Protein associated with SMAD1 (PAWS1/FAM83G) is a substrate for type I bone morphogenetic protein receptors and modulates bone morphogenetic protein signalling

Bone morphogenetic proteins (BMPs) control multiple cellular processes in embryos and adult tissues. BMPs signal through the activation of type I BMP receptor kinases, which then phosphorylate SMADs 1/5/8. In the canonical pathway, this triggers the association of these SMADs with SMAD4 and their translocation to the nucleus, where they regulate gene expression. BMPs can also signal independently of SMAD4, but this pathway is poorly understood. Here, we report the discovery and characterization of PAWS1/FAM83G as a novel SMAD1 interactor. PAWS1 forms a complex with SMAD1 in a SMAD4-independent manner, and BMP signalling induces the phosphorylation of PAWS1 through BMPR1A. The phosphorylation of PAWS1 in response to BMP is essential for activation of the SMAD4-independent BMP target genes NEDD9 and ASNS. Our findings identify PAWS1 as the first non-SMAD substrate for type I BMP receptor kinases and as a novel player in the BMP pathway. We also demonstrate that PAWS1 regulates the expression of several non-BMP target genes, suggesting roles for PAWS1 beyond the BMP pathway

USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling

Protein kinase ALK3/BMPR1A mediates bone morphogenetic protein (BMP) signalling through phosphorylation and activation of SMADs 1/5/8. SMAD6, a transcriptional target of BMP, negatively regulates the BMP pathway by recruiting E3 ubiquitin ligases and targeting ALK3 for ubiquitin-mediated degradation. Here, we identify a deubiquitylating enzyme USP15 as an interactor of SMAD6 and ALK3. We show that USP15 enhances BMP-induced phosphorylation of SMAD1 by interacting with and deubiquitylating ALK3. RNAi-mediated depletion of USP15 increases ALK3 K48-linked polyubiquitylation, and reduces both BMP-induced SMAD1 phosphorylation and transcription of BMP target genes. We also show that loss of USP15 expression from mouse myoblast cells inhibits BMP-induced osteoblast differentiation. Furthermore, USP15 modulates BMP-induced phosphorylation of SMAD1 and transcription during Xenopus embryogenesis

Physiological and Molecular Effects of in vivo and ex vivo Mild Skin Barrier Disruption

The success of topically applied treatments on skin relies on the efficacy of skin penetration. In order to increase particle or product penetration, mild skin barrier disruption methods can be used. We previously described cyanoacrylate skin surface stripping as an efficient method to open hair follicles, enhance particle penetration, and activate Langerhans cells. We conducted ex vivo and in vivo measurements on human skin to characterize the biological effect and quantify barrier disruption-related inflammation on a molecular level. Despite the known immunostimulatory effects, this barrier disruption and hair follicle opening method was well accepted and did not result in lasting changes of skin physiological parameters, cytokine production, or clinical side effects. Only in ex vivo human skin did we find a discrete increase in IP-10, TGF-β, IL-8, and GM-CSF mRNA. The data underline the safety profile of this method and demonstrate that the procedure per se does not cause substantial inflammation or skin damage, which is also of interest when applied to non-invasive sampling of biomarkers in clinical trials

Bamberg in the Early Modern Period. New Essays on the History of Town and Bishopric

Die Beiträge dieses Bandes behandeln Aspekte der Verwaltungs-, Herrschafts-, Wirtschafts-, Sozial- und Kulturgeschichte Bambergs zwischen 1500 und 1800 und schließen damit einige der weißen Flecken auf der Landkarte der frühneuzeitlichen Stadt- und Regionalforschung. Zugleich werden aktuelle geschichtswissenschaftliche Fragestellungen und Konzepte empirisch erprobt. Damit sollen die Möglichkeiten, die Bamberg als Forschungsfeld bietet, und das Potential, das sich mit der Anwendung von Konzepten und Methoden der modernen Geschichtswissenschaft auf das reichhaltige Bamberger Material verbindet, aufgezeigt und Anregungen für künftige Forschungen gegeben werden.The essays in this volume cover aspects of Bamberg’s political, administrative, economic, social and cultural history from 1500 to 1800 and thus close some of the gaps in the city’s and region’s historiography. At the same time the essays provide empirical explorations of current scholarly concepts and approaches. They intend to point out the possibilities which Bamberg offers as a field of research and the potentials inherent in the application of modern historical concepts and methods on the rich source materials available for Bamberg

