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

Mechanistische und Synthetische Ansätze zur Aktivierung von Wasser- und Sauerstoff-Spezies durch Biomimetische Systeme (Mangan- und Cobalt-basierend)

The current work deals with elementary reaction steps involved in the mechanisms that lead to the activation of water and oxygen species by biomimetic systems featuring redox-active manganese and cobalt centers, respectively. The first part of this work (Chapter 2 and Chapter 3) deals with the role of water exchange on metal centers that are relevant for water oxidation in nature. The first of two studies about this subject is addressing the role of manganese(III) in the oxygen evolving cluster (OEC) of the Photosystem-II (PSII), exemplified by two manganese(III) porphyrins, [Mn(III)(TPPS)S2]n– and [Mn(III)(TMpyP)S2]n+ (S = H2O and/or HO) (Chapter 2). For the first time the rate constants (kex) and the activation parameters for the water exchange process on Mn(III) centers have experimentally been determined using temperature and pressure dependent 17O NMR techniques. The calculated effective charge on the Mn centre for the studied complexes is in excellent agreement with the calculated net charges on dangling Mn of the OEC model. In another study a cobalt polyoxometalate, [Co4(II)(H2O)2 [P1W9O34]2]10–, recently discovered to exhibit catalytic water oxidation activity, was investigated in terms of water exchange kinetics to elucidate the water oxidation reaction of this catalyst in regard to its solvent exchange mechanism and stability in the catalytically relevant pH region (pH 610) utilizing temperature and pressure dependent 17O NMR spectroscopy and ultra-high-resolution (UHR) electrospray ionization (ESI) mass spectrometry (MS) and compared with those of the inactive [Co(II)(H2O)1Si1W11O39]6– (Chapter 3). These results provide mechanistic details of the elementary reaction step related to the water oxidation on homogeneous metal oxide catalysts. The influence of a second catalytically active manganese center in close proximity of the SOD-active Mn center on the overall superoxide dismutation rate was studied in the second part (Chapter 4) of this thesis. Two dinuclear seven-coordinate manganese(II) complexes were synthesized and characterized in the solid state as well as in aqueous solutions by performing x-ray structure analyses, SQUID, potentiometry, UHR-ESI-MS, electrochemical and 17O NMR water exchange measurements (varying temperature and pressure), and by determination of SOD-activity. The two manganese(II) centers behave independently from each other and similar to the corresponding mononuclear complexes. The dinuclear amine complex possesses increased complex stability and acidity of the coordinated water molecules in comparison to the mononuclear analogue thus enabling to observe a stable trans-aqua-hydroxo-Mn(II) species. In addition, an influence of this hydroxo ligand on the SOD-activity of the dinuclear complex could be evaluated for the first time. Part three deals with the mechanistic study of a class of literature known pentaazamacrocyclic MnSODm M40401M40404 (Chapter 5). A wide variety of experimental techniques was used to clarify the specific (physico)chemical properties of the single diastereoisomers (M40401, M40402 and M40404) in order to evaluate their influence on the different SOD catalytic ability. In vitro studies for the SOD-activity in deuterated media revealed small secondary kinetic isotopic effects (SKIE) that are most probably related to the involvement of ligand protons/deuterons in the catalytic SOD dismutation cycle. For the first time the SOD reaction was followed by time dependent mass spectrometry at cryogenic temperatures (i.e., –55 °C) to evidence Mn(II)-hydroperoxo and Mn(III)-peroxo species during the course of the SOD cycle in DMF. The +3 character for manganese in the Mn(III)-peroxo intermediate (M40401) was proven by parallel mode EPR spectroscopy. At last, new MnSODm for enhanced cell and mitochondrial uptake were synthesized, analyzed and ultimately tested ex vivo in cell cultures to prove a higher accumulation of the complexes. Two approaches were considered. For one, long aliphatic chains were introduced to the organic framework of the metal complexes (Chapter 6) to accelerate the general passage of the cell membrane (phospholipid bilayers) by either formation of macromolecular structures or by enhanced diffusion resulting from the lipophilic chains. Besides, the second approach introduced an additional positive charge via a cationic and lipophilic triphenylphosphonium (TPP+) moiety to the ligand framework in order to overcome the membrane potential and to increase the accumulation of the complex in the mitochondria (Chapter 7). Overall, the current work gives valuable information about fundamental biochemical processes relevant for the activation of water and oxygen species via synthetic biomimetic compounds of low molecular weight, important for further development and design of successful