Rolle des Adaptermoleküls MyD88 im Mausmodell der Lichtalterung und Photokarzinogenese

Die Haut ist eines der größten Barriereorgane des Körpers und schützt diesen vor Pathogenen oder Umwelteinflüssen wie UV-Strahlung. Die chronische Exposition gegenüber UVB-Strahlen induziert die Bildung von sterilen Gefahrensignalen (DAMPs) und führt zur vorzeitigen Alterung der Haut (Lichtalterung) und zu nicht melanozytären Hauttumoren (Photokarzinogenese). DAMPs führen über TLR-abhängige Signalwege zu der Aktivierung des angeborenen Immunsystems, bei denen das Adapterprotein MyD88 eine zentrale Rolle spielt. In dieser Arbeit wurde im Mausmodell untersucht, ob das angeborene Immunsystem die Entwicklung der Lichtalterung und Photokarzinogenese beeinflusst. Im Modell der Lichtalterung wiesen MyD88-defiziente Mäuse eine erhöhte Bildung von DNS-Schäden auf, die durch die Expression von MyD88 exklusiv in Makrophagen auf das Niveau der MyD88-profizienten Mäuse reduziert werden konnte, wohingegen die MyD88-abhängige Expression in Mastzellen partiell und in Keratinozyten oder DZ keinen Einfluss hatten. Dies zeigt, dass MyD88-abhängige Signalwege besonders in Makrophagen zu verminderten DNS-Schäden in der Haut führen. Des Weiteren zeigte sich, dass die Verdickung der Epidermis und die Bildung der Mastozytose durch chronische Exposition gegenüber UVB-Strahlung abhängig von MyD88-induzierten Signalwegen waren. Während die Expression von MyD88 in Keratinozyten, DZ oder Mastzellen die Epidermisverdickung wiederherstellen konnte, wurde die Mastozytose alleinig durch die MyD88-Expression in Mastzellen und partiell in Makrophagen und DZ beeinflusst. Diese Arbeit zeigt, dass MyD88-abhängige Signalwege einen Einfluss auf die verschiedenen Charakteristika der Lichtalterung hatten. Jedoch wirkten sich diese stark abhängig vom Zelltyp aus. In Abwesenheit des Adapterproteins MyD88 wurde eine verzögerte Bildung von UVB-induzierten Hauttumoren beobachtet. Interessanterweise führte die Expression von MyD88-abhängigen Signalwegen in Keratinozyten zu einer späten Bildung von Hauttumoren, die auch mit einer verringerten Tumoranzahl pro Maus einhergingen. In weiteren Studien könnten die genauen Mechanismen, die zur UVB-induzierten Entstehung von DNS-Schäden, der Epidermisverdickung und der Mastozytose in Abhängigkeit vom angeborenen Immunsystems führen, näher untersucht werden.The skin is the first line of defense against pathogens or environmental influences as UVBirradiation. Chronic exposure of UVB-irradiation induces the formation of danger-associated molecular patterns (DAMPs) and leads to skin aging (photoaging) and tumor formation (photocarcinogenesis). DAMPs can activate TLR signaling pathways via the central adapter protein MyD88. This study aims to analyse whether the activation of MyD88-induced signaling pathways contributes to UVB-induced photoaging and photocarcinogenesis. In the in vivo model of photoaging MyD88-deficiency led to enhanced DNA damage such as formation of cyclobutane pyrimidine dimers (CPDs). MyD88-signaling exclusively in macrophages attenuated CPD levels, while the expression of MyD88 in mast cells could only partially decrease the formation of CPDs. In contrast MyD88-dependent signaling pathways in keratinocytes or CCL17-positive dendritic cells had no influence of the CPD formation. Furthermore chronic UVB-irradiation led to epidermal hyperplasia and an increase of dermal mast cell numbers. In MyD88-deficient mice reduced epidermal thickening and reduced dermal mast cell numbers were detected compared to wildtype mice. Expression of MyD88 contributed to epidermal thickening in keratinocytes, CCL17-positive dendritic cells or mast cells, while the expression of MyD88 solely in mast cells could restore the effect of mastocytosis. These data indicate that MyD88 influences many hallmarks of UVB-induced photoaging, but these effects of MyD88-signaling are dependent on the different cell types. Furthermore the deficiency of MyD88 led to delayed formation of skin tumors in an in vivo model of photocarcinogenesis. Interestingly the expression of MyD88 only in keratinocytes showed a later development of skin tumors and decreased numbers of tumors per mouse. Additional studies may focus on the detailed mechanisms which are required for the MyD88- dependent and UVB-induced formation of DNA damage, epidermal thickening and mastocytosis

