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Social Sciences and Humanities research is divided across a wide array of disciplines, sub- disciplines and languages. While this specialisation makes it possible to investigate the extensive variety of SSH topics, it also leads to a fragmentation that prevents SSH research from reaching its full potential. Use and reuse of research is suboptimal, interdisciplinary collaboration possibilities are often missed partially because of missing standards and referential keys between disciplines. Often, the reuse of data may paradoxically complicate a relevant sorting of data and a trust relationship between researchers. As a result, societal, economic and academic impacts are limited. Conceptually, there is a wealth of transdisciplinary collaborations, but in practice there is a need to help researchers and research institutions to connect them and support them, to prepare the research data for these overarching approaches and to make them findable and usable. The TRIPLE (Targeting Researchers through Innovative Practices and Linked Exploration) project is a practical answer to the above issues, as it aims at designing and developing the European discovery platform dedicated to Social Sciences and Humanities resources. Funded under the European Commission program INFRAEOSC-02-2019 “Prototyping new innovative services”, thanks to a consortium of 19 partners, TRIPLE will develop a full multilingual and multicultural solution for the discovery and the reuse of Social Sciences and Humanities resources. The project started in October 2019 for a duration of 42 months thanks to European funding of 5.6 million €.

Objective: Smoking, with a prevalence of about 25%-30% in Switzerland, is proven to cause major systemic, avoidable diseases including lung cancer, increasing societies morbidity and mortality. Diverse strong quitting smoking recommendations have been made available providing advice facilitating smoking cessation globally. In other European countries like Germany, clinical practice guidelines for smoking cessation services have been implemented. However, in Switzerland, there is still no national consensus on a comprehensive smoking cessation program for lung cancer patients nor on the adequate provider. Our primary aim was to assess the current status of smoking cessation practice among specialists, mainly involved in lung cancer care, in Switzerland in order to uncover potential shortcomings., Material and Methods: A self-designed 14-items questionnaire, which was reviewed and approved by our working group consisting of pneumologists and thoracic surgeons, on demographics of the participants, the status of smoking cessation in Switzerland and specialists' opinion on smoking cessation was sent to thoracic surgeons and pneumologists between January 2024 and March 2024 via the commercially available platform www.surveymonkey.com. Data was collected and analysed with descriptive statistics., Results: Survey response rate was 22.25%. Smoking cessation was felt to positively affect long term survival and perioperative outcome in lung cancer surgery. While 33 (37.08%) physicians were offering smoking cessation themselves usually and always (35.96%), only 12 (13.48%) were always referring their patients for smoking cessation. Patient willingness was clearly identified as main factor for failure of cessation programs by 63 respondents (70.79%). Pneumologists were deemed to be the most adequate specialist to offer smoking cessation (49.44%) in a combination of specialist counselling combined with pharmaceutic support (80.90%)., Conclusion: The development of Swiss national guidelines for smoking cessation and the implementation of cessation counselling in standardized lung cancer care pathways is warranted in Switzerland to improve long-term survival and perioperative outcome of lung cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Minervini, Kestenholz, Rassouli, Pohle and Mayer.)

Aims: With the 2022 pulmonary hypertension (PH) definition, the mean pulmonary artery pressure (mPAP) threshold for any PH was lowered from ≥25 to >20 mmHg, and the pulmonary vascular resistance (PVR) value to differentiate between isolated post-capillary PH (IpcPH) and combined pre- and post-capillary PH (CpcPH) was reduced from >3 Wood units (WU) to >2 WU. We assessed the impact of this change in the PH definition in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR)., Methods and Results: Severe AS patients ( n = 503) undergoing pre-AVR cardiac heart catheterization were classified according to both the 2015 and 2022 definitions. The post-AVR mortality [median follow-up 1348 (interquartile range 948-1885) days] was assessed. According to the 2015 definition, 219 (44% of the entire population) patients had PH: 63 (29%) CpcPH, 125 (57%) IpcPH, and 31 (14%) pre-capillary PH. According to the 2022 definition, 321 (+47%) patients were diagnosed with PH, and 156 patients (31%) were re-classified: 26 patients from no PH to IpcPH, 38 from no PH to pre-capillary PH, 38 from no PH to unclassified PH, 4 from pre-capillary PH to unclassified PH, and 50 from IpcPH to CpcPH (CpcPH: +79%). With both definitions, only the CpcPH patients displayed increased mortality (hazard ratios ≈ 4). Among the PH-defining haemodynamic components, PVR was the strongest predictor of death., Conclusion: In severe AS, the application of the 2022 PH definition results in a substantially higher number of patients with any PH as well as CpcPH. With either definition, CpcPH patients have a significantly increased post-AVR mortality., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Progressive pulmonary Fibrosis Abstract: Cough and dyspnea on excertion are common and early symptoms of interstitial lung diseases (ILD). Thoracic imaging (particularly computed tomography) detects such lung structural alterations early in the disease course. Knowledge of these diseases and their management is necessary in the daily business. The term "progressive pulmonary fibrosis" subsumes a heterogene group of interstitial lung diseases with a similar course of progressive fibrosis. The management of these diseases should be discussed interdisciplinary, similar to the management of the Idiopathic pulmonary fibrosis (IPF). Antifibrotic drugs are new therapeutic options., Competing Interests: Die Autoren haben keine Interessenskonflikte im Zusammenhang mit diesem Artikel deklariert., (© 2024 Aerzteverlag medinfo AG.)