catalytic and therapeutic metal complexes.In der vorliegenden Arbeit wurden elementare Reaktionsschritte untersucht, welche zur Aktivierung von Aqua- und Sauerstoffspezies durch auf Mangan und Cobalt basierende biomimetische Systeme führen. Der erste Abschnitt dieser Arbeit (Kapitel 2 und Kapitel 3) behandelt die Rolle des Wasseraustausches an Metallzentren, welche für die Wasseroxidation in der Natur eine Rolle spielen. Die erste der beiden Studien mit dieser Thematik addressiert die Rolle von Mangan(III) im Sauerstoffentwickelnden Komplex des Photosystem-II, für welche die beiden Mangan(III) Porphyrine [Mn(III)(TPPS)S2]n- und [Mn(III)TmpyP)S2]n+ (S = H2O und/oder OH-) dienen (Kapitel 2). Erstmals wurden die Geschwindigkeitskonstanten und Aktivierungsparameter für den Wasseraustausch an Mn(III) Metallzentren experimentell mittels temperatur- und druckabhängigen 17O NMR ermittelt. Die berechnete effektive Ladung am Mangan-Zentrum der untersuchten Komplexe ist in exzellenter Übereinstimmung mit den berechneten Nettoladungen eines der Mangan-Zentren des OEC Modells. In einer anderen Studie wurde Wasseraustausch an einem molekularen, rein anorganischen Wasser Oxidationskatalysator basierend auf Cobalt, [Co4(II)(H2O)2 [a-P1W9O34]2]10–, im katalytisch relevanten pH Bereich (pH 6.0 bis pH 10.0) mittels temperatur- und druckabhängiger 17O NMR Spektroskopie sowie ultra-hochauflösender Elektrospray Ionisierungs (UHR-ESI) Massenspektrometrie untersucht und mit dem katalytisch inaktiven [Co(II)(H2O)1Si1W11O39]6– verglichen. Die erhaltenen Ergebnisse liefern mechanistische Details über elementare Reaktionsschritte bei der Wasseroxidation mittels homogener Metalloxid-Katalysatoren unter katalytisch relevanten Bedingungen. Der Einfluss eines zweiten, katalytisch aktiven Manganzentrums in unmittelbarer Nähe eines SOD-aktiven Mangans auf die Gesamtaktivität wurde im zweiten Abschnitt der Arbeit untersucht (Kapitel 4). Zwei dinukleare siebenfach-koordinierte Mn(II)-Komplexe wurden synthetisiert und mittels Röntgenstrukturanalyse, SQUID, UHR-ESI-MS, Potentiometrie, Elektrochemie und 17O NMR Wasseraustausch charakterisiert. Des weiteren wurde die SOD-Aktivität bestimmt. Die beiden Mangan(II) Zentren verhalten sich unabhängig voneinander und ähnlich den entsprechenden mononuklearen Komplexen. Der dinukleare Amino-Komplex besitzt eine erhöhte Komplexstabilität und Acidität des koordinierten Wassermoleküls im Vergleich zum mononuklearen Analogon und ermöglicht es somit eine stabile trans-aqua-hydroxo-Mn(II) Spezies zu beobachten. Darüber hinaus konnte erstmals der Einfluss eines solchen Hydroxo-Liganden auf die SOD-Aktivität untersucht werden. Der dritte Teil der Arbeit befasst sich mit mechanistischen Studien an einer Klasse von pentaazamakrozyklischen MnSODm, M40401-M40404 (Kapitel 5). Eine Vielzahl experimenteller Methoden wurde angewandt, um die spezifischen (physico)chemischen Eigenschaften der einzelnen Diastereomere (M40401, M40402 und M40404) aufzuklären und deren Einfluss auf die unterschiedliche katalytische SOD Fähigkeit dieser Verbindungsklasse abzuschätzen. In vitro Studien zur SOD-Aktivität in deuteriertem Medium ergaben geringe sekundäre kinetische Isotopeneffekte (SKIE), welche wahrscheinlich im Zusammenhang mit der Beteiligung von Ligandprotonen/deuteronen bei der katalytischen SOD Dismutierung stehen. Des Weiteren wurde zum ersten Mal die SOD Reaktion zeitabhängig mittels Massenspektrometrie bei kryogenen Temperaturen (–55 °C) in DMF verfolgt, um Mn(II)-Hydroperoxo (im Fall von M40401/M40403) und Mn(III)-Peroxo (für M40401, M40403, M40404) im Verlauf des katalytischen SOD Zyklus nachzuweisen. Der +3 Charakter beim Mangan im Falle des Mn(III)-Peroxo Intermediates wurde durch EPR Spektroskopie im Parallelmodus bestätigt. Zuletzt wurden neue MnSODm zur besseren Aufnahme in die Mitochondrien und Zellen synthetisiert, analysiert und letzlich in Zellstudien ex vivo getested, um eine erhöhte Akkumulation der Komplexe nachzuweisen. Zwei Ansatzpunkte wurden dabei angegangen. Zum einen wurden lange, aliphatische Kohlenwasserstoffketten in das organische Grundgerüst des Metallkomplexes eingeführt (Kapitel 6), um generell die Passage durch die Zellmembrane (Phosphorlipid-Bilayers) zu beschleunigen - entweder durch Ausbildung makromolekularer Strukturen oder durch erhöhte Diffusion als Resultat der lipophilen Ketten. Der zweite Ansatzpunkt führte eine zusätzliche Ladung mittels einer kationischen Triphenylphosphonium (TPP+) Gruppe in die Ligandstruktur ein, um das Membranpotential zu überwinden und die Akkumulation des Komplexes in den Mitochondrien zu erhöhen (Kapitel 7). Die vorliegende Arbeit gibt insgesamt wertvolle Informationen über fundamentale biochemische Prozesse, welche für die Aktivierung von Aqua- und Sauerstoffspezies durch synthetische, biomimetische Verbindungen niedriger molekularer Masse von Bedeutung sind. Dies ist sowohl entscheidend für eine Weiterentwicklung als auch dem Design von katalytisch und therapeutisch erfolgreichen Metallkomplexen

