Effects of parabolic flight and spaceflight on the endocannabinoid system in humans

The endocannabinoid system (ECS) plays an important role in the regulation of physiological functions, from stress and memory regulation to vegetative control and immunity. The ECS is considered a central and peripheral stress response system to emotional or physical challenges and acts through endocannabinoids (ECs), which bind to their receptors inducing subsequent effecting mechanisms. In our studies, the ECS responses have been assessed through blood concentrations of the ECs anandamide and 2-arachidonoylglycerol. In parallel, saliva cortisol was determined and the degree of perceived stress was quantified by questionnaires. This report summarizes the reactivity of the ECS in humans subjected to brief periods of kinetic stress and weightlessness during parabolic flights and to prolonged stress exposure during life onboard the International Space Station (ISS). Both conditions resulted in a significant increase in circulating ECs. Under the acute stress during parabolic flights, individuals who showed no evidence of motion sickness were in low-stress conditions and had a significant increase of plasma ECs. In contrast, highly stressed individuals with severe motion sickness had an absent EC response and a massive increase in hypothalamic-pituitary-adrenal axis activity. Likewise, chronic but well-tolerated exposure to weightlessness and emotional and environmental stressors on the ISS for 6 months resulted in a sustained increase in EC blood concentrations, which returned to baseline values after the cosmonauts' return. These preliminary results suggest that complex environmental stressors result in an increase of circulating ECs and that enhanced EC signaling is probably required for adaptation and tolerance under stressful conditions

Motion sickness, stress and the endocannabinoid system

A substantial number of individuals are at risk for the development of motion sickness induced nausea and vomiting (N&V) during road, air or sea travel. Motion sickness can be extremely stressful but the neurobiologic mechanisms leading to motion sickness are not clear. The endocannabinoid system (ECS) represents an important neuromodulator of stress and N&V. Inhibitory effects of the ECS on N&V are mediated by endocannabinoid-receptor activation

Triggering and characterisation of realistic internal short circuits in lithium-ion pouch cells: a new approach using precise needle penetration

The internal short circuit (ISC) in lithium-ion batteries is a serious problem because it is probably the most common cause of a thermal runaway (TR) that still presents many open questions although it has been intensively investigated. Therefore this article focuses on the generation and characterisation of the local single-layer ISC, which is particularly relevant in practice application. A new, very promising method of precise needle penetration made it possible to generate the most safety-critical short-circuit type, the contact between the Al-Collector and the graphite active material of the anode reliable, demonstrated on a 10 Ah Graphite/NMC pouch cell. The special efforts in achieving high reproducibility as well as the detailed analysis of the initiated internal short-circuit conditions led to more reliable and meaningful results. A comprehensive approach to characterisation has been made by detailed measurement of the dynamic short-circuit evolution and a subsequent post-characterisation, which included the application of different electrochemical measurement techniques as well as a post-abuse analysis. It was shown that the cells demonstrated a very individual and difficult-to-predict behaviour, which is a major challenge for early failure detection and risk assessment of cells with an existing or former ISC. On the one hand, it is found that despite high local temperatures of over 1260 ◦C and significant damage to the cell-internal structure, the cell did not develop a TR even with further cycling. On the other hand, it was observed that the TR occurs spontaneously without any previous abnormalities. Based on the overall test results, it was shown that at the high state of charge (SOC = 100 %) even small, dynamically developing voltage drops must be classified as safety-critical for the cell. For reliable and early failure detection, the first voltage drops of the ISC must already be detected

Systematic approach for the test data generation and validation of ISC/ ESC detection methods

Various methods published in recent years for reliable detection of battery faults (mainly internal short circuit (ISC)) raise the question of comparability and cross-method evaluation, which cannot yet be answered due to significant differences in training data and boundary conditions. This paper provides a Monte Carlo-like simulation approach to generate a reproducible, comprehensible and large dataset based on an extensive literature background on common assumptions and simulation parameters. In some cases, these assumptions are quite different from field data, as shown by comparison with experimentally determined values. Two relatively simple ISC detection methods are tested on the generated dataset and their performance is evaluated to illustrate the proposed approach. The evaluation of the detection performance by quantitative measures such as the Youden-index shows a high divergence with respect to internal and external parameters such as threshold level and cell-to-cell variations (CtCV), respectively. These results underline the importance of quantitative evaluations based on identical test data. The proposed approach is able to support this task by providing cost-effective test data generation with incorporation of known factors affecting detection quality

Systematic approach for the test data generation and validation of ISC/ESC detection methods

Various methods published in recent years for reliable detection of battery faults (mainly internal short circuit (ISC)) raise the question of comparability and cross-method evaluation, which cannot yet be answered due to significant differences in training data and boundary conditions. This paper provides a Monte Carlo-like simulation approach to generate a reproducible, comprehensible and large dataset based on an extensive literature search on common assumptions and simulation parameters. In some cases, these assumptions are quite different from field data, as shown by comparison with experimentally determined values. Two relatively simple ISC detection methods are tested on the generated dataset and their performance is evaluated to illustrate the proposed approach. The evaluation of the detection performance by quantitative measures such as the Youden-index shows a high divergence with respect to internal and external parameters such as threshold level and cell-to-cell variations (CtCV), respectively. These results underline the importance of quantitative evaluations based on identical test data. The proposed approach is able to support this task by providing cost-effective test data generation with incorporation of known factors affecting detection quality