A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and longterm community efforts required to overcome them, both within and beyond the IPASC group

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Chronic fatigue syndromes: real illnesses that people can recover from

The ‘Oslo Chronic Fatigue Consortium’ consists of researchers and clinicians who question the current narrative that chronic fatigue syndromes, including post-covid conditions, are incurable diseases. Instead, we propose an alternative view, based on research, which offers more hope to patients. Whilst we regard the symptoms of these conditions as real, we propose that they are more likely to reflect the brain's response to a range of biological, psychological, and social factors, rather than a specific disease process. Possible causes include persistent activation of the neurobiological stress response, accompanied by associated changes in immunological, hormonal, cognitive and behavioural domains. We further propose that the symptoms are more likely to persist if they are perceived as threatening, and all activities that are perceived to worsen them are avoided. We also question the idea that the best way to cope with the illness is by prolonged rest, social isolation, and sensory deprivation. Instead, we propose that recovery is often possible if patients are helped to adopt a less threatening understanding of their symptoms and are supported in a gradual return to normal activities. Finally, we call for a much more open and constructive dialogue about these conditions. This dialogue should include a wider range of views, including those of patients who have recovered from them

Complex facial reconstruction with invasive and non-invasive conventional interventions

Summary: Background: Despite the obvious advantages, face transplantation requires strict patient selection to guarantee optimal outcomes. Therefore, it is not suitable for all patients with severe facial disfigurements. Simultaneously, conventional plastic and reconstructive surgery techniques, as well as medical spa techniques, have evolved, offering minimally invasive treatment of complex deformities. Methods: The entire face of a young woman was severely disfigured because of a mistreated juvenile acne, with severe ectropions, oral incompetence and substantial midfacial tissue defect. We are describing the reconstruction with a combination of conventional reconstructive methods, such as scar release, skin transplantation, local flaps, medical needling and lipofilling. Results: Oral competence, unhindered breathing and adequate lid closure was achieved. Previously unable to participate in social life in any meaningful way, our patient was able to reintegrate fully and take a job. Conclusion: For selected patients, combined, invasive and non-invasive conventional techniques can provide satisfying outcomes in complex facial reconstruction. Modern regenerative approaches such as lipofilling and medical needling should be considered as integral parts of treatment strategies. Keywords: Face transplantation, Facial disfigurement, Vascularized composite allotransplantatio

The role of a checklist for assessing the quality of basic life support performance: an observational cohort study

Abstract Background Training lay rescuers in Basic Life Support (BLS) is essential to improve bystander cardiopulmonary resuscitation (CPR) rates; in addition, simple methods are needed to provide feedback on CPR performance. This study evaluated whether a simple observational checklist can be used by BLS instructors to adequately measure the quality of BLS performance as an alternative to other feedback devices. Methods The BLS performances of 152 first-year medical students (aged 21.4 ± 3.9 years) were recorded on video, and objective data regarding the quality of the BLS were documented using Laerdal PC SkillReporting software. The performances were categorized according to quality. Ten BLS instructors observed the videos and completed a ten-point checklist based on the Cardiff Test of BLS (version 3.1) to assess the performances. The validity of the checklist was reviewed using interrater reliability as well as by comparing the checklist-based results with objective performance data. Results Matching the checklist-based evaluation with the objective performance data revealed high levels of agreement for very good (82%) and overall insufficient (75%) performances. Regarding the checklist-based evaluation, interrater reliability depended on the checklist item; thus, some items were more easily identified correctly than others. The highest and lowest levels of agreement were observed for the items “undressed torso” and “complete release between compressions” (mean joint-probability 95 and 67%, respectively). Conclusions The observational checklist adequately distinguished sufficient from insufficient BLS performances and offered an assessment of items not incorporated by SkillReporting software such as the initial assessment or undressing the chest. Although its usefulness was reduced for scaling intermediate performance groups, the checklist may be overall a useful rating tool in BLS-training if objective feedback devices are not available, for example, due to large groups of participants or limited training time