ADAM17—A Potential Blood-Based Biomarker for Detection of Early-Stage Ovarian Cancer

Ovarian cancer has the highest mortality rate among gynecological tumors. This is based on late diagnosis and the lack of early symptoms. To improve early detection, it is essential to find reliable biomarkers. The metalloprotease ADAM17 could be a potential marker, as it is highly expressed in many solid tumors, including ovarian and breast cancer. The aim of this work is to evaluate the relevance of ADAM17 as a potential diagnostic blood-based biomarker in ovarian cancer. Ovarian cancer cell lines IGROV-1 and A2780, as well as primary patient-derived tumor cells obtained from tumor tissue and ascitic fluid, were cultured to analyze ADAM17 abundance in the culture supernatant. In a translational approach, a cohort of 117 well-characterized ovarian cancer patients was assembled and ADAM17 levels in serum and corresponding ascitic fluid were determined at primary diagnosis. ADAM17 was quantified by enzyme-linked immunosorbent assay (ELISA). In the present study, ADAM17 was detected in the culture supernatant of ovarian cancer cell lines and primary cells. In addition, ADAM17 was found in serum and ascites of ovarian cancer patients. ADAM17 level was significantly increased in ovarian cancer patients compared to an age-matched control group (p < 0.0001). Importantly early FIGO I/II stages, which would not have been detected by CA-125, were associated with higher ADAM17 concentrations (p = 0.007). This is the first study proposing ADAM17 as a serum tumor marker in the setting of a gynecological tumor disease. Usage of ADAM17 in combination with CA-125 and other markers could help detect early stages of ovarian cancer