Aims: Pulmonary hypertension (PH) is a complex clinical condition, and left heart disease is the leading cause. Little is known about the epidemiology and prognosis of combined post- and pre-capillary PH (CpcPH)., Methods and Results: This retrospective analysis of the Swiss PH Registry included incident patients with CpcPH registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient baseline characteristics [age, sex, mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP), pulmonary vascular resistance (PVR), and risk factors, including World Health Organization (WHO)-functional class (FC), 6 min walk distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), treatment, days of follow-up, and events (death or loss to follow-up) at last visit] were analysed by Kaplan-Meier and Cox regression analyses. Two hundred and thirty-one patients (59.3% women, age 65 ± 12 years, mPAP 48 ± 11 mmHg, PAWP 21 ± 5 mmHg, PVR 7.2 ± 4.8 WU) were included. Survival analyses showed a significantly longer survival for women [hazard ratio (HR) 0.58 (0.38-0.89); P = 0.01] and a higher mortality risk for mPAP > 46 mmHg [HR 1.58 (1.03-2.43); P = 0.04] but no association with age or PVR. Patients stratified to high risk according to four-strata risk assessment had an increased mortality risk compared with patients stratified to low-intermediate risk [HR 2.44 (1.23-4.84); P = 0.01]. A total of 46.8% of CpcPH patients received PH-targeted pharmacotherapy; however, PH-targeted medication was not associated with longer survival., Conclusion: Among patients with CpcPH, women and patients with an mPAP ≤46 mmHg survived longer. Furthermore, risk stratification by using non-invasively assessed risk factors, such as WHO-FC, 6MWD, and NT-proBNP, as proposed for pulmonary arterial hypertension, stratified survival in CpcPH, and might be helpful in the management of these patients., Competing Interests: Conflict of interest: A.M.D. reports personal fees from Astra Zeneca, Gebro Pharma, GSK, and MSD and financial support to attend scientific meetings from Janssen and OrPha Swiss outside the submitted work. S.A.G. reports grants and personal fees from MSD, Gebro, and Orpha outside the submitted work. M.L. reports personal fees from Janssen, personal fees from MSD, and personal fees from OrphaSwiss outside the submitted work. S.U. receives research grants from the Swiss National Science Foundation, Zurich, and Swiss Lung League and EMDO foundation and grants, travel support and consultancy fees from Orpha Swiss, Janssen SA, MSD SA, and Novartis, all unrelated to the present work. All other authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: The rate of relapse in smokers attempting to quit is generally high. In order to maximize the chances of success, it is of interest to better understand the dynamic of lapse and relapse during smoking cessation. We hypothesized that specific behavioral patterns in tobacco consumption could predict the probability of quitting success and could open the possibility for a more targeted approach. The aim of the current study was to characterize clusters of quitting trajectories among participants involved in a smoking cessation program., Methods: In a retrospective real-world cohort study, data from 843 consecutive participants between March 2012 and December 2014 were collected. Data consisted of baseline information on demographics, smoking history and dependence level, as well as longitudinal data about tobacco consumption. The correlations among time series were characterized using principal coordinates analysis. Clusters were identified using k -means clustering and the average profile associated with each cluster was computed. The association between the participant's baseline characteristics and clusters of tobacco consumption was assessed., Results: Four distinct clusters of transition phenotypes were identified based on tobacco consumption during the cessation phase: the long-term quitters (30%), the persistent smokers/reducers (44%), the short-term returners (16%) and the repeated try and failers (10%). Significant between-cluster differences were found in terms of baseline characteristics and smoking behavior during follow-up., Conclusions: Meaningful clusters of quitting trajectories could be identified. Such specific behavioral patterns were useful for the application of personalized assistance needed to achieve successful and long-term cessation., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2022 Paciorkowski M. et al.)

