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  • 1
    Online Resource
    Online Resource
    The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 5 ( 2021-03-04), p. 2578-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 5 ( 2021-03-04), p. 2578-
    Abstract: Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22052578
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
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    Online Resource
    The Origins and Future of Sentinel: An Early-Warning System for Pandemic Preemption and Response
    MDPI AG ; 2021
    In:  Viruses Vol. 13, No. 8 ( 2021-08-13), p. 1605-
    Details
    In: Viruses, MDPI AG, Vol. 13, No. 8 ( 2021-08-13), p. 1605-
    Abstract: While investigating a signal of adaptive evolution in humans at the gene LARGE, we encountered an intriguing finding by Dr. Stefan Kunz that the gene plays a critical role in Lassa virus binding and entry. This led us to pursue field work to test our hypothesis that natural selection acting on LARGE—detected in the Yoruba population of Nigeria—conferred resistance to Lassa Fever in some West African populations. As we delved further, we conjectured that the “emerging” nature of recently discovered diseases like Lassa fever is related to a newfound capacity for detection, rather than a novel viral presence, and that humans have in fact been exposed to the viruses that cause such diseases for much longer than previously suspected. Dr. Stefan Kunz’s critical efforts not only laid the groundwork for this discovery, but also inspired and catalyzed a series of events that birthed Sentinel, an ambitious and large-scale pandemic prevention effort in West Africa. Sentinel aims to detect and characterize deadly pathogens before they spread across the globe, through implementation of its three fundamental pillars: Detect, Connect, and Empower. More specifically, Sentinel is designed to detect known and novel infections rapidly, connect and share information in real time to identify emerging threats, and empower the public health community to improve pandemic preparedness and response anywhere in the world. We are proud to dedicate this work to Stefan Kunz, and eagerly invite new collaborators, experts, and others to join us in our efforts.
    Type of Medium: Online Resource
    ISSN: 1999-4915
    URL: Article
    DOI: 10.3390/v13081605
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2516098-9
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  • 3
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    Online Resource
    Biomarkers of Cholestasis and Liver Injury in the Early Phase of Acute Respiratory Distress Syndrome and Their Pathophysiological Value
    MDPI AG ; 2021
    In:  Diagnostics Vol. 11, No. 12 ( 2021-12-14), p. 2356-
    Details
    In: Diagnostics, MDPI AG, Vol. 11, No. 12 ( 2021-12-14), p. 2356-
    Abstract: Background: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). Methods: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. Results: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p 〈 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p 〈 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO2. Conclusions: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO2, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels.
    Type of Medium: Online Resource
    ISSN: 2075-4418
    URL: Article
    DOI: 10.3390/diagnostics11122356
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2662336-5
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  • 4
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    Online Resource
    Two Decades of Brain Tumour Imaging with O-(2-[18F]fluoroethyl)-L-tyrosine PET: The Forschungszentrum Jülich Experience
    MDPI AG ; 2022
    In:  Cancers Vol. 14, No. 14 ( 2022-07-08), p. 3336-
    Details
    In: Cancers, MDPI AG, Vol. 14, No. 14 ( 2022-07-08), p. 3336-
    Abstract: O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians’ rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.
    Type of Medium: Online Resource
    ISSN: 2072-6694
    URL: Article
    DOI: 10.3390/cancers14143336
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527080-1
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  • 5
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    Online Resource
    Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah−/−) Model
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 18 ( 2022-09-16), p. 10841-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 18 ( 2022-09-16), p. 10841-
    Abstract: Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the mdx mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the Cmah gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of ‘structural weakness’, intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from extensor digitorum longus (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in mdx Cmah−/− diaphragm was similar to wt mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in mdx Cmah−/− diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in mdx Cmah−/− single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the mdx Cmah−/− genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms231810841
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 6
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    Online Resource
    Machine Learning Prediction of Estimated Risk for Bipolar Disorders Using Hippocampal Subfield and Amygdala Nuclei Volumes
    MDPI AG ; 2023
    In:  Brain Sciences Vol. 13, No. 6 ( 2023-05-27), p. 870-
    Details
    In: Brain Sciences, MDPI AG, Vol. 13, No. 6 ( 2023-05-27), p. 870-
    Abstract: The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI (n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPIbipolar. We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2–74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0–71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.
    Type of Medium: Online Resource
    ISSN: 2076-3425
    URL: Article
    DOI: 10.3390/brainsci13060870
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2651993-8
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  • 7
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    Online Resource
    The Status of Earth Observation Techniques in Monitoring High Mountain Environments at the Example of Pasterze Glacier, Austria: Data, Methods, Accuracies, Processes, and Scales
    MDPI AG ; 2020
    In:  Remote Sensing Vol. 12, No. 8 ( 2020-04-15), p. 1251-
    Details
    In: Remote Sensing, MDPI AG, Vol. 12, No. 8 ( 2020-04-15), p. 1251-
    Abstract: Earth observation offers a variety of techniques for monitoring and characterizing geomorphic processes in high mountain environments. Terrestrial laserscanning and unmanned aerial vehicles provide very high resolution data with high accuracy. Automatic cameras have become a valuable source of information—mostly in a qualitative manner—in recent years. The availability of satellite data with very high revisiting time has gained momentum through the European Space Agency’s Sentinel missions, offering new application potential for Earth observation. This paper reviews the status of recent techniques such as terrestrial laserscanning, remote sensed imagery, and synthetic aperture radar in monitoring high mountain environments with a particular focus on the impact of new platforms such as Sentinel-1 and -2 as well as unmanned aerial vehicles. The study area comprises the high mountain glacial environment at the Pasterze Glacier, Austria. The area is characterized by a highly dynamic geomorphological evolution and by being subject to intensive scientific research as well as long-term monitoring. We primarily evaluate landform classification and process characterization for: (i) the proglacial lake; (ii) icebergs; (iii) the glacier river; (iv) valley-bottom processes; (v) slope processes; and (vi) rock wall processes. We focus on assessing the potential of every single method both in spatial and temporal resolution in characterizing different geomorphic processes. Examples of the individual techniques are evaluated qualitatively and quantitatively in the context of: (i) morphometric analysis; (ii) applicability in high alpine regions; and (iii) comparability of the methods among themselves. The final frame of this article includes considerations on scale dependent process detectability and characterization potentials of these Earth observation methods, along with strengths and limitations in applying these methods in high alpine regions.