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (TFH cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting TFH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFH cell differentiation and a promising target for TFH cell–skewing vaccine adjuvants

IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression

Immune checkpoint blockade therapy induces the AHR-activating enzyme IL4I1, which promotes tumor progression, through its effects on tumor cell motility and adaptive immunity

A consensus document on definition and diagnostic criteria for orthorexia nervosa

Purpose: Since the term orthorexia nervosa (ON) was coined from the Greek (ὀρθός, right and ὄρεξις, appetite) in 1997 to describe an obsession with “correct” eating, it has been used worldwide without a consistent definition. Although multiple authors have proposed diagnostic criteria, and many theoretical papers have been published, no consensus definition of ON exists, empirical primary evidence is limited, and ON is not a standardized diagnosis. These gaps prevent research to identify risk and protective factors, pathophysiology, functional consequences, and evidence-based therapeutic treatments. The aims of the current study are to categorize the common observations and presentations of ON pathology among experts in the eating disorder field, propose tentative diagnostic criteria, and consider which DSM chapter and category would be most appropriate for ON should it be included. Methods: 47 eating disorder researchers and multidisciplinary treatment specialists from 14 different countries across four continents completed a three-phase modified Delphi process, with 75% agreement determined as the threshold for a statement to be included in the final consensus document. In phase I, participants were asked via online survey to agree or disagree with 67 statements about ON in four categories: A–Definition, Clinical Aspects, Duration; B–Consequences; C–Onset; D–Exclusion Criteria, and comment on their rationale. Responses were used to modify the statements which were then provided to the same participants for phase II, a second round of feedback, again in online survey form. Responses to phase II were used to modify and improve the statements for phase III, in which statements that met the predetermined 75% of agreement threshold were provided for review and commentary by all participants. Results: 27 statements met or exceeded the consensus threshold and were compiled into proposed diagnostic criteria for ON. Conclusions: This is the first time a standardized definition of ON has been developed from a worldwide, multidisciplinary cohort of experts. It represents a summary of observations, clinical expertise, and research findings from a wide base of knowledge. It may be used as a base for diagnosis, treatment protocols, and further research to answer the open questions that remain, particularly the functional consequences of ON and how it might be prevented or identified and intervened upon in its early stages. Although the participants encompass many countries and disciplines, further research will be needed to determine if these diagnostic criteria are applicable to the experience of ON in geographic areas not represented in the current expert panel. Level of evidence_ Level V: opinions of expert committee

Distribution Analysis of Hydrogenases in Surface Waters of Marine and Freshwater Environments