Pulmonary hypertension (PH), especially pulmonary arterial and chronic thromboembolic pulmonary hypertension (PAH/CTEPH), are rare and progressive conditions. Despite recent advances in treatment and prognosis, PH is still associated with impaired quality of life and survival. Long-term PH-registry data provide information on the changing PH-epidemiology and may help to direct resources to patient's needs. This retrospective analysis of the Swiss Pulmonary Hypertension Registry includes patients newly diagnosed with PH (mainly PAH/CTEPH) registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient characteristics (age, body mass index, gender, diagnosis), hemodynamics at baseline, treatment, days of follow-up, and events (death, transplantation, pulmonary endarterectomy, or loss to follow-up) at last visit were analyzed. Patients were stratified into four time periods according to their date of diagnosis. Survival was analyzed overall and separately for PAH/CTEPH and time periods. 1427 PH patients were included (thereof 560 PAH, 383 CTEPH). Over the years, age at baseline (mean ± SD) significantly increased from 59 ± 14 years in 2001-2005 to 66 ± 14 years in 2016-2019 ( p  < 0.001) while the gender distribution tended toward equality. Mean pulmonary artery pressure and pulmonary vascular resistance significantly decreased over time (from 46 ± 15 to 41 ± 11 mmHg, respectively, 9 ± 5 to 7 ± 4 WU, p  < 0.001). Three-year survival substantially increased over consecutive periods from 69% to 91% (for PAH 63%-95%, for CTEPH 86%-93%) and was poorer in PAH than CTEPH independently of time period ( p  < 0.001). Most patients were treated with mono- or combination therapy and an increasing number of CTEPH underwent pulmonary endarterectomy (40% 2016-2019 vs. 15% 2001-2005). This long-term PH registry reveals that over two decades of observation, newly diagnosed patients are older, less predominantly female, have less impaired hemodynamics and a better survival., Competing Interests: Dr. Lichtblau reports personal fees from Boehringer‐Ingelheim, personal fees from MSD, outside the submitted work. Dr. Lador reports personal fees from Actelion, personal fees from MSD, grants and personal fees from Orpha Swiss, outside the submitted work. Prof. Schwerzmann reports personal fees from Orpha Suisse, personal fees from MSD, personal fees from Actelion Janssen, outside the submitted work. Prof. Ulrich reports grants and personal fees from Actelion SA, personal fees from MSD SA, grants and personal fees from Orpha Swiss, personal fees from Novartis SA, grants from Swiss National Science Foundation, grants from Zurich Lung, from null, outside the submitted work. The remaining authors declare that there are no conflict of interests., (© 2021 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4 + T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sehnert, Pohle, Heuberger, Rzepka, Seidl, Nimmerjahn, Chevalier, Titze and Voll.)

Background: The new 2018 pulmonary hypertension (PH) definition includes a lower mean pulmonary artery pressure (mPAP) cut-off (>20 mmHg rather than ≥25 mmHg) and the compulsory requirement of a pulmonary vascular resistance (PVR) ≥3 Wood units (WU) to define precapillary PH. We assessed the clinical impact of the 2018 compared to the 2015 PH definition in aortic stenosis (AS) patients undergoing aortic valve replacement (AVR)., Methods: Severe AS patients (n = 487) undergoing pre-AVR right heart catheterization were classified according to the 2015 and 2018 definitions. Post-AVR mortality (median follow-up 44 months) was assessed., Results: Based on the 2015 definition, 66 (13%) patients exhibited combined pre and postcapillary PH (CpcPH), 116 (24%) isolated post-capillary PH (IpcPH), 28 (6%) precapillary PH, and 277 (57%) no PH at all. Overall, 52 (11%) patients were reclassified: 23 no PH into IpcPH; 8 no PH into precapillary PH; 20 precapillary PH into no PH; 1 CpcPH into IpcPH. By the 2015 definition, only CpcPH patients displayed increased mortality, whereas by the 2018 definition, precapillary PH patients also experienced higher mortality than those without PH. Among the PH definition components, PVR ≥3 WU was the strongest predictor of death (hazard ratio > 4)., Conclusions: In severe AS, a higher number of IpcPH patients are diagnosed by the 2018 definition, even though they have the same prognosis as those without PH. Patients with true precapillary PH are more accurately identified by the 2018 definition that includes a pulmonary vascular disease criterion, that is, PVR ≥3 WU, a strong mortality predictor., (© 2021 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