Abschlussbericht zum Verbundprojekt InKola: Infrastrukturkopplung - Platzierung und Betrieb von Ladestationen aus Verkehrs- und Energienetzsicht

Im Mittelpunkt des Vorhabens InKola „Infrastrukturkopplung – Platzierung und Betrieb von Ladestationen aus Verkehrs- und Energienetzsicht“ steht die infrastrukturübergreifende Planung und der Betrieb für Verkehr- und Energiesysteme. Das Ziel ist es, zusammen der Stadt Burg ein anwendungsorientiertes Konzept zur optimalen Platzierung, Versorgung und Betrieb von Ladeinfrastruktur aus Netz- und Verkehrssicht unter Einbindung erneuerbarer Erzeugung zu entwickeln, und an ausgewählten Standorten in der Stadt Burg Ladeinfrastruktur zu installieren

Progranulin signaling in sepsis, community-acquired bacterial pneumonia and COVID-19: a comparative, observational study

BACKGROUND Progranulin is a widely expressed pleiotropic growth factor with a central regulatory effect during the early immune response in sepsis. Progranulin signaling has not been systematically studied and compared between sepsis, community-acquired pneumonia (CAP), COVID-19 pneumonia and a sterile systemic inflammatory response (SIRS). We delineated molecular networks of progranulin signaling by next-generation sequencing (NGS), determined progranulin plasma concentrations and quantified the diagnostic performance of progranulin to differentiate between the above-mentioned disorders using the established biomarkers procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) for comparison. METHODS The diagnostic performance of progranulin was operationalized by calculating AUC and ROC statistics for progranulin and established biomarkers in 241 patients with sepsis, 182 patients with SIRS, 53 patients with CAP, 22 patients with COVID-19 pneumonia and 53 healthy volunteers. miRNAs and mRNAs in blood cells from sepsis patients (n = 7) were characterized by NGS and validated by RT-qPCR in an independent cohort (n = 39) to identify canonical gene networks associated with upregulated progranulin at sepsis onset. RESULTS Plasma concentrations of progranulin (ELISA) in patients with sepsis were 57.5 (42.8-84.9, Q25-Q75) ng/ml and significantly higher than in CAP (38.0, 33.5-41.0~ng/ml, p < 0.001), SIRS (29.0, 25.0-35.0~ng/ml, p < 0.001) and the healthy state (28.7, 25.5-31.7~ng/ml, p < 0.001). Patients with COVID-19 had significantly higher progranulin concentrations than patients with CAP (67.6, 56.6-96.0 vs. 38.0, 33.5-41.0~ng/ml, p < 0.001). The diagnostic performance of progranulin for the differentiation between sepsis vs. SIRS (n = 423) was comparable to that of procalcitonin. AUC was 0.90 (95% CI = 0.87-0.93) for progranulin and 0.92 (CI = 0.88-0.96, p = 0.323) for procalcitonin. Progranulin showed high discriminative power to differentiate bacterial CAP from COVID-19 (sensitivity 0.91, specificity 0.94, AUC 0.91 (CI = 0.8-1.0) and performed significantly better than PCT, IL-6 and CRP. NGS and partial RT-qPCR confirmation revealed a transcriptomic network of immune cells with upregulated progranulin and sortilin transcripts as well as toll-like-receptor 4 and tumor-protein 53, regulated by miR-16 and others. CONCLUSIONS Progranulin signaling is elevated during the early antimicrobial response in sepsis and differs significantly between sepsis, CAP, COVID-19 and SIRS. This suggests that progranulin may serve as a novel indicator for the differentiation between these disorders. TRIAL REGISTRATION Clinicaltrials.gov registration number NCT03280576 Registered November 19, 2015

A Preoperative Clinical Risk Score Including C-Reactive Protein Predicts Histological Tumor Characteristics and Patient Survival after Surgery for Sporadic Non-Functional Pancreatic Neuroendocrine Neoplasms:An International Multicenter Cohort Study

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients >60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off >= 0.2 mg/dL; hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size >= 3.0 cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p <0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival

Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1.Preclinical characterization and good manufacturing practice (GMP) production of mutant Cyp (mCyp) c 1.Escherichia coli-produced mCyp c 1 was purified using standard chromatographic techniques. Physicochemical properties were investigated by gel electrophoresis, size exclusion chromatography, circular dichroism spectroscopy, reverse-phase high-performance liquid chromatography and mass spectrometry. Allergenicity was assessed by ImmunoCAP inhibition and basophil histamine release assay, immunogenicity by immunization of laboratory animals and stimulation of patients' peripheral blood mononuclear cells (PBMCs). Reference molecules were purified wild-type Cyp c 1 (natural and/or recombinant). GMP-compliant alum-adsorbed mCyp c 1 was tested for acute toxicity in mice and rabbits and for repeated-dose toxicity in mice. Accelerated and real-time protocols were used to evaluate stability of mCyp c 1 as drug substance and drug product.Purified mCyp c 1 behaves as a folded and stable molecule. Using sera of 26 double-blind placebo-controlled food-challenge-proven fish-allergic patients, reduction in allergenic activity ranged from 10- to 5,000-fold (1,000-fold on average), but with retained immunogenicity (immunization in mice/rabbits) and potency to stimulate human PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability.The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine.info:eu-repo/grantAgreement/EC/FP7/20187

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children