Beneficial Effects of a Dietary Weight Loss Intervention on Human Gut Microbiome Diversity and Metabolism Are Not Sustained during Weight Maintenance

Objective: In the present study, we examined the effect of a very low-calorie diet(VLCD)-based obesity program on human gut microbiome diversity and metabolism during weight loss and weight maintenance. Methods: Obese subjects underwent 3 months of VLCD followed by 3 months of weight maintenance. A lean and an obese control group were included. The microbiome was characterized by performing high-throughput dual-indexed 16S rDNA amplicon sequencing. Results: At baseline, a significant difference in the Firmicutes/Bacteroidetes ratio between the lean and obese individuals was observed (p = 0.047). The VLCD resulted in significant alterations in gut microbiome diversity from baseline to 3 months (p = 0.0053). Acinetobacter represented an indicator species for the observed effect (indicator value = 0.998, p = 0.006). Metabolic analyses revealed alterations of the bacterial riboflavin pathway from baseline to 3 months (pnom = 0.0078). These changes in diversity and bacterial metabolism induced by VLCD diminished during the weight maintenance phase, despite sustained reductions in body weight and sustained improvements of insulin sensitivity. Conclusion: The present data show that a VLCD is able to beneficially alter both gut microbiome diversity and metabolism in obese humans, but that these changes are not sustained during weight maintenance. This finding might suggest that the microbiome should be targeted during obesity programs

Dinuclear Seven-Coordinate Mn(II) Complexes: Effect of Manganese(II)-Hydroxo Species on Water Exchange and Superoxide Dismutase Activity

Two dinuclear seven-coordinate manganese­(II) complexes containing two pentaazamacrocyclic subunits, with imine or amine functionalities, respectively, have been synthesized and characterized in the solid state as well as in aqueous solutions of different pH, by performing X-ray structure analyses, SQUID, potentiometric, electron spray ionization-mass spectrometry (ESI-MS), electrochemical, and ¹⁷O NMR water exchange measurements (varying temperature and pressure), and by determination of SOD activity. The two manganese­(II) centers within the dinuclear structures behave independently from each other and similarly to the manganese centers in the corresponding mononuclear complexes. However, the dinuclear amine complex possesses increased complex stability and acidity of the coordinated water molecules (p<i>K</i>_a2 = 8.92) in comparison to the corresponding mononuclear analogue. This allowed us to observe a stable <i>trans</i>-aqua-hydroxo-Mn­(II) species in an aqueous solution and to study for the first time the <i>trans</i>-effect of the hydroxo group on the water lability on any divalent metal center in general. The observed <i>trans</i>-labilizing effect of the hydroxo ligand is much smaller than in the case of aqua-hydroxo-M­(III) trivalent metal species. Whether this is a general property of <i>trans</i>-aqua-hydroxo-M­(II) species, or if it is specific for Mn­(II) and/or to the seven-coordinate structures, remains to be seen and motivates future studies. In addition, an influence of the hydroxo ligand on the SOD activity of manganese­(II) complexes could be evaluated for the first time as well. Compared with the mononuclear analogue, which is not able to form stable hydroxo species, our pH dependent studies on the SOD activity of the dinuclear amine complex have indicated that the hydroxo ligand may promote protonation and release of the product H₂O₂, especially in solutions of higher pH values, by increasing its p<i>K</i>_a value

Dinuclear Seven-Coordinate Mn(II) Complexes: Effect of Manganese(II)-Hydroxo Species on Water Exchange and Superoxide Dismutase Activity