Chiral amines are valuable building blocks for the pharmaceutical industry. ω-TAms have emerged as an exciting option for their synthesis, offering a potential "green alternative" to overcome the drawbacks associated with conventional chemical methods. In this review, we explore the application of ω-TAms for pharmaceutical production. We discuss the diverse array of reactions available involving ω-TAms and process considerations of their use in both kinetic resolution and asymmetric synthesis. With the aid of specific drug intermediates and APIs, we chart the development of ω-TAms using protein engineering and their contribution to elegant one-pot cascades with other enzymes, including carbonyl reductases (CREDs), hydrolases and monoamine oxidases (MAOs), providing a comprehensive overview of their uses, beginning with initial applications through to the present day.

Sarcoidosis is a multisystem disease with an unpredictable and sometimes fatal course while the underlying pathomechanism is still unclear. Reasons of the increasing hospitalization rate and mortality in the United States remain in dispute but incriminated are a number of distinct comorbidities and risk factors as well as the application of more aggressive therapeutic agents. Studies reflecting the recent development in central Europe are lacking. Our aim was to investigate the recent mortality and hospitalization rates as well as the underlying comorbidities of hospitalized sarcoidosis patients in Switzerland. In this longitudinal, nested case-control study, a nation-wide database provided by the Swiss Federal Office for Statistics enclosing every hospital entry covering the years 2002-2012 (n = 15,627,573) was analyzed. There were 8,385 cases with a diagnosis of sarcoidosis representing 0.054% (8,385 / 15,627,573) of all hospitalizations in Switzerland. These cases were compared with age- and sex-matched controls without the diagnosis of sarcoidosis. Hospitalization and mortality rates in Switzerland remained stable over the observed time period. Comorbidity analysis revealed that sarcoidosis patients had significantly higher medication-related comorbidities compared to matched controls, probably due to systemic corticosteroids and immunosuppressive therapy. Sarcoidosis patients were also more frequently re-hospitalized (median annual hospitalization rate 0.28 [IQR 0.15-0.65] vs. 0.19 [IQR 0.13-0.36] per year; p < 0.001), had a longer hospital stay (6 [IQR 2-13] vs. 4 [IQR 1-8] days; p < 0.001), had more comorbidities (4 [IQR 2-7] vs. 2 [IQR 1-5]; p < 0.001), and had a significantly higher in-hospital mortality (2.6% [95% CI 2.3%-2.9%] vs. 1.8% [95% CI 1.5%-2.1%] (p < 0.001). A worse outcome was observed among sarcoidosis patients having co-occurrence of associated respiratory diseases. Moreover, age was an important risk factor for re-hospitalization.

Introduction: Abdominal wall hernias are increasingly treated by laparoscopic placement of an intraperitoneal onlay mesh (IPOM). We present an alternative technique for women: the laparoscopic-assisted transvaginal IPOM., Methods: Before surgery, all patients underwent a gynecological examination. The patients agreed to IPOM repair via a transvaginal approach, and written informed consent for surgery was obtained. Pneumoperitoneum was established with a Veress needle at the umbilicus. This access was subsequently dilated to 5 mm (VersaStep), and a 5-mm laparoscope was inserted. Under laparoscopic view, the transvaginal trocars (12-mm VersaStep and 5-mm flexible accesses) were safely inserted after lifting the uterus with a uterus manipulator. After preparation of the falciform ligament, the ligamentum teres and the preperitoneal fat, a lightweight composite mesh was introduced through the transvaginal access and fixed with absorbable tacks using the double-crown technique., Results: From September 2011 to December 2012, we performed six laparoscopic-assisted transvaginal IPOM procedures (one epigastric, three umbilical, two combined epigastric and umbilical hernias; all were primary hernias). In the initial phase, only patients with small or medium primary abdominal wall hernia were selected (max. 3 cm diameter). Median hospital stay was 3 days (range 2-6 days). One minor complication occurred perioperatively (second-degree skin burn to the labia majora). At 1-year follow-up, we identified one recurrence in a high-risk patient with a body mass index higher than 35 kg/m(2). No infection and no mortality were observed., Conclusion: Although no final conclusion can be made regarding the presumed non-inferiority of this technique in terms of recurrence and mesh infection compared with traditional laparoscopic IPOM, laparoscopic-assisted transvaginal IPOM is a feasible alternative to treat abdominal wall hernias.

