Investigation of the role of neutrophils in the production of autoantigens in patients with rheumatoid arthritis

In most patients with rheumatoid arthritis (RA), citrullinated autoantigens are targeted by autoantibodies (ACPA). However, the process leading to protein citrullination by peptidylarginine deiminases (PADs) in the joint remains unclear. In this thesis, I tested the hypothesis that generation of neutrophil extracellular traps (NETosis), can contribute to release of enzymatically active PADs and citrullinated autoantigens in inflamed joints. I have shown that in vitro induced NETosis leads to release of citrullinated proteins and enzymatically active PADs both attached to NETs and free in the supernatant. In the SF from RA patients DNA levels correlated with neutrophil concentrations, and DNA levels and PAD activity were found to be increased compared with OA patients. Finally, I demonstrated the antigenicity of in vitro generated NETs and identified citrullinated histone H3 as a NET-component recognised by ACPA and RA sera. Based on the findings in this thesis release of active PADs into SF by neutrophil cell death is a plausible explanation for the generation of citrullinated extracellular autoantigens. In ACPA positive RA patients the continuous production of these autoantigens combined with pre-existing ACPA may result in the formation of immune complexes and perpetuation of the inflammatory response

WRaINfo: An Open Source Library for Weather Radar INformation for FURUNO Weather Radars Based on Wradlib

WRaINfo is a software for real-time weather radar data processing developed by the Helmholtz Innovation Lab FERN.Lab, a technology and innovation platform of the German Research Centre for Geosciences Potsdam (GFZ). WRaINfo is specifically designed for processing X-band weather radar data of FURUNO devices. The modules of the package allow to read and process raw data of the WR2120 and WR2100. For this purpose, many functions of the library wradlib are used and adapted. The processing is controlled by a configuration file, main functionalities include formatting, attenuation correction, clutter detection, georeferencing and gridding of the data. This allows the construction of reproducible, automatic data processing chains. The package is written in the Python programming language. The source code is publicly available on GitLab. Compiled versions are also available on PyPi. The package is distributed under the Apache 2.0 license

Changes of hemodynamic and cerebral oxygenation after exercise in normobaric and hypobaric hypoxia: associations with acute mountain sickness

Objective: Normobaric (NH) and hypobaric hypoxia (HH) are associated with acute mountain sickness (AMS) and cognitive dysfunction. Only few variables, like heart-rate-variability, are correlated with AMS. However, prediction of AMS remains difficult. We therefore designed an expedition-study with healthy volunteers in NH/HH to investigate additional non-invasive hemodynamic variables associated with AMS.Methods: Eleven healthy subjects were examined in NH (FiO(2) 13.1%;equivalent of 3.883m a.s.l;duration 4h) and HH (3.883ma.s.l.;duration 24h) before and after an exercise of 120min. Changes in parameters of electrical cardiometry (cardiac index (CI), left-ventricular ejection time (LVET), stroke volume (SV), index of contractility (ICON)), near-infrared spectroscopy (cerebral oxygenation, rScO(2)), Lake-Louise-Score (LLS) and cognitive function tests were assessed. One-Way-ANOVA, Wilcoxon matched-pairs test, Spearman's-correlation-analysis and Student's t-test were performed.Results: HH increased heart rate (HR), mean arterial pressure (MAP) and CI and decreased LVET, SV and ICON, whereas NH increased HR and decreased LVET. In both NH and HH cerebral oxygenation decreased and LLS increased significantly. After 24h in HH, 6 of 11 subjects (54.6%) developed AMS. LLS remained increased until 24h in HH, whereas cognitive function remained unaltered. In HH, HR and LLS were inversely correlated (r=-0.692;p<0.05). More importantly, the rScO2-decrease after exercise in NH significantly correlated with LLS after 24h in HH (r=-0.971;p<0.01) and rScO2 correlated significantly with HR (r=0.802;p<0.01), CI (r=0.682;p<0.05) and SV (r=0.709;p<0.05) after exercise in HH.Conclusion: sBoth acute NH and HH altered hemodynamic and cerebral oxygenation and induced AMS. Subjects, who adapted their CI had higher rScO2 and lower LLS. Furthermore, rScO2 after exercise under normobaric conditions was associated with AMS at high altitudes

DKK1 expression by synovial fibroblasts in very early rheumatoid arthritis associates with lymphocyte adhesion in an in vitro flow co-culture system