Two dinuclear seven-coordinate manganese­(II) complexes containing two pentaazamacrocyclic subunits, with imine or amine functionalities, respectively, have been synthesized and characterized in the solid state as well as in aqueous solutions of different pH, by performing X-ray structure analyses, SQUID, potentiometric, electron spray ionization-mass spectrometry (ESI-MS), electrochemical, and ¹⁷O NMR water exchange measurements (varying temperature and pressure), and by determination of SOD activity. The two manganese­(II) centers within the dinuclear structures behave independently from each other and similarly to the manganese centers in the corresponding mononuclear complexes. However, the dinuclear amine complex possesses increased complex stability and acidity of the coordinated water molecules (p<i>K</i>_a2 = 8.92) in comparison to the corresponding mononuclear analogue. This allowed us to observe a stable <i>trans</i>-aqua-hydroxo-Mn­(II) species in an aqueous solution and to study for the first time the <i>trans</i>-effect of the hydroxo group on the water lability on any divalent metal center in general. The observed <i>trans</i>-labilizing effect of the hydroxo ligand is much smaller than in the case of aqua-hydroxo-M­(III) trivalent metal species. Whether this is a general property of <i>trans</i>-aqua-hydroxo-M­(II) species, or if it is specific for Mn­(II) and/or to the seven-coordinate structures, remains to be seen and motivates future studies. In addition, an influence of the hydroxo ligand on the SOD activity of manganese­(II) complexes could be evaluated for the first time as well. Compared with the mononuclear analogue, which is not able to form stable hydroxo species, our pH dependent studies on the SOD activity of the dinuclear amine complex have indicated that the hydroxo ligand may promote protonation and release of the product H₂O₂, especially in solutions of higher pH values, by increasing its p<i>K</i>_a value

Amphiphilic Pentaazamacrocyclic Manganese Superoxide Dismutase Mimetics

Five newly functionalized pentaazamacrocyclic manganese complexes, with variable lengths and amounts of the aliphatic groups (three compounds with one linear chain containing 12, 16, and 22 carbon atoms, i.e., Mn<b>L1</b>, Mn<b>L2</b>, and Mn<b>L3</b>, respectively, as well as two compounds containing two C12 and C16 chains, Mn<b>L4</b> and Mn<b>L5</b>, respectively) that are derivatives of the known SOD mimetic, Mn­(Me₂-Pyane), have been synthesized. These amphiphilic complexes were characterized by the ESI mass spectrometry, potentiometric titrations, light scattering, cyclic voltammetry, and direct stopped-flow determination of their SOD activity at pH 8.1 and 7.4 (in phosphate and HEPES buffers). The formation of supramolecular aggregates that predominantly exist in the solution as a defined micellar/nanostructure assembly, with an average 400 nm size, has been demonstrated for Mn<b>L1</b>. The biological effects of the selected complexes (Mn<b>L1</b> and Mn<b>L2</b>) on the superoxide level in cytosol and mitochondria have been tested, as well as their effects on the prevention of the lipid peroxidation induced by paraquat. Advantages and disadvantages of the lipophilic pentaazamacrocyclic manganese SOD mimetics in comparison to the corresponding nonsubstituted SOD active complex have been discussed

A comprehensive evaluation of catalase-like activity of different classes of redox-active therapeutics

