catastrophes is a possible strategy for an optimal immune response, reducing the range of allowed viral mutation rates to a minimum. From this requirement one obtains constraints on B-cell mutation rates and receptor lengths, yielding an estimate of somatic hypermutation rates in the germinal center in accordance with observation.Comment: 4 pages RevTeX including 2 figure

Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4<sup>+</sup> T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system <i>in</i> <i>vivo</i>. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

HUBUNGAN ANTARA PENGETAHUAN DENGAN PERSEPSI DAN RESPON PERILAKU MAHASISWA DALAM UPAYA MEMUTUSKAN MATA RANTAI PENULARAN COVID-19 DI PERBATASAN NKRI-RDTL

Latar belakang: Pandemi covid-19 menyebar sangat pesat dan belum ditemukan obat yang spesifik sehingga masyarakat lebih rentan tertular karena kurangnya pengetahuan dan persepsi serta praktik perilaku tidak memadai. Tujuan: mengidentifikasi hubungan pengetahuan dengan persepsi dan perilaku mahasiswa dalam memutuskan mata rantai penularan covid-19. Metodologi: Desain kuantitatif dengan pendekatan cross sectional, dilakukan pada Desember 2020. Instrumen pengetahuan, persepsi dan perilaku telah dilakukan uji validitas dan reliabilitas, nilai alfa chronbach 0,697-0,793. Karakteristik responden dianalisis dengan statistik deskriptif, sedangkan hubungan antar variabel menggunakan uji chi square  dengan tingkat signifikansi p<0,05. Hasil: 502 responden menyelesaikan  survei, rata-rata berumur 21,14 tahun (2,56), terbanyak perempuan (69,7%). Terdapat 67,1% mendapatkan informasi covid-19 melalui media sosial. Mayoritas memiliki pengetahuan memadai, namun 47,4% memiliki pengetahuan kurang. Dilaporkan pula persepsi dan perilaku negatif terkait upaya memutuskan mata rantai penularan covid-19, masing-masing  44,6% dan 50,4%. Sekitar 73,11% menyatakan bahwa antibiotik dan vaksin tidak efektif menghambat penyebaran covid-19. Hasil uji chi square menunjukkan tidak ada hubungan antara pengetahuan dengan persepsi (p=0,900) dan perilaku memutuskan mata rantai penularan covid-19 (p=0,781). Kesimpulan: Penting untuk meningkatkan pengetahuan dan keyakinan masyarakat untuk memutuskan mata rantai penularan covid-19. Mahasiswa memiliki peran penting sebagai agen pengubah di masyarakat untuk memutuskan mata rantai penularan covid-19

Root-Colonizing Endophytic Fungi of the Dominant Grass Stipa krylovii From a Mongolian Steppe Grassland

In several terrestrial ecosystems such as grasslands, plants live together with various root-colonizing dark septate endophytes (DSEs), fungi that are relatively frequent colonizers of healthy belowground tissues of plants in these environments. They are important members of the plant microbiota and may have various effects on plant survival under different stress conditions; however, their general functions in relation to plants and the greater ecosystem remain elusive. Although an increasing number of studies has been published focusing on DSEs in Asian grasslands, our knowledge is limited. Especially in Mongolia, where the steppe region represents a significant area, information is not available on these root colonizers. In this study, we aimed to characterize DSEs of a common dominant gramineous plant species, Stipa krylovii in a semiarid grassland of Mongolia. Root samples were collected in a natural steppe and were processed for isolation of fungal endophytes. For molecular identification of the isolates, the internal transcribed spacer (ITS) region of the nrDNA was obtained for all the isolates investigated; furthermore, the partial translation elongation factor 1-a (TEF) gene and large subunit (LSU) and small subunit (SSU) of rDNA were also amplified and sequenced in case of representative isolates. In vitro tests were used to examine the rough symbiotic nature of the fungi, and root colonization was visualized. A majority of the 135 isolates examined in detail was found to belong to several orders of Ascomycota (110 isolates) and some to Basidiomycota (25 isolates). A significant number of the isolates represented presumably novel taxa, and dominant similarities of the lineages have been found with relatively frequent and known grass root endophytes of semiarid areas in other geographic regions. These endophytes included Periconia macrospinosa, Microdochium bolley, and Darksidea, the genus of which comprised one fourth of the isolates. We found numerous lineages, which have been detected not only from Asian steppe ecosystems, but also from prairies in North America and sandy grasslands in Europe. Therefore, our results strengthen the hypothesized worldwide presence of a common and dominant core group of a DSE community in arid and semiarid grasslands

Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomised phase III study

A randomised phase III trial was conducted to assess the role of interferon-alpha (INFα) 2a as maintenance therapy following surgery and/or chemotherapy in patients with epithelial ovarian carcinoma. Patients were randomised following initial surgery/chemotherapy to interferon-alpha 2a as 4.5 mega-units subcutaneously 3 days per week or to no further treatment. A total of 300 patients were randomised within the study between February 1990 and July 1997. No benefit for interferon maintenance was seen in terms of either overall or clinical event-free survival. We conclude that INF-α is not effective as a maintenance therapy in the management of women with ovarian cancer. The need for novel therapeutics or strategies to prevent the almost inevitable relapse of patients despite increasingly effective surgery and chemotherapy remains