Objective: Colony-stimulating factor 1 receptor (CSF-1R) essentially modulates monocyte proliferation, migration, and activation, which are considered important for the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine CSF-1R expression in human RA as well as the efficacy of a specific anti-CSF-1R monoclonal antibody (AFS98) in 2 different animal models of RA., Methods: CSF-1R expression was examined in blood, synovium, and bone samples from RA patients, osteoarthritis (OA) patients, and healthy subjects. The efficacy of AFS98 was examined by clinical assessment, histology, and bone histomorphometry in collagen-induced arthritis (CIA) and serum-transfer arthritis., Results: CSF-1R expression was increased in the synovium of RA patients compared to OA patients and healthy controls in fibroblast-like synoviocytes, follicular dendritic cells, macrophages, and osteoclasts. Circulating RA monocytes and neutrophils but not lymphocytes were CSF-1R+. In mice, blockade of CSF-1R abrogated cartilage damage, bone erosion, and systemic bone loss, and this was associated with the depletion of osteoclasts in both models. While blockade of CSF-1R did not affect inflammation in passive serum-transfer arthritis, it significantly reduced inflammation in CIA, and this was associated with the absence of synovial macrophages and reduced splenic CD11b+Gr-1- monocytes., Conclusion: CSF-1R was broadly expressed in human RA. Blockade of CSF-1R protected against bone and cartilage destruction in both mouse models and also showed significant antiinflammatory effects in the CIA model. These data provide evidence for CSF-1R as a therapeutic target in RA., (Copyright © 2014 by the American College of Rheumatology.)

Objective: The mechanisms involved in breaking immunologic tolerance against nuclear autoantigens in systemic lupus erythematosus (SLE) are not fully understood. Our recent studies in nonautoimmune mice provided evidence of an important role of Toll-like receptor 2 (TLR-2) in antichromatin autoantibody induction by high mobility group box chromosomal protein 1-nucleosome complexes derived from apoptotic cells. The objective of this study was to investigate whether TLR-2 signaling is required for the induction of autoantibodies and the development of SLE-like disease in murine pristane-induced lupus., Methods: Lupus-like disease in C57BL/6 and TLR-2(-/-) mice was induced by pristane injection. The numbers of immune cells and serum cytokine concentrations were determined by flow cytometry. Renal disease was assessed by quantification of proteinuria, histologic analyses, and enzyme-linked immunospot assay., Results: Pristane-injected TLR-2(-/-) mice generated reduced numbers of splenic CD138+/cytoplasmic κL/λL chain-positive plasma cells and displayed diminished IgG responses against double-stranded DNA, histones, nucleosomes, some extractable nuclear autoantigens, and cardiolipin when compared with wild- type controls. TLR-2 deficiency prevented the pristane-induced systemic release of interleukin-6 (IL-6) and IL-10. The absence of TLR-2 attenuated peritoneal recruitment of CD11c+ cells and formation of lipogranulomas. Importantly, the renal disease that developed in pristane-treated TLR-2(-/-) mice was less severe than that in control mice, as reflected by milder proteinuria, reduced glomerular deposition of IgG and complement, and decreased renal infiltration of autoantibody-secreting cells., Conclusion: TLR-2 is required for the production of prototypical lupus autoantibodies and the development of renal disease in pristane-induced murine lupus. Interference with TLR-2 signaling may be a promising novel strategy for the treatment of SLE., (Copyright © 2013 by the American College of Rheumatology.)

The cyclic depsipeptide skyllamycin A is a potent inhibitor of the platelet-derived growth factor (PDGF) signaling pathway by inhibiting binding of homodimeric PDGF BB to the PDGF β-receptor. Its structure contains a cinnamoyl side chain and shows a high amount of β-hydroxylated amino acids as well as an unusual α-hydroxyglycine moiety as a rare structural modification. The skyllamycin biosynthetic gene cluster was cloned and sequenced from Streptomyces sp. Acta 2897. Its analysis revealed the presence of open reading frames encoding proteins for fatty acid precursor biosynthesis, non-ribosomal peptide synthetases, regulators, and transporters along with other modifying enzymes. Specific in-frame mutagenesis of these tailoring enzymes resulted in the production of novel skyllamycin derivatives revealing that β-hydroxy groups in skyllamycin A are introduced by a promiscuous cytochrome P450 monooxygenase, whereas a two-component flavin-dependent monooxygenase is involved in α-hydroxylation.