Because of the increased insight into the biological role of hydrogen peroxide (H2O2) under physiological and pathological conditions and the role it presumably plays in the action of natural and synthetic redox-active drugs, there is a need to accurately define the type and magnitude of reactions that may occur with this intriguing and key species of redoxome. Historically, and frequently incorrectly, the impact of catalase-like activity has been assigned to play a major role in the action of many redox-active drugs, mostly SOD mimics and peroxynitrite scavengers, and in particular MnTBAP3- and Mn salen derivatives. The advantage of one redox-active compound over another has often been assigned to the differences in catalase-like activity. Our studies provide substantial evidence that Mn(III) N-alkylpyridylporphyrins couple with H2O2 in actions other than catalase-related. Herein we have assessed the catalase-like activities of different classes of compounds: Mn porphyrins (MnPs), Fe porphyrins (FePs), Mn(III) salen (EUK-8), and Mn(II) cyclic polyamines (SOD-active M40403 and SOD-inactive M40404). Nitroxide (tempol), nitrone (NXY-059), ebselen, and MnCl2, which have not been reported as catalase mimics, were used as negative controls, while catalase enzyme was a positive control. The dismutation of H2O2 to O2 and H2O was followed via measuring oxygen evolved with a Clark oxygen electrode at 25°C. The catalase enzyme was found to have kcat(H2O2)=1.5×106 M-1 s-1. The yield of dismutation, i.e., the maximal amount of O2 evolved, was assessed also. The magnitude of the yield reflects an interplay between the kcat(H2O2) and the stability of compounds toward H2O2-driven oxidative degradation, and is thus an accurate measure of the efficacy of a catalyst. The kcat(H2O2) values for 12 cationic Mn(III) N-substituted (alkyl and alkoxyalkyl) pyridylporphyrin-based SOD mimics and Mn(III) N,N′-dialkylimidazolium porphyrin, MnTDE-2-ImP5+, ranged from 23 to 88 M-1 s-1. The analogous Fe(III) N-alkylpyridylporphyrins showed ∼10-fold higher activity than the corresponding MnPs, but the values of kcat(H2O2) are still ∼4 orders of magnitude lower than that of the enzyme. While the kcat(H2O2) values for Fe ethyl and n-octyl analogs were 803.5 and 368.4 M-1 s-1, respectively, the FePs are more prone to H2O2-driven oxidative degradation, therefore allowing for similar yields in H2O2 dismutation as analogous MnPs. The kcat(H2O2) values are dependent on the electron deficiency of the metal site as it controls the peroxide binding in the first step of the dismutation process. SOD-like activities depend on electron deficiency of the metal site also, as it controls the first step of O2•- dismutation. In turn, the kcat(O2•-) parallels the kcat(H2O2). Therefore, the electron-rich anionic non-SOD mimic MnTBAP3- has essentially very low catalase-like activity, kcat(H2O2)=5.8 M-1 s-1. The catalase-like activities of Mn(III) and Fe(III) porphyrins are at most, 0.0004 and 0.05% of the enzyme activity, respectively. The kcat(H2O2) values of 8.2 and 6.5 M-1 s-1 were determined for electron-rich Mn(II) cyclic polyamine-based compounds, M40403 and M40404, respectively. The EUK-8, with modest SOD-like activity, has only slightly higher kcat(H2O2)=13.5 M-1 s-1. The biological relevance of kcat(H2O2) of MnTE-2-PyP5+, MnTDE-2-ImP5+, MnTBAP3-, FeTE-2-PyP5+, M40403, M40404, and Mn salen was evaluated in wild-type and peroxidase/catalase-deficient E. coli

Detailed Transcriptional Landscape of Peripheral Blood Points to Increased Neutrophil Activation in Treatment-Naive Inflammatory Bowel Disease

Background and Aims Inflammatory bowel disease [IBD] is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohns disease [CD] or ulcerative colitis [UC]. These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and, thus, common immune regulatory pathways. Methods Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naive [n = 110] and treatment-exposed [n = 177] IBD patients as well as symptomatic [n = 65] and healthy controls [n = 95]. Results Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naive IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, IL1B was identified as the central gene. Levels of co-expression among IL1B and chemosensing receptor [CXCR1/2 and FPR1/2] genes were reduced in the blood of IBD patients when compared with healthy controls. Conclusions Immune dysregulation seen in peripheral blood transcriptomes of treatment-naive IBD patients is mainly driven by neutrophil activation.Funding Agencies|European UnionEuropean Commission [733100]; German Research Foundation (DFG) Excellence Cluster Precision Medicine in Chronic Inflammation [PMI]German Research Foundation (DFG) [EXC 2167]; Swedish Foundation for Strategic Research [BIO IBD] [RB13-0160]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2020-02021]</p