HISTONE DEACETYLASES IN INFLAMMATORY BOWEL DISEASES - INFLUENCE ON THE ANTIMICROBIAL BARRIER

The development and clinical behavior of the two major inflammatory bowel diseases (IBD) subgroups Crohn’s disease (CD) and ulcerative colitis (UC), are determined by multiple underlying factors leading to an impaired antimicrobial barrier and chronic inflammation. Contributing environmental influences on the onset of the diseases such as the intestinal microbiota, antibiotics use, smoking, or nutrition have more and more entered the limelight of the field. The increasing incidence of IBD, the big variance in disease progression, and the discrepancy between monocygotic twins urgently impose the question how exactly environmental factors might impact on IBD risk and progression. The emerging field of epigenetics offers a mechanistic framework to dissect the present interplay between environment and genome in the context of IBD and will allow a better understanding of disease pathology. Histone deacetylases (HDACs) are important epigenetic factors implicated in intestinal tissue homeostasis. They deacetylate histones but also a vast number of non-histone proteins, e.g. the transcription factor NF-κB, thereby impacting on transcriptional regulation on different levels. A role for HDACs in the epigenetically-mediated modulation of hBDs has been demonstrated in a number of studies, underscoring a potential involvement of HDACs in the β-defensin-related defects found in colonic IBD. In addition, inhibiting HDACs has been proposed as an IBD intervention, making more detailed studies on the role of HDACs in gut antimicrobial barrier function indespensible. Firstly, in this work, a systematic overview of class I HDAC mRNA intestinal expression has been performed in a large cohort of IBD patients. First insights on the expression pattern on the protein level are also given. Secondly, this study aimed to contribute to the small body of knowledge on HDAC-mediated epigenetic control of antimicrobial peptide (AMP) expression; focusing on human β-defensin 2 (hBD2). Herein, emphasis has been laid on the therapeutically relevant probiotic E. coli Nissle 1917 (EcN) as a potent hBD2-inducing factor in addition to the pro-inflammatory cytokine IL1β and the bacterial membrane component LPS. In vitro HDAC inhibition (HDACi) in colonic epithelial cells generated a strong, NF-κB-dependent enhancement of EcN- and LPS-induced hBD2 expression, but also of the pro-inflammatory cytokine IL8. For IL1β-induced hBD2, the observed augmentation seems to be mediated by additional transducing factors and conditions depending on which HDACs are inhibited. In the case of IL1β, the enhancing effect of HDACi on hBD2 could be evinced in a second colonic epithelial cell line. In an effort to closer mimic the in vivo situation, an ex vivo human colonic biopsy culture has been established with almost identical culture conditions using IBD and healthy control tissue. This was aimed to allow a comparison to the in vitro results, since it is of substantial importance to learn how a more complex, non-tumorous human tissue compound reacts to HDACi. Strikingly, in this context, an opposing impact of HDACi on EcN-stimulated hBD2 expression was observed. Inhibiting HDAC function using pan-HDAC inhibitors hindered hBD2 expression instead of enhancing it, but did not impede IL8 expression. Whether these contrary results could be due to the malignant nature of the in vitro cell lines was investigated using ex vivo treated human colorectal cancer tissue showing the same response as non-cancerous intestinal biopsies. In addition, first insights into the reactivity of a primary, non-transformed gingival epithelial cell line towards HDACi showed a comparable hBD2 response upon IL1β-stimulation as did the cancerous intestinal cell lines. Furthermore, ex vivo fold induction levels of hBD2 in CD patients have been reduced hinting towards a disturbance in hBD2 inducibility in response to EcN. In this study, differential intestinal mRNA expression patterns have been unveiled for class I HDACs. Importantly, a strong regulatory influence of HDACs on the expression of hBD2 could be demonstrated. The simultaneous upregulation of IL8 in epithelial cells and the missing downregulation of the same in biopsy culture under HDACi, advises caution in considering HDACi as therapeutic in IBD. Furthermore, a dependency of the HDACi-induced hBD2 enhancement on NF-κB could be found. Utilizing different culture approaches, the obtained results argue for a cellular context-dependent modulation of the epigenetic regulation of hBD2 expression by HDACs. Overall, this work promotes the understanding of epigenetics as the conjoining integrative mechanism between genome and environment, bridging the way to answering many yet elusive questions in the pathogenesis of IBD

Responsible Artificial Intelligence: A Structured Literature Review

Our research endeavors to advance the concept of responsible artificial intelligence (AI), a topic of increasing importance within EU policy discussions. The EU has recently issued several publications emphasizing the necessity of trust in AI, underscoring the dual nature of AI as both a beneficial tool and a potential weapon. This dichotomy highlights the urgent need for international regulation. Concurrently, there is a need for frameworks that guide companies in AI development, ensuring compliance with such regulations. Our research aims to assist lawmakers and machine learning practitioners in navigating the evolving landscape of AI regulation, identifying focal areas for future attention. This paper introduces a comprehensive and, to our knowledge, the first unified definition of responsible AI. Through a structured literature review, we elucidate the current understanding of responsible AI. Drawing from this analysis, we propose an approach for developing a future framework centered around this concept. Our findings advocate for a human-centric approach to Responsible AI. This approach encompasses the implementation of AI methods with a strong emphasis on ethics, model explainability, and the pillars of privacy, security, and trust