BACKGROUND: Synovial fibroblasts play a key role in joint destruction and regulation of the inflammatory infiltrate in established rheumatoid arthritis (RA). The mechanisms by which this occurs in the earliest stages of RA are largely unknown. We investigated the role of Dickkopf-related protein 1 (DKK1) produced by synovial fibroblasts of patients with very early rheumatoid arthritis (VeRA). METHODS: Fibroblasts were isolated from the disease-modifying anti-rheumatic drug–naive Birmingham early arthritis cohort of patients with new onset of clinically apparent arthritis and inflammatory symptoms of ≤12 weeks’ duration, who at follow-up had either resolving arthritis or RA. Endothelial fibroblast co-cultures were formed using porous filters, and lymphocyte adhesion to co-cultures was assessed using phase-contrast microscopy. DKK1 gene expression and secretion were quantified by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Synovial fibroblasts from patients with VeRA expressed significantly higher levels of DKK1 messenger RNA than those from patients with resolving arthritis. A similar trend was observed for DKK1 protein secretion. In co-culture constructs, more DKK1 tended to be secreted in co-cultures incorporating fibroblasts from VeRA than in co-cultures from non-inflamed joints and resolving arthritis. DKK1 secretion during co-culture positively correlated with lymphocyte adhesion. CONCLUSIONS: Alterations in DKK1 could be involved in the pathogenesis and perpetuation of the inflammatory response in the earliest clinically apparent stages of RA

Early Pastoral Economies and Herding Transitions in Eastern Eurasia

While classic models for the emergence of pastoral groups in Inner Asia describe mounted, horse-borne herders sweeping across the Eurasian Steppes during the Early or Middle Bronze Age (ca. 3000–1500 BCE), the actual economic basis of many early pastoral societies in the region is poorly characterized. In this paper, we use collagen mass fingerprinting and ancient DNA analysis of some of the first stratified and directly dated archaeofaunal assemblages from Mongolia’s early pastoral cultures to undertake species identifications of this rare and highly fragmented material. Our results provide evidence for livestock-based, herding subsistence in Mongolia during the late 3rd and early 2nd millennia BCE. We observe no evidence for dietary exploitation of horses prior to the late Bronze Age, ca. 1200 BCE – at which point horses come to dominate ritual assemblages, play a key role in pastoral diets, and greatly influence pastoral mobility. In combination with the broader archaeofaunal record of Inner Asia, our analysis supports models for widespread changes in herding ecology linked to the innovation of horseback riding in Central Asia in the final 2nd millennium BCE. Such a framework can explain key broad-scale patterns in the movement of people, ideas, and material culture in Eurasian prehistory

Author Correction: Early Pastoral Economies and Herding Transitions in Eastern Eurasia (Scientific Reports, (2020), 10, 1, (1001), 10.1038/s41598-020-57735-y)

This Article contains a typographical error in the Introduction section under subheading ‘Understanding Early Horse Domestication and Transport’ where, “Historical records refer to horse-mounted warriors in western Asia by the 8th century BCE, while archaeological finds from localities like Arzhan 2 in southern Tuva show specialized horse equipment (bronze snaffle bits) and equine vertebral pathologies linked with mounted riding in Central Asia by the late 9th century BCE31.” should read: “Historical records refer to horse-mounted warriors in western Asia by the 8th century BCE, while archaeological finds from localities like Arzhan in southern Tuva show specialized horse equipment (bronze snaffle bits) and equine vertebral pathologies linked with mounted riding in Central Asia by the late 9th century BCE31.”

Early Pastoral Economies and Herding Transitions in Eastern Eurasia

While classic models for the emergence of pastoral groups in Inner Asia describe mounted, horse-borne herders sweeping across the Eurasian Steppes during the Early or Middle Bronze Age (ca. 3000-1500 BCE), the actual economic basis of many early pastoral societies in the region is poorly characterized. In this paper, we use collagen mass fingerprinting and ancient DNA analysis of some of the first stratified and directly dated archaeofaunal assemblages from Mongolia's early pastoral cultures to undertake species identifications of this rare and highly fragmented material. Our results provide evidence for livestock-based, herding subsistence in Mongolia during the late 3rd and early 2nd millennia BCE. We observe no evidence for dietary exploitation of horses prior to the late Bronze Age, ca. 1200 BCE - at which point horses come to dominate ritual assemblages, play a key role in pastoral diets, and greatly influence pastoral mobility. In combination with the broader archaeofaunal record of Inner Asia, our analysis supports models for widespread changes in herding ecology linked to the innovation of horseback riding in Central Asia in the final 2nd millennium BCE. Such a framework can explain key broad-scale patterns in the movement of people, ideas, and material culture in Eurasian prehistory

Successful direct acting antiviral (DAA) treatment of HCV/HIV-coinfected patients before and after liver transplantation

Objectives The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. Methods When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1);MELD range 7-21;HCC (n = 2);HCV genotype la (n = 8), 1 b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). Results Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy;subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in followup. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation;in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. Conclusion DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted