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Dectin‐1 is a C‐type lectin‐receptor involved in sensing fungi by innate immune cells. Encoded by the Clec7a gene, Dectin‐1 exists in two major splice isoforms, Dectin‐1a and 1b, which differ in the presence of a membrane‐proximal stalk domain. As reported previously, this domain determines degradative routes for Dectin‐1a and 1b leading to the generation of a stable N‐terminal fragment exclusively from Dectin‐1a. Here, we narrow down the responsible part of the stalk and demonstrate the stabilisation of the Dectin‐1a N‐terminal fragment in tetraspanin‐enriched microdomains. C57BL/6 and BALB/c mice show divergent Dectin‐1 isoform expression patterns, which are caused by a single nucleotide polymorphism in exon 3 of the Clec7a gene, leading to a non‐sense Dectin‐1a mRNA in C57BL/6 mice. Using backcrossing, we generated mice with the C57BL/6 Clec7a allele on a BALB/c background and compared these to the parental strains. Expression of the C57BL/6 allele leads to the exclusive presence of the Dectin‐1b protein. Furthermore, it was associated with higher Dectin‐1 mRNA expression, but less Dectin‐1 at the cell surface according to flow cytometry. In neutrophils, this altered ROS production induced by Dectin‐1 model ligands, while cellular responses in macrophages and dendritic cells were not significantly influenced by the Dectin‐1 isoform pattern. [ABSTRACT FROM AUTHOR]

This document is an editorial from the International Journal of Practical Theology, reflecting on the author's twelve-year tenure as managing editor. The author discusses the submissions received during their time, noting that approximately 25% were published after a rigorous peer review process. The author highlights the diverse range of topics and methodologies in practical theology, including pastoral theology and public theology. They also acknowledge the challenges of internationalization, such as language barriers and different academic cultures. The editorial concludes by introducing the articles featured in the current issue, covering topics such as religious education, liturgics, and piety research. The text discusses the challenges and benefits of internationalizing Practical Theology. It highlights the diversity and breadth of the field, which ranges from public theological and religious matters to pastoral theological approaches. The author emphasizes the need for readers to engage with unfamiliar details, understand different perspectives, and be tolerant of solutions that may not apply in their own context. The text also acknowledges the difficulties faced by editors in evaluating submissions from different cultural and linguistic backgrounds. The article concludes by expressing curiosity about the future of the journal and the dynamics of internationalizing Practical Theology. It also provides a brief overview of the articles included in the current issue, which cover topics such as church education policy, liturgy and autism, baptism practices, experiences of grace, and the longing for social connection in a church community. [Extracted from the article]

Signal peptide peptidase (SPP) and the four SPP‐like proteases SPPL2a, SPPL2b, SPPL2c and SPPL3 constitute a family of aspartyl intramembrane proteases with homology to presenilins. The different members reside in distinct cellular localisations within the secretory pathway and the endo‐lysosomal system. Despite individual cleavage characteristics, they all cleave single‐span transmembrane proteins with a type II orientation exhibiting a cytosolic N‐terminus. Though the identification of substrates is not complete, SPP/SPPL‐mediated proteolysis appears to be rather selective. Therefore, according to our current understanding cleavage by SPP/SPPL proteases rather seems to serve a regulatory function than being a bulk proteolytic pathway. In the present review, we will summarise our state of knowledge on SPP/SPPL proteases and in particular highlight recently identified substrates and the functional and/or (patho)‐physiological implications of these cleavage events. Based on this, we aim to provide an overview of the current open questions in the field. These are connected to the regulation of these proteases at the cellular level but also in context of disease and patho‐physiological processes. Furthermore, the interplay with other proteostatic systems capable of degrading membrane proteins is beginning to emerge. [ABSTRACT FROM AUTHOR]

More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase‐like (SPPL) proteases have been identified based on their sequence similarity to presenilins, a related family of intramembrane aspartyl proteases. Other than those for the presenilins, no high‐resolution structures for the SPP/SPPL proteases are available. Despite this limitation, over the years bioinformatical and biochemical data have accumulated, which altogether have provided a picture of the overall structure and topology of these proteases, their localization in the cell, the process of substrate recognition, their cleavage mechanism, and their function. Recently, the artificial intelligence‐based structure prediction tool AlphaFold has added high‐confidence models of the expected fold of SPP/SPPL proteases. In this review, we summarize known structural aspects of the SPP/SPPL family as well as their substrates. Of particular interest are the emerging substrate recognition and catalytic mechanisms that might lead to the prediction and identification of more potential substrates and deeper insight into physiological and pathophysiological roles of proteolysis. [ABSTRACT FROM AUTHOR]

Human genetic variants that introduce an AG into the intronic region between the branchpoint (BP) and the canonical splice acceptor site (ACC) of protein-coding genes can disrupt pre-mRNA splicing. Using our genome-wide BP database, we delineated the BP-ACC segments of all human introns and found extreme depletion of AG/YAG in the [BP+8, ACC-4] high-risk region. We developed AGAIN as a genome-wide computational approach to systematically and precisely pinpoint intronic AG-gain variants within the BP-ACC regions. AGAIN identified 350 AG-gain variants from the Human Gene Mutation Database, all of which alter splicing and cause disease. Among them, 74% created new acceptor sites, whereas 31% resulted in complete exon skipping. AGAIN also predicts the protein-level products resulting from these two consequences. We performed AGAIN on our exome/genomes database of patients with severe infectious diseases but without known genetic etiology and identified a private homozygous intronic AG-gain variant in the antimycobacterial gene SPPL2A in a patient with mycobacterial disease. AGAIN also predicts a retention of six intronic nucleotides that encode an in-frame stop codon, turning AG-gain into stop-gain. This allele was then confirmed experimentally to lead to loss of function by disrupting splicing. We further showed that AG-gain variants inside the high-risk region led to misspliced products, while those outside the region did not, by two case studies in genes STAT1 and IRF7. We finally evaluated AGAIN on our 14 paired exome-RNAseq samples and found that 82% of AG-gain variants in high-risk regions showed evidence of missplicing. [ABSTRACT FROM AUTHOR]

The International Handbook of Practical Theology, edited by Birgit Weyel, Wilhelm Gräb, Emmanuel Y. Lartey, and Cas Wepener, is a groundbreaking work that takes a global approach to practical theology. It brings together approximately 60 authors from around the world and explores various aspects of religion and religious practices. The handbook does not provide an overview of practical theological debates in specific countries or religious cultures but instead focuses on theoretical approaches, practices, and research settings. While the handbook broadens the horizons of practical theological reflection, it also raises questions about the relevance of individual cases and the need for methodological approaches to establish relationships between different contexts. Overall, the handbook is a rich and provocative resource, although it may not fully address the central aim of practical theology in providing guidance for religious practice. [Extracted from the article]

The article situates religious education and philosophy/ethics didactics - as well as the teaching subjects they open up - into a field of tension between competition and cooperation. On the one hand, both subjects are more established than ever before and are therefore able to enter into dialogue with each other (see section 1). On the other hand, although the didactics of religion has a considerable thematic, methodological and perspectival breadth (see section 2), it does not pay particular attention to the relationship with the didactics of ethics/philosophy - rather, this is to be seen as a "special subject" (see section 3). This is problematic insofar as the didactics of religion could learn a lot from the didactics of ethics, and the question of whether and what ethics and religion(s) can contribute to the interpretation and guidance of life in a modern society is of great importance (see section 4). [ABSTRACT FROM AUTHOR]