Selective Abrogation of Major Histocompatibility Complex Class II Expression on Extrahematopoietic Cells in Mice Lacking Promoter IV of the Class II Transactivator Gene

MHC class II (MHCII) molecules play a pivotal role in the induction and regulation of immune responses. The transcriptional coactivator class II transactivator (CIITA) controls MHCII expression. The CIITA gene is regulated by three independent promoters (pI, pIII, pIV). We have generated pIV knockout mice. These mice exhibit selective abrogation of interferon (IFN)-γ–induced MHCII expression on a wide variety of non-bone marrow–derived cells, including endothelia, epithelia, astrocytes, and fibroblasts. Constitutive MHCII expression on cortical thymic epithelial cells, and thus positive selection of CD4+ T cells, is also abolished. In contrast, constitutive and inducible MHCII expression is unaffected on professional antigen-presenting cells, including B cells, dendritic cells, and IFN-γ–activated cells of the macrophage lineage. pIV−/− mice have thus allowed precise definition of CIITA pIV usage in vivo. Moreover, they represent a unique animal model for studying the significance and contribution of MHCII-mediated antigen presentation by nonprofessional antigen-presenting cells in health and disease

Epigenomic modifications mediating antibody maturation

Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches. It has been shown that alternate chromatin modifications, in concert with ncRNAs and potentially DNA methylation, regulate AID recruitment and stabilize DNA repair factors. We, hereby, assess the combination of these distinct modifications and discuss how they contribute to initiating differential DNA repair pathways at the Ig locus, which ultimately leads to enhanced antibody-antigen binding affinity (SHM) or antibody isotype switching (CSR). We will also highlight how misregulation of epigenomic regulation during DNA repair can compromise antibody development and lead to a number of immunological syndromes and cancer

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Geosciences Roadmap for Research Infrastructures 2025 - 2028 by the Swiss Geosciences Community

This roadmap is the product of a grassroots effort by the Swiss Geosciences community. It is the first of its kind, outlining an integrated approach to research facilities for the Swiss Geosciences. It spans the planning period 2025-2028. Swiss Geoscience is by its nature leading or highly in-volved in research on many of the major national and global challenges facing society such as climate change and meteorological extreme events, environmental pol-lution, mass movements (land- and rock-slides), earth-quakes and seismic hazards, global volcanic hazards, and energy and other natural resources. It is essential to under- stand the fundamentals of the whole Earth system to pro-vide scientific guidelines to politicians, stakeholders and society for these pressing issues. Here, we strive to gain efficiency and synergies through an integrative approach to the Earth sciences. The research activities of indivi- dual branches in geosciences were merged under the roof of the 'Integrated Swiss Geosciences'. The goal is to facilitate multidisciplinary synergies and to bundle efforts for large research infrastructural (RI) requirements, which will re-sult in better use of resources by merging sectorial acti- vities under four pillars. These pillars represent the four key RIs to be developed in a synergistic way to improve our understanding of whole-system processes and me- chanisms governing the geospheres and the interactions among their components. At the same time, the roadmap provides for the required transition to an infrastructure adhering to FAIR (findable, accessible, interoperable, and reusable) data principles by 2028.The geosciences as a whole do not primarily profit from a single large-scale research infrastructure investment, but they see their highest scientific potential for ground-break-ing new findings in joining forces in establishing state-of-the-art RI by bringing together diverse expertise for the benefit of the entire geosciences community. Hence, the recommendation of the geoscientific community to policy makers is to establish an integrative RI to support the ne- cessary breadth of geosciences in their endeavor to ad-dress the Earth system across the breadth of both temporal and spatial scales. It is also imperative to include suffi-cient and adequately qualified personnel in all large RIs. This is best achieved by fostering centers of excellence in atmospheric, environmental, surface processes, and deep Earth projects, under the roof of the 'Integrated Swiss Geosciences'. This will provide support to Swiss geo-sciences to maintain their long standing and internatio- nally well-recognized tradition of observation, monitor-ing, modelling and understanding of geosciences process-es in mountainous environments such as the Alps and beyond

Conceptual Spaces of the Immune System

The immune system can be looked at as a cognitive system. This is often done inanalogy to the neuro-psychological system. Here, it is demonstrated that the cognitivefunctions of the immune system can be properly described within a new theory ofcognitive science. Gärdenfors’ geometrical framework of conceptual spaces is appliedto immune cognition. Basic notions, like quality dimensions, natural properties andconcepts, similarities, prototypes, saliences etc., are related to cognitive phenomena ofthe immune system. Constraints derived from treating the immune system within acognitive theory, like Gärdenfors’ conceptual spaces, might well prove to beinstrumental for the design of vaccines, immunological diagnostic tests, andimmunotherapy

Age-Related Macular Degeneration: A Connection between Human Herpes Virus-6A-Induced CD46 Downregulation and Complement Activation?

Viruses are able to interfere with the immune system by docking to receptors on host cells that are important for proper functioning of the immune system. A well-known example is the human immunodeficiency virus that uses CD4 cell surface molecules to enter host lymphocytes and thereby deleteriously destroying the helper cell population of the immune system. A more complicated mechanism is seen in multiple sclerosis (MS) where human herpes virus-6A (HHV-6A) infects astrocytes by docking to the CD46 surface receptor. Such HHV-6A infection in the brain of MS patients has recently been postulated to enable Epstein–Barr virus (EBV) to transform latently infected B-lymphocytes in brain lesions leading to the well-known phenomenon of oligoclonal immunoglobulin production that is widely used in the diagnosis of MS. The cellular immune response to HHV-6A and EBV is one part of the pathogenic mechanisms in MS. A more subtle pathogenic mechanism can be seen in the downregulation of CD46 on astrocytes by the infecting HHV-6A. Since CD46 is central in regulating the complement system, a lack of CD46 can lead to hyperactivation of the complement system. In fact, activation of the complement system in brain lesions is a well-known pathogenic mechanism in MS. In this review, it is postulated that a similar mechanism is central in the development of age-related macular degeneration (AMD). One of the earliest changes in the retina of AMD patients is the loss of CD46 expression in the retinal pigment epithelial (RPE) cells in the course of geographic atrophy. Furthermore, CD46 deficient mice spontaneously develop dry-type AMD-like changes in their retina. It is also well known that certain genetic polymorphisms in the complement-inhibiting pathways correlate with higher risks of AMD development. The tenet is that HHV-6A infection of the retina leads to downregulation of CD46 and consequently to hyperactivation of the complement system in the eyes of susceptible individuals

Likelihood ratios of quantitative laboratory results in medical diagnosis: The application of Bézier curves in ROC analysis

<div><p>Receiver operating characteristic (ROC) analysis is widely used to describe the discriminatory power of a diagnostic test to differentiate between populations having or not having a specific disease, using a dichotomous threshold. In this way, positive and negative likelihood ratios (LR+ and LR-) can be calculated to be used in Bayes’ way of estimating disease probabilities. Similarly, LRs can be calculated for certain ranges of test results. However, since many diagnostic tests are of quantitative nature, it would be desirable to estimate LRs for each quantitative result. These LRs are equal to the slope of the tangent to the ROC curve at the corresponding point. Since the exact distribution of test results in diseased and non-diseased people is often not known, the calculation of such LRs for quantitative test results is not straightforward. Here, a simple distribution-independent method is described to reach this goal using Bézier curves that are defined by tangents to a curve. The use of such a method would help in standardizing quantitative test results, which are not always comparable between different test providers, by reporting them as LRs for a specific diagnosis, in addition to, or instead of, quantities such as mg/L or nmol/L, or even indices or units.</p></div