Background Surface waters of aquatic environments have been shown to both evolve and consume hydrogen and the ocean is estimated to be the principal natural source. In some marine habitats, H2 evolution and uptake are clearly due to biological activity, while contributions of abiotic sources must be considered in others. Until now the only known biological process involved in H2 metabolism in marine environments is nitrogen fixation. Principal Findings We analyzed marine and freshwater environments for the presence and distribution of genes of all known hydrogenases, the enzymes involved in biological hydrogen turnover. The total genomes and the available marine metagenome datasets were searched for hydrogenase sequences. Furthermore, we isolated DNA from samples from the North Atlantic, Mediterranean Sea, North Sea, Baltic Sea, and two fresh water lakes and amplified and sequenced part of the gene encoding the bidirectional NAD(P)-linked hydrogenase. In 21% of all marine heterotrophic bacterial genomes from surface waters, one or several hydrogenase genes were found, with the membrane-bound H2 uptake hydrogenase being the most widespread. A clear bias of hydrogenases to environments with terrestrial influence was found. This is exemplified by the cyanobacterial bidirectional NAD(P)-linked hydrogenase that was found in freshwater and coastal areas but not in the open ocean. Significance This study shows that hydrogenases are surprisingly abundant in marine environments. Due to its ecological distribution the primary function of the bidirectional NAD(P)-linked hydrogenase seems to be fermentative hydrogen evolution. Moreover, our data suggests that marine surface waters could be an interesting source of oxygen-resistant uptake hydrogenases. The respective genes occur in coastal as well as open ocean habitats and we presume that they are used as additional energy scavenging devices in otherwise nutrient limited environments. The membrane-bound H2-evolving hydrogenases might be useful as marker for bacteria living inside of marine snow particles

Clinical and virological characteristics of hospitalised COVID-19 patients in a German tertiary care centre during the first wave of the SARS-CoV-2 pandemic: a prospective observational study

Purpose: Adequate patient allocation is pivotal for optimal resource management in strained healthcare systems, and requires detailed knowledge of clinical and virological disease trajectories. The purpose of this work was to identify risk factors associated with need for invasive mechanical ventilation (IMV), to analyse viral kinetics in patients with and without IMV and to provide a comprehensive description of clinical course. Methods: A cohort of 168 hospitalised adult COVID-19 patients enrolled in a prospective observational study at a large European tertiary care centre was analysed. Results: Forty-four per cent (71/161) of patients required invasive mechanical ventilation (IMV). Shorter duration of symptoms before admission (aOR 1.22 per day less, 95% CI 1.10-1.37, p < 0.01) and history of hypertension (aOR 5.55, 95% CI 2.00-16.82, p < 0.01) were associated with need for IMV. Patients on IMV had higher maximal concentrations, slower decline rates, and longer shedding of SARS-CoV-2 than non-IMV patients (33 days, IQR 26-46.75, vs 18 days, IQR 16-46.75, respectively, p < 0.01). Median duration of hospitalisation was 9 days (IQR 6-15.5) for non-IMV and 49.5 days (IQR 36.8-82.5) for IMV patients. Conclusions: Our results indicate a short duration of symptoms before admission as a risk factor for severe disease that merits further investigation and different viral load kinetics in severely affected patients. Median duration of hospitalisation of IMV patients was longer than described for acute respiratory distress syndrome unrelated to COVID-19

Tumor Microenvironment in Pancreatic Intraepithelial Neoplasia

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression

Late Holocene coastline and landscape changes to the west of Ephesus, Turkey

Palaeogeographical research regarding coastline and landscape changes has been conducted in the Kucuk Menderes graben and the environs of the ancient city of Ephesus in Western Turkey for a few decades. Based on geophysical data, multi-proxy and microfaunal analyses of sediment cores, 14C-AMS age estimates and diagnostic ceramics, this study presents for the first time results of an area close to the present coastline, where a Byzantine church is located on top of a small hill. The results reveal that this mica schist hill turned into an island during the 2nd/1st millennium BCE. It was reconnected to the mainland via a tombolo during the 5th century CE. Drill cores and geophysical measurements surrounding the hill show massive stone layers which were deposited intentionally during the 5th/6th century CE when the Byzantine church was built. Geophysical images point to wall structures in the surroundings of the hill. The area to the northeast hosts a small harbour site. When the coastline continued to shift further to the west, this site was still connected to the sea by the Kucuk Menderes river. (C) 2017 Elsevier Ltd and INQUA. All rights reserved