    Type of Medium: Online Resource
    ISSN: 2072-4292
    URL: Article
    DOI: 10.3390/rs12081251
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2513863-7
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  • 8
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    Online Resource
    Phase Angle Is a Stronger Predictor of Hospital Outcome than Subjective Global Assessment—Results from the Prospective Dessau Hospital Malnutrition Study
    MDPI AG ; 2022
    In:  Nutrients Vol. 14, No. 9 ( 2022-04-24), p. 1780-
    Details
    In: Nutrients, MDPI AG, Vol. 14, No. 9 ( 2022-04-24), p. 1780-
    Abstract: This prospective cohort study of 16,943 consecutive patients compared phase angle (PhA, foot-to-hand at 50 kHz) and subjective global assessment (SGA) to predict outcomes length of hospital stay (LOS) and in-hospital mortality in patients at risk of malnutrition (NRS-2002 ≥ 3). In 1505 patients, the independent effects on LOS were determined by competing risk analysis and on mortality by logistic regression. In model I, including influence factors age, sex, BMI, and diagnoses, malnourished (SGA B and C) patients had a lower chance for a regular discharge (HR 0.74; 95%CI 0.69–0.79) and an increased risk of mortality (OR 2.87; 95%CI 1.38–5.94). The association of SGA and outcomes regular discharge and mortality was completely abrogated when PhA was added (model II). Low PhA reduced the chance of a regular discharge by 53% in patients with a PhA ≤ 3° (HR 0.47; 95%CI 0.39–0.56) as compared to PhA 〉 5°. Mortality was reduced by 56% for each 1° of PhA (OR 0.44; 95%CI 0.32–0.61). Even when CRP was added in model III, PhA ≤ 3° was associated with a 41% lower chance for a regular discharge (HR 0.59; 95%CI 0.48–0.72). In patients at risk of malnutrition, the objective measure PhA was a stronger predictor of LOS and mortality than SGA.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu14091780
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2518386-2
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  • 9
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    Online Resource
    Individualisation of Inflight Catering Meals—An Automation Concept for Integrating Pre-Ordered Meals during the Flight for All Passengers
    MDPI AG ; 2022
    In:  Aerospace Vol. 9, No. 11 ( 2022-11-21), p. 736-
    Details
    In: Aerospace, MDPI AG, Vol. 9, No. 11 ( 2022-11-21), p. 736-
    Abstract: Inflight catering services are crucial for air travel. Airlines provide food and beverages to the passengers during the flight with different options depending on, e.g., the flying class, distance, and type of service. Our contribution outlines previous efforts to optimise the inflight catering processes and highlights the possibilities to individualise the current services. Individualisation is a growing trend and may challenge the processes that are possibly not wholly prepared to deliver a customised meal for each passenger onboard the aircraft. We present our passenger survey which confirms the demand for the individualisation of inflight meals; we explored which dimensions can be supported by incorporating automation. We performed an analysis of the current inflight catering process for developing automation concepts. Subsequently, an automation concept for the individualisation of inflight meals through pre-ordering is introduced, followed by an evaluation scenario. Within the evaluation, it was possible to consider the feasibility of the individualisation of inflight catering meals and to deliver requirements for the further development of automated services.
    Type of Medium: Online Resource
    ISSN: 2226-4310
    URL: Article
    DOI: 10.3390/aerospace9110736
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2756091-0
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  • 10
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    Online Resource
    Ferrocenophanium Stability and Catalysis
    MDPI AG ; 2023
    In:  Molecules Vol. 28, No. 6 ( 2023-03-17), p. 2729-
    Details
    In: Molecules, MDPI AG, Vol. 28, No. 6 ( 2023-03-17), p. 2729-
    Abstract: Ferrocenium catalysis is a vibrant research area, and an increasing number of ferrocenium-catalyzed processes have been reported in the recent years. However, the ferrocenium cation is not very stable in solution, which may potentially hamper catalytic applications. In an effort to stabilize ferrocenium-type architectures by inserting a bridge between the cyclopentadienyl rings, we investigated two ferrocenophanium (or ansa-ferrocenium) cations with respect to their stability and catalytic activity in propargylic substitution reactions. One of the ferrocenophanium complexes was characterized by single crystal X-ray diffraction. Cyclic voltammetry experiments of the ferrocenophane parent compounds were performed in the absence and presence of alcohol nucleophiles, and the stability of the cations in solution was judged based on the reversibility of the electron transfer. The experiments revealed a moderate stabilizing effect of the bridge, albeit the effect is not very pronounced or straightforward. Catalytic propargylic substitution test reactions revealed decreased activity of the ferrocenophanium cations compared to the ferrocenium cation. It appears that the somewhat stabilized ferrocenophanium cations show decreased catalytic activity.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules28062729
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2008644-1
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