Biblio-Tekken – niemand kämpft für sich allein

Seit Herbst 2020 gibt es die Online-Community Gamebrarians, die Menschen zusammenbringt, die einerseits eine Leidenschaft für Videospiele und andererseits einen beruflichen Bezug zu Bibliotheken haben oder anstreben. Basierend auf einer Umfrage unter den knapp 200 Mitgliedern im Frühling 2023, wird die Community mit ihren Geschichten vorgestellt und analysiert. Am Ende steht ein Fazit und die Frage, was wir als Bibliothekswelt von den Gamebrarians über Community-Building lernen können

Bibliotheken als Safe(r) Spaces für die LGBTQIA+ Community? Hands-on Lab auf der BiblioCon 2024

Dieser Artikel fasst die ursprünglichen Erwartungen und die am Ende tatsächlich entwickelten Ergebnisse des Hands-on Labs „Mehr Glitzer? How to LGBTQIA+ Safe Space für Bibliotheken“ auf der BiblioCon 2024 zusammen. Neben der Konzeptentwicklung wird auch auf die Entstehung des Themenwunschs eingegangen. Am Ende steht ein Fazit, welches die hohe Resonanz für den Workshop, die Diskussionstiefe sowie die Ergebnisse in den Kontext zukünftiger Entwicklungen in der Bibliothekswelt setzt

CXC receptor-4 mRNA silencing abrogates CXCL12-induced migration of colorectal cancer cells

<p>Abstract</p> <p>Background</p> <p>Interactions between CXCR4 and its ligand CXCL12 have been shown to be involved in cancer progression in colorectal cancer (CRC). We performed a comparative CXCL12/CXCR4 expression analysis and assessed the effect of external CXCL12 stimulation on migration of CRC cells without and with CXCR4 inhibition.</p> <p>Methods</p> <p>Expression of CXCL12/CXCR4 was assessed by quantitative real-time PCR, ELISA and immunohistochemistry in resection specimens of 50 CRC patients as well as in the corresponding normal tissues and in three human CRC cell lines with different metastatic potential (Caco-2, SW480 and HT-29). Migration assays were performed after stimulation with CXCL12 and CXCR4 was inhibited by siRNA and neutralizing antibodies.</p> <p>Results</p> <p>In CRC tissues CXCL12 was significantly down-regulated and CXCR4 was significantly up-regulated compared to the corresponding normal tissues. In cell lines CXCR4 was predominantly expressed in SW480 and less pronounced in HT-29 cells. CXCL12 was only detectable in Caco-2 cells. CXCL12 stimulation had no impact on Caco-2 cells but significantly increased migration of CXCR4 bearing SW480 and HT-29 cells. This effect was significantly abrogated by neutralizing anti-CXCR4 antibody as well as by CXCR4 siRNAs (P < 0.05).</p> <p>Conclusions</p> <p>CXCR4 expression was up-regulated in CRC and CXCL12 stimulation increased migration in CXCR4 bearing cell lines. Migration was inhibited by both neutralizing CXCR4 antibodies and CXCR4 siRNAs. Thus, the expression and functionality of CXCR4 might be associated with the metastatic potential of CRC cells and CXCL12/CXCR4 interactions might therefore constitute a promising target for specific treatment interventions.</p

Eleven strategies for making reproducible research and open science training the norm at research institutions

Across disciplines, researchers increasingly recognize that open science and reproducible research practices may accelerate scientific progress by allowing others to reuse research outputs and by promoting rigorous research that is more likely to yield trustworthy results. While initiatives, training programs, and funder policies encourage researchers to adopt reproducible research and open science practices, these practices are uncommon inmanyfields. Researchers need training to integrate these practicesinto their daily work. We organized a virtual brainstorming event, in collaboration with the German Reproducibility Network, to discuss strategies for making reproducible research and open science training the norm at research institutions. Here, weoutline eleven strategies, concentrated in three areas:(1)offering training, (2)adapting research assessment criteria and program requirements, and (3) building communities. We provide a brief overview of each strategy, offer tips for implementation,and provide links to resources. Our goal is toencourage members of the research community to think creatively about the many ways they can contribute and collaborate to build communities,and make reproducible research and open sciencetraining the norm. Researchers may act in their roles as scientists, supervisors, mentors, instructors, and members of curriculum, hiring or evaluation committees. Institutionalleadership and research administration andsupport staff can accelerate progress by implementing change across their institution

Eleven strategies for making reproducible research and open science training the norm at research institutions

Across disciplines, researchers increasingly recognize that open science and reproducible research practices may accelerate scientific progress by allowing others to reuse research outputs and by promoting rigorous research that is more likely to yield trustworthy results. While initiatives, training programs, and funder policies encourage researchers to adopt reproducible research and open science practices, these practices are uncommon inmanyfields. Researchers need training to integrate these practicesinto their daily work. We organized a virtual brainstorming event, in collaboration with the German Reproducibility Network, to discuss strategies for making reproducible research and open science training the norm at research institutions. Here, weoutline eleven strategies, concentrated in three areas:(1)offering training, (2)adapting research assessment criteria and program requirements, and (3) building communities. We provide a brief overview of each strategy, offer tips for implementation,and provide links to resources. Our goal is toencourage members of the research community to think creatively about the many ways they can contribute and collaborate to build communities,and make reproducible research and open sciencetraining the norm. Researchers may act in their roles as scientists, supervisors, mentors, instructors, and members of curriculum, hiring or evaluation committees. Institutionalleadership and research administration andsupport staff can accelerate progress by implementing change